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By M.D., PhD, Associate Professor, Marta R. Gerasymchuk
Department of Pathophysiology
Ivano-Frankivsk National
Medical University

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  • Cancer develops when cells in a part of the body begin to grow out of control. Although there are many kinds of cancer, they all start because of out-of-control growth of abnormal cells.
    Normal body cells grow, divide, and die in an orderly fashion. During the early years of a person's life, normal cells divide more rapidly until the person becomes an adult. After that, cells in most parts of the body divide only to replace worn-out or dying cells and to repair injuries.
    Because cancer cells continue to grow and divide, they are different from normal cells. Instead of dying, they outlive normal cells and continue to form new abnormal cells.
    Cancer cells develop because of damage to DNA. This substance is in every cell and directs all activities. Most of the time when DNA becomes damaged the body is able to repair it. In cancer cells, the damaged DNA is not repaired. People can inherit damaged DNA, which accounts for inherited cancers. More often, though, a person's DNA becomes damaged by exposure to something in the environment, like smoking.
    Cancer usually forms as a tumor. Some cancers, like leukemia, do not form tumors. Instead, these cancer cells involve the blood and blood-forming organs and circulate through other tissues where they grow.
  • – Cancer is the common term for all malignant tumors.
    – Carcinoma is the common term for malignant
    epithelial tumors.
    – Sarcoma is the common term for malignant nonepithelial
    – Solid tumors are circumscribed tumors such as
    carcinomas and sarcomas.
    – Non-solid tumors are systemic autonomous proliferations of noncohesive individual cells, such as
    occur in leukemias
  • Universal and obligatory property of benign and malignant neoplasms – is their capacity for unlimited growth.
    In base growth up lies uncontrolled surplus proliferation of cellular elements.
    Neoplastic cells mitoses speed does not exceed the one of normal cells – embryonic bone marrow cells, bowels epithelium and other.
    Tumor cells differ from normal not by the cell division speed, but  character of proliferation.
    Neoplastic cells acquire ability to cell-fission boundless.
    Growth unlimitation carries the fact, that the tumor cells are not able to exhaust division resources. In each cell a genetic program is pawned, which limits its division amount.
    Tumor cells do not have  limiting program. They lost it owing to somatic mutation.
  • Physical and chemical peculiarities of neoplastic cells:
    acidosis owing to lactic acid accumulation,
    intracellular hydration,
    raised electroconductivity,
    colloid viscosity decrease,
    membranes surface-tension decrease,
    negative membranes charge increase.
  • This slide lists the different carcinogenic agents identified. By far, chemical carcinogens are the most common. More significant though are lifestyle carcinogens such as the following:
    Cigarette smoking
    Diet – high fat, high sodium, low fiber diets have predisposed populations to increase rates of gastrointestinal cancers.
    Sexual practices – multiple sexual partners can result in the spread of the human papilloma virus (causes cervical cancer), the Hepatitis B virus (causes liver cancer), and the HIV virus (causes AIDS related malignancies)
    Knowledge of these carcinogens are important because cancer may be prevented if these are avoided. Also, lifestyle related cancers are important to consider because of the role of behavior modification in their avoidance.
  • Substances, that contain three or more benzoic cycles belong to the first group. More than 200 of them are known. But the only one of them, which is 3,4-benzopyrene is carcinogenic for a human.
    Carcinogenes of this group, are usually of antropogenous origin. They are in tobacco smoke, car-petroleum gases, blast-furnaces smoke, chemical productions wastes, overfried food. They cause cancer or sarcoma by their injection way. Polycyclic aromatic hydrocarbons exude from organism by kidneys, skin, mammal glands, therefore are followed with the neoplasms of these organs.
    Aromatic amines and amides
    Aromatic amines and amides are mainly dyestuffs.
    They include:
    chlornaphthisine and others.
    These substances are usually used for natural or synthetic fabrics colouring, polygraphy, cosmetics production, colour-photography processes, medications or eather insecticides synthesis that is followed with neoplastic growth attached to skin or gastrointestinal contacts.
    Tumors are usually located in liver, urinary cyst, bowels, kidneys.
    Nitrosamines and Nitrosamides
    The third carcinogenes group (nitrosamines and nitrosamides) cause neoplastic processes in 40 animals species.
    Their carcinogenous effects upon the humans are not proved, however the experimental data are of the great attention. A man contacts to nitrosamines at productions.
    Besides, they form in digestive canal of nitrites, nitrates and other junctions of nitrogen.
    Almost all of carcinogenic matters are not active. But they acquire carcinogenic properties due to their entering the organism.
    The final cancerogenes get formed with them. Nominally these matters are followed with neoplastic growth. It is proved, that carcinogenes  react with purine bases of DNA obligatorily.
    The most frequent target – is guanine, which gets methylated or eather alkylated by cancerogenes (that means its combining to the methyl or eather alkyl group).
    Changed guanine is unable to bind with cytosine, but gets associated with thymine.
    The sequence of bases in DNA molecule gets disturbed. Genes mutation arises.
    The Story of the Nut http://www.takaoclub.com/binlang/
    The Myth
         Once upon a time on the unspoilt island of Formosa dwelt a peace-loving people who lived by hunting and gathering. Amongst the trees that they found in the forests spread across the lower southern valleys was the Betel Palm (Areca catechu) which was possessed of a green nut that turned into gold. So much pleasure did this small nut give, when correctly prepared, that the natives of the island agreed that it was a gift from the gods.
         Myths were created, temples were built and processions were held to celebrate the power that possession of the nut gave. All were happy to chew upon the nut and the fortunate coveted their knowledge of the fruit of the Areca Palm or Betel-Nut Tree.
    (Click on image to read the Vietnamese myth)
    (Click on image for more about the betel-nut myth)
         The tradition had begun. Times would change on the island of Formosa as invaders came from the islands to the north and from the great land to the west but none was mightier than the nut. The chewing of the nut was to become a potent symbol of 'being Taiwanese', and was sufficiently widespread to be known as Taiwanese chewing gum.
    (Click for full image)
    The Source
         The betel nut is the fruit of the Betel Palm (Areca catechu).
         The betel-nut tree today still grows in the verdant valleys of southern Taiwan but no longer does it need to be sought out in the dangerous forests. The ease of cultivation, the almost insatiable demand prior to Taiwan's entry into the World Trade Organization and the lure of money led to an ever greater encroachment of cleared land for areca cultivation. Mountain sides have been denuded to allow for illegal planting on the watersheds of this shallow-rooting palm that fails to bind the topsoil.
         In recent years, following the massive lethal mudslides in Nantou County of 2001 that were partially caused by the illegal planting of betel palms on slopeland, the government has sought to curb this practice. However, with few alternative cash crops the farmers have seen little incentive to change.
    Areca Catechu or Betel Palm
    (Click on image to enlarge)
       The shallow gravels, the climactic conditions and the plentiful groundwater of the eastern part of the Pingtung plain have proved ideal for the cultivation of the areca palm.   Yielding some three tonnes of nuts per hectare each year the crop of the areca palm has been termed as Taiwan's 'green gold'. The rich agricultural and financial harvest has drawn in both local farmers and local businessmen.
    Betel palms on the Pingtung foothills
         Binlang is chewed in a betel quid giving rise to the misnaming of the areca nut as a 'betel nut'. The betel quid as chewed in Taiwan consists of three basic elements: the areca nut itself; the leaf, and, uniquely in Taiwan, the inflorescence, of the piper betel plant: and a paste of slaked lime. Each of these elements has its own purpose and effect, but combine together in the mouth to give the distinctive stimulation or 'high' of the betel nut.     The areca nut contains two significant alkaloids. The main alkaloid is arecoline, which also causes the excessive salivation characteristic of betel-nut chewing.
         Two parts of the piper betel, a member of the piperaceae or pepper family, are used in Taiwan. The betel leaf contains a aromatic phenol, betel-phenol, and the inflorescence contains safrole. Although safrole is safely used as a food flavouring, it is thought to be a carcinogenic in larger amounts.
         The final component of the betel quid is slaked lime. In Taiwan two slaked lime pastes are used: the more palatable red paste, and the more efficacious white paste. The lime acts as a catalyst to draw out the arecoline, guvacoline and phenols into the saliva and thence into the bloodstream.
         As to the effects of binlang, you are probably best to try it for yourself. It is certainly not a stimulant that has the instant and gripping effect of amphetamine or cocaine. It is natural, and thus more akin to drinking coffee or tea, or chewing coca leaves. The effect is thus softer and subtle, giving a feeling of energy and yet well-being, offsetting hunger and fatigue, and bringing a warmth to the body that tempts so many young Taiwanese conscripts on early morning guard duty.
    Another fine botanical drawing of betel nuts
    (click to enlarge)
    Betel leaves (Piper sarmentosum)
    Areca nuts ready for preparation
    Betel nuts prepared for sale
         The strength of the 'green gold' merchants can be envisioned from the very size of the betel-nut, or bin-lang, market. There are estimated to be over 2 million chewers of the nut on Taiwan, which represents around a quarter of the adult male population. Annual revenue is authoritatively given as 'nearly 100 billion NT dollars', and the area under cultivation as 57,000 hectares.     An updated assessment of the betel-nut trade can be seen from this page of the Taipei Times.
         The trade in bin-lang is utterly unregulated and remains untaxed despite its economic importance. Such huge undocumented cash flows have attracted of the interest of people from all walks of life and the need to use creative marketing strategies.
  • The first clinical supervisions in this direction had been done by Pott. He described scrotum, internal thighs surfaces and stomach cancer in young chimney-sweepers.
    Yamagiva and Ichikawa proved a carcinogenous of chemical matters in experiment at first. They drifted carbonic resin onto the rabbit ear for fifteenth months. This process was followed with skin cancer in rabbit. In 1930-1932 pure carcinogenes were extracted out of carbonic resin, including benzoapyrene, dibenzanthracene, methylcholanthrene. 
    Chemical carcinogenes are presented by several groups. The main are:
    polycyclic aromatic hydrocarbons,
    aromatic amines and amides,
    nitrosamines and nitrosamides.
  • The first stage
    (transformational stage) is followed with the cell oncogene activation. The cell acquires unusual property, which is called immortalisation. This is a potential unlimited division, immortality ability. However, the presence of active oncogene is a readiness to division only.
    A cell with active oncogene can resist in latent (condition) for years. It does not display itself with anything.
    Supplementary influences upon immortalisated cell, are necessary to exit it out of the latent state, for giving a push to irrepressible division. These are provoking factors, which are supplementary doses of chemical cancerogenes or x-rays, retroviral superinfection. They are named promotors.
    Progression is the very last and the most protracted stage of neoplastic growth development. The clearest determination of this notion Fulds has given: “Progression is a neoplasm development in a way of constant, irreversible, qualitative changes of its one or a few signs". Progression is not just quantitative tumor growth, but native change of its biological properties. One of the major Fuld’s principles is an independent progression of separate neoplastic signs.
    Its essence is the following - each tumor sign:
    morphological anaplasia degree,
    hormones dependence degree, 
    invasive growth capacity,
    metastasing ability evolutionizes irrespectively to the other signs, however  to the malignisation side always.
    Neoplastic growth progression reflects tumor admiring to autonomy. It holds a neoplastic cell much more further from maternal. The main progression  index is   organs and tissues structure loss by the tumor with simultaneous cell differentiation lowering.
    Neoplastic growth progression reflects in its clinical symptoms and therapy possibilities.  For example, some tumors (mammal gland cancer, uterius corpus, prostata) on the definite development stages react to hormones. In other words, these neoplasms are hormone dependent. Tumor cells lose the specific receptors  and stop reacting to the hormones influence during the progression. Neoplastic growth becomes hormone independent. It is not sensitive to hormonal therapy.
  • Radiation-induced mutation in the host cell
    Transmits irreversible changes in gene expression to cell progeny
    includes electromagnetic rays & particulate matter
    mechanism:  free radicals & mutations
    pathology: leukemias > thyroid ca > lung & breast ca
    resistant tissues: bone, skin and the GIT
  • To physical cancerogenes belong ionizing and ultraviolet rays.
    The ionizing rays cause diverse genetical and chromosomal mutations. They are followed with neoplastic growth in all of organs almost. Skin, bones, lungs, thyroid, mammal gland neoplasms arise in case of external irradiation. In case of ionizing radionuclides entering inside, the tumor arises at their accumulation locations.
    For example barium, calcium, strontium radionuclides  cause the bone neoplasms.
    Caesium, thorium radionuclides, able to cause liver, bone marrow, stomach, thick bowel tumors.
    The ultraviolet rays render weak carcinogenic action, but they damage the mechanisms of DNA reparation. In particular, dimerization of thymine takes place under their dominance. As a result  an usual bases sequence in DNA molecule gets disturbed.
  • Viral carcinogens are classified into RNA and DNA viruses.
    Most RNA oncogenic viruses belong to the family of retroviruses that contain reverse transcriptase mediates transfer of viral RNA
    into virus specific DNA.
  • Retroviruses are the cause of cellular DNA damage
    due to the transforming genes invasion, they are called
    viral oncogenes and have cellular origin. These are the
    cellular DNA areas, which were seized by virus into the
    own genome occasionally. Now more than 20 viral
    oncogenes are known. All of them have cell twins.
    These cell twins (cell oncogenes) are situated in different chromosomes. Examples are: Raus sarcoma virus in hens is located in 20-th chromosome, Molone sarcoma virus in mice – in 8-th chromosome, Rorru-Donal virus in cats – in 5-th chromosome, sarcoma virus in hairy moukeys – in 22-th chromosome.
    Viral oncogenes differ from their cell predecessors. Usually, retroviruses holder cell oncogenes not totally, without the regulatory (repressive) genes. Viral oncogene preserves an ability to stimulate cells growth and differentiation, but at the same time loses genes-repressors and becomes uncontrolled. Therefore a recurrent entrance into the infected cell DNA is followed with unrestricted cell division. Cell oncogen itself gets changed also in its seizure by retrovirus process. It consists of exones (encoding areas) and intrones (unencoding areas) in the cell. It combines exones only (encoding areas) in virus genome. Therefore it is very active.
  • It is proved, that tumors can be caused by viruses. Here are some neoplasms examples of viral origin: Rauss sarcoma in chicken, Shope papilloma in rabbits, mammal gland cancer in rats, which arises in case of Bittner milk factor.
    Viruses, which cause neoplastic growth, are called oncogenous.
    They belong to the group of retroviruses.
    Not many human tumors, which get caused by viruses are known. They are Burkitt’s lymphoma (Central Africa), nasopharyngeal cancer (China), cervix cancer.
  • All cancers are similar in that the different diseases will all have these basic characteristics.
  • It is believed that all tumors arise as clones from a genetically damaged cell. Hence, at the molecular level, cancer is a genetic and a clonal disease.
    The results of genetic instability are as follows:
    The resulting cells appear different from the parent cells so that a tumor that arises from the lung may have features similar to normal lung cells but do not act nor function as lung cells or may even look totally different from normal lung cells.
    The result of genetic instability is the production of abnormal proteins that stimulate cellular proliferation. This results in uncontrolled division and tumor formation.
    Proto-oncogenes are precursors of oncogenes (inactivated oncogenes). They occur naturally and are normally activated when increased cellular proliferation is required (as in, embryonic development). However, in a normal individual, these proto-oncogenes are normally inactivated or kept in check by suppressor genes.
    A dominant mutation occurs when an event results in the conversion of a proto-oncogene to an oncogene.
    A recessive mutation occurs when there is damage or loss of a tumor suppressor gene resulting in an unchecked, and therefore expressed, oncogene.
    Cancer is a genetic disease at the cellular level.
    Genetic mutations play a critical role in pathogenesis of cancer.
    Consequences of genetic instability:
    Phenotypic heterogeneity
    Tumor progression
    Proto-oncogenes and oncogenes
    Dominant and recessive mutations
  • A basic characteristic of cancer is its capacity to proliferate outside the normal control mechanisms of the organism. This capacity, as previously seen, arises from damage inflicted on the cell’s genetic apparatus. Uncontrolled growth can be stimulated by either:
    Secretion of growth factors
    Increased growth factor receptors (making the cell sensitive to normal levels of growth factors).
    Independent activation of certain enzyme or protein production pathways.
    To understand the biology of cellular proliferation, one musty be familiar with the cell regeneration cycle.
    Tumor cells have one more typical caracteristic – growth autonomy. 
    Cultural growth is controlled at two levels – organism and tissue ones. 
    At organism level such control is realized with  nervous and endocrine systems 
    At tissues level – with biologically active substances which are mitogenes and keylones.
    Neoplastic cells display independence, growth autonomy. Its stop reacting upon nervous, endocrine and local regulative stimuls.
    Autonomy of tumor cells develops gradually. At first tumor cell gets partially hormonal regulated (hormone dependent tumor). Later it is perfectly irresponsible for hormones (hormone independent tumor).
    Some researchers mention considerable role of cultural division local regulation violations. In particular, in neoplastic tissue keylones maintenance decrease sharply.
  • The Hayflick limit (or Hayflick phenomenon) is the number of times a normal human cell population will divide until cell division stops. Empirical evidence shows that the telomeresassociated with each cell's DNA will get slightly shorter with each new cell division until they shorten to a critical length.
    Hayflick found that cells go through three phases. The first is rapid, healthy cell division. In the second phase, mitosis slows. In the third stage, senescence, cells stop dividing entirely. They remain alive for a time after they stop dividing, but sometime after cellular division ends, cells do a particularly disturbing thing: Essentially, they commit suicide. Once a cell reaches the end of its life span, it undergoes a programmed cellular death called apoptosis.
    The concept of the Hayflick limit was advanced by Leonard Hayflick in 1961, at the Wistar Institute in Philadelphia. Hayflick demonstrated that a population of normal human fetal cells in a cell culture will divide between 40 and 60 times. The population will then enter a senescence phase, which refutes the contention by Nobel laureate Alexis Carrel that normal cells are immortal. Eachmitosis slightly shortens each of the telomeres on the DNA of the cells. Telomere shortening in humans eventually makes cell division impossible, and this aging of the cell population appears to correlate with the overall physical aging of the human body. This mechanism also appears to prevent genomic instability. Telomere shortening may also prevent the development of cancer in human aged cells by limiting the number of cell divisions. However, shortened telomeres impair immune function that might also increase cancer susceptibility.
  • Growth Factors
    Definition: Collective term of mitogenic peptide hormones that promote:
    — Receptor-mediated proliferation and
    — Cell differentiation and motility. In the latter case, a cell can only divide by mitosis after first having broken off contact with adjacent cells under the influence of a scatter factor.
    Growth factors are produced by autocrine secretion or paracrine secretion:
    — Autocrine secretion: The growth factor is created by a cell also possessing the respective growth factor receptor. Limited autocrine secretion occurs during embryogenesis and tissue regeneration; continuous autocrine secretion occurs in tumor growth.
    — Paracrine secretion: The growth factor is produced by a cell not itself responding to the substance. This is the typical type of growth factor secretion.
    Pathogenetic function: Growth factors occur only in small concentrations in normal postnatal tissue. Hyperfunction of these factors contributes significantly to the development of tumors.
    Growth factor hyperfunction is usually attributable either to:
    — Autocrine secretion (in which the target cell is the producing cell) or to
    — Over expression of a growth factor gene resulting in excessive growth factor production.
    Growth factor hyperfunction has several consequences typically encountered in tumors:
    — Disruption of intercellular communication: Tumor cells talk to themselves in the sense that they create scatter factors by autocrine secretion. These form a functional complex (“motility factor”) with the receptor of the oncogene c-met.
    — Cell motility causes tumor cells to leave the cellular aggregate and to divide; the daughter cells migrate away from one another.
    — Tissue invasion occurs with the aid of proteases (tissue metalloproteinase) on the tumor cell surface.
    — A permanent proliferation signal results from abnormal quantities and types of receptors and/or excessive generation of growth factor.
  • proto-oncogenes
    Definition: Collective term of normal gene sequences whose gene products contribute to regulating proliferation processes. When abnormally activated, they can transform the cells into malignant cells
    Pathogenetic function: There are two mechanisms by which the physiologic proto-oncogenes (c-onc) are transformed into cancercausing oncogenes.
    Structural alteration of a proto-oncogene may occur in one of two ways:
    A single-point mutation (1) of a c-onc allele with substitution of a nucleotide causes synthesis of an abnormal protein or oncoprotein. Because the proto-oncogenes are dominant, mutation of only a single c-onc allele is sufficient to cause this change.
    Translocation of a proto-oncogene (2) with rearrangement of the genetic material.
    Gene amplification (3) may result from autocrine secretion (4) or invasion by a highly expressive retrovirus in the vicinity of the proto-oncogene’s locus (5).
    In these cases, the controlling gene no longer has any influence; the gene copies are replaced, leading to overproduction of oncoproteins.
  • A special theory was formulated by the end of last century, due to the  foundation of contemporary knowledge, which united all of known carcinogenesis forms (chemical, physical, biological) into a single universal mechanism. It had been called as conception of oncogen.
    Appearance of neoplastic growth is related to genetic system somatic cells changes. Tumor is a hereditary phenomenon at the cell level. There are many causes of cancer and all of them get DNA damaged. This damage must be located in that area DNA, where  cellular oncogenes are situated. These gens are the usual components of the cell genome. They control growth and cells differentiation. 
    These growth stimulators normal function can be preserved in case of insignificant damages, but they stop to submit the supervisory dominances of the surrounding genes and the cell. The normal dirigible cells reproduction and maturation  process get lost. It is substituted by an unterminable stream of cellular division.
    Cellular oncogenes are also called as cancer genes. Carcinogenic agents damage either oncogenes or genes-repressors, which are serial located. In effect of chemical, physical and viral factors, their activity gets raised sharply and they turn the normal cell into the neoplastic one.
    A few cellular oncogenes  activative mechanisms  are known. They are: viral transduction, chromosomal mutation, genetic material insertion, genetic amplification, point mutations.
  • Chromosomal aberration. Translocatons are observed in human neoplastic growth cells  more often. It is thought, that translocation is one of the cell oncogenes activation ways majority. Chromosomes breaking  takes place close to the cellular oncogenes frequently. They get activated right after the breaking. Such tumor example is Berkit lymphoma. Mutual translocation between eigth and fourteenth chromosomes is typical for such lymphoma kind.
    Insertion of genetic material. Neoplastic growth arises not only, in case of viral oncogene injury into the cell DNA. Cell oncogene activation is also possible, when any heterologous (viral) genetic material encroaches into the cell DNA close to it. It is not suppose to keep oncogene. Any viral DNA is able to activate cell oncogene, due to its incorporation into the cell DNA beside the oncogene.
    Amplification of cell oncogene. Usually, cell oncogenes are represented by one copy. Amount of copies can increase as a result of spontaneous DNA replication anomalies. Such phenomenon is named amplification. DNA copies mount augmentation causes their summary expression augmentation. Supplementary RNA and oncoalbumen amount gets synthesized on supplementary DNA matrices. Amplification is typical for some human tumors. Neuroblastoma and thick bowels carcinoma  arises due to such mechanism.
    Point mutations. All cell oncogenes activation mechanisms, which were characterized earlier, obligatorily related to cell DNA changes. Eventually, all of them are of mutational origin. Now it is admitted, that point mutations are a major carcinogenesis mechanism. 
  • Synonym: anti-oncogenes
    Definition: Collective term for genes whose products physiologically inhibit cell proliferation, promote cell differentiation, and also suppress certain steps in tumorogenesis and metastasis.
    A single copy of such a tumor suppressor gene is sufficient to maintain control over growth. Therefore the defect only becomes apparent where both alleles are affected, i.e., in a recessive mutation (loss of heterozygosity).
    Pathogenesis: The function of these genes can be blocked by single-point mutation, deletion, or association with viral or endogenous proteins. They can be categorized functionally as:
    — “Gatekeeper” genes that directly regulate tumorogenesis by inhibiting its growth or by promoting their death. They are rate-limiting for tumor initiation
    — Other suppressor genes whose inactivation leads to tumor progression.
    The next section examines the role of those most thoroughly-researched tumor suppressor genes.
    Retinoblastoma Gene
    This gene (= RB-gene)was discovered in retinoblastoma, a malignant retinal tumor.
    RB-gene: The product of this gene binds transcription factors, inhibiting the expression of genes that control the transition from the G1 phase to the S phase in the cell cycle. This inhibits mitosis.
    RB-gene inactivation occurs in extremely aggressive rapidly proliferating carcinomas (breast carcinomas, small-cell bronchogenic carcinomas, and glioblastomas) and sarcomas (osteosarcoma).
    Wilms’ Tumor Genes
    These genes (= WT-genes) were discovered in Wilms’ tumor or nephroblastoma, a malignant renal tumor.
    WT-1 gene: The product of this gene inhibits the transcription of a mitogen1. In this manner, it promotes differentiation of the embryonic primordium of the kidney and inhibits adjacent genes such as IGF-22 that control initiation of the cell cycle.
    WT-2 gene: This gene regulates proliferation.
    WT-gene inactivation: AWilms’ tumor is frequently associated with congenital malformations of the kidney in the form of simultaneous occurrence of medullary tissue, cortical tissue, and nephroblastoma nodules.
    p 21:
    inhibits cell cycle progression and permits DNA repair to take place.
    p53 Tumor Suppressor Gene
    p53 gene:“the guardian of the genome”
    The product of this gene arrests the cell in the G1 phase in the event of DNA damage, giving it the opportunity to repair the DNA. Where this is unsuccessful, p53 initiates apoptosis in the respective cell. p53 inactivation may occur as a result of mutation.
    Mutated p53 protein inactivation promotes tumor development. Its gene product is broken down more slowly than normal protein, leading to intranuclear accumulation of p53 protein. This occurs in acquired somatic mutations in many tumors and in constitutional mutations in members of families with a history of familial cancer.
    In the presence of DNA damage, influences transcription to either:
    Halt cell cycle progression to facilitate DNA repair.
    In cases of severe DNA damage, activates apoptosis.
    The gene may also be inactivated by association with viral proteins or endogenous proteins.
  • Those genes responsible for DNA repair are also called caretaker genes. Their defects are based on a germ line mutation that only takes effect when both alleles are defective.
    The initial result is genetic instability, which affects primarily tumor suppressor and oncogenes, leaving unrestrained proliferation and immortalization of the affected cells in its wake.
    Examples of caretaker gene defects:
    — Nucleotide excision repair in xeroderma pigmentosum, ataxia teleangiectatica, Bloom’s syndrome, Fanconi’s anemia.
    — DNA mismatch repair: in hereditary nonpolyosis colon cancer.
    Note: Because they cannot repair radiation damage, tumors with defective caretaker genes are radiocurable.
    — Defects in the DNA-repair mechanism cause an accumulation of DNA defects, one of which can affect the proliferation signalling
    — Unrestrained growth: Unregulated activation of growth-inducing genes (oncogenes) and ineffectiveness of growth-inhibiting genes
    (tumor suppressor genes) leads to excessive, chaotic, and ruthlessly proliferative tissue growth.
    — Cellular immortality: Genetic defects affecting apoptosis and the retardation of programmed cell death by re-expressing of telomerase lead to uninhibited inter and intracellular proliferation.
    — Lack of integration into tissue: Defective differentiation genes lead in turn to defective intercellular communication and communication between cells and the extracellular matrix. This means that tumor cells are poorly integrated into cohesive cellular aggregates and into the extracellular matrix.
    — Alienation: Defective differentiation genes lead to false “self” characteristics that deceive
    the immune system, which overlooks alienated tumor cells.
    — Cellular “vagrancy”: Disturbed regulation of the formation of mobility factors and abnormal
    activation of these factors causes cells to migrate in the body.
  • The definite role in neoplastic cells abruption from the tumor node belongs to mechanical factors.
    The part of abrupted cells is carried with blood and lymph channel.
    95-99,9 % get necrotiesed.
    An important role in their elimination the anti-neoplasm immunity mechanisms has. They are performed by Т-lymphocytes and natural killers (NК-cells).
    Natural killers recognize and kill the mutante cells without preliminary sensibilization. 
    The tumor cells lysis gets realized with proteolytical and lipolytical blood enzymes also.
    The secondary tumor nodes form at the third stage.
    Neoplastic cells delay by the vessel intima and thrombus forming around them arises firstly.
    Tumor cells accumulation in capillaries is sometimes provoked by mechanical causes: capillary lumen happens to be more narrow, than neoplastic cells diameter.
    Tumor cells exit into the out of vessels space after their adhesion to the endothelium. This exit is related to capillaries penetrability rising. Cells fate out of blood channel is different. Many cells get perished. Other cells are staying  in a latent condition for a very long time, pending of years. And only small part of cells receive the further development. They reproduct and establish a new neoplastic node (metastasis).
  • Neoplastic growth and human  organism correlation
    Tumor appearance and growth depends on the organism state strongly. Two system perform the primary role here, they are: endocrine and immune.
    Endocrine system and oncogenesis. Neoplasms divide into two groups: dyshormonal tumors and unendocrine ones.
    Dyshormonal neroplasms totally depend on the organism hormonal  status. Endocrine glands and organs-targets tumors, which underlie hormonal influence belong here. Human dyshormonal mammal gland, uterus, prostate neoplasms are the most expanded. 
    In case of mammal gland and uterus tumors development an important role belongs to the surplus production of estrogens, which stimulate cells proliferation in these organs.
    Follicle stimulating hormone role in mammal gland cancer formation is proved. It activates estrogens synthesis and renders the straight influence upon the gland tissue.
    The high estrogens synthesis regulation tension is observed in case of menopause.
    Menopause in women is followed with high hypothalamo-hypophyseal system activity. A big amount of gonadotrophic hormones get producted.
    The Sexual steroids synthesis get increased accordingly in ovaries. But they are out of hormonal properties already in this age, and still preserved their ability to stimulate proliferation. Therefore the tumor appearance risk is very high in this period.
    Due to its way, the neoplasm, while growing, renders the influence upon the hormonal profile of an organism. 
    If the tumor does not appear from endocrine gland, it affects upon the hormonal background anyway. So-called paraneoendocrine syndrome arises.
    Many neoplasms synthesize matters, which are similar to hormones.
    For example,
    bronchogenous cancer, synthesizes the matters with adrenocorticotrophin or antidiuretic hormone activity.
    Chorionepithelioma synthesizes a thyrotropic hormone.
    Some incretion glands tumors begin synthesing heterologous for the mentioned gland hormones – heterohormones. So, thyroid neoplasms synthesizes adrenocorticotrophin  hormone sometimes. Langerhans islands tumors are able to product up to seven hormones.
    Neoplastic growth synthesizes normal hormones in some circumstances, but can not transfer them into the active state.
  • It is important to know what some of the general (non-specific) signs and symptoms of cancer are. They include unexplained weight loss, fever, fatigue, pain, and changes in the skin. Of course, it’s important to remember that having any of these does not necessarily mean that cancer is present -- there are many other conditions that can cause these signs and symptoms as well.
    Unexplained weight loss: Most people with cancer will lose weight at some time with their disease. An unexplained (unintentional) weight loss of 10 pounds or more may be the first sign of cancer, particularly cancers of the pancreas, stomach, esophagus, or lung.
    Fever: Fever is very common with cancer, but is more often seen in advanced disease. Almost all patients with cancer will have fever at some time, particularly if the cancer or its treatment affects the immune system and reduces resistance to infection. Less often, fever may be an early sign of cancer, such as with leukemia or lymphoma.
    Fatigue: Fatigue may be a significant symptom as cancer progresses. It may occur early, however, in cancers such as with leukemia or if the cancer is causing a chronic loss of blood, as in some colon or stomach cancers.
    Pain: Pain may be an early symptom with some cancers, such as bone cancers or testicular cancer. Most often, however, pain is a symptom of advanced disease.
    Skin changes: In addition to cancers of the skin (see next section), some internal cancers can produce visible skin signs such as darkening (hyperpigmentation), yellowing (jaundice), reddening (erythema), itching, or excessive hair growth.
    In addition to the above general symptoms, you should be watchful for the following common symptoms, which could be an indication of cancer. Again, there may be other causes for each of these, but it is important to bring them to your doctor’s attention as soon as possible so that they can be investigated.
    Change in bowel habits or bladder function: Chronic constipation, diarrhea, or a change in the size of the stool may indicate colon cancer. Pain with urination, blood in the urine, or a change in bladder function (such as more frequent or less frequent urination) could be related to bladder or prostate cancer. Any changes in bladder or bowel function should be reported to your doctor.
    Sores that do not heal: Skin cancers may bleed and resemble sores that do not heal. A persistent sore in the mouth could be an oral cancer and should be dealt with promptly, especially in patients who smoke, chew tobacco, or frequently drink alcohol. Sores on the penis or vagina may either be signs of infection or an early cancer, and should not be overlooked in either case.
    Unusual bleeding or discharge: Unusual bleeding can occur in either early or advanced cancer. Blood in the sputum (phlegm) may be a sign of lung cancer. Blood in the stool (or a dark or black stool) could be a sign of colon or rectal cancer. Cancer of the cervix or the endometrium (lining of the uterus) can cause vaginal bleeding. Blood in the urine is a sign of possible bladder or kidney cancer. A bloody discharge from the nipple may be a sign of breast cancer.
    Thickening or lump in breast or other parts of the body: Many cancers can be felt through the skin, particularly in the breast, testicle, lymph nodes (glands), and the soft tissues of the body. A lump or thickening may be an early or late sign of cancer. Any lump or thickening should be reported to your doctor, especially if you’ve just discovered it or noticed it has grown in size. You may be feeling a lump that is an early cancer that could be treated successfully.
    Indigestion or trouble swallowing: While they commonly have other causes, these symptoms may indicate cancer of the esophagus, stomach, or pharynx (throat).
    Recent change in a wart or mole: Any change in color or shape, loss of definite borders, or an increase in size should be reported to your doctor without delay. The skin lesion may be a melanoma which, if diagnosed early, can be treated successfully.
    Nagging cough or hoarseness: A cough that does not go away may be a sign of lung cancer. Hoarseness can be a sign of cancer of the larynx (voice box) or thyroid.
    While the signs and symptoms listed above are the more common ones seen with cancer, there are many others that are less common and are not listed here. If you notice any major changes in the way your body functions or the way you feel, especially if it lasts for a long time or gets worse, let your doctor know. If it has nothing to do with cancer, your doctor can investigate it and treat it, if needed. If it is cancer, you’ll give yourself the best chance to have it treated early, when treatment is most likely to be effective.
  • Tumors

    1. 1. Plan of the lecture 1. Neoplastic growth. Definition. 2. Features of benign and malignant tumors. 3. Classification of cancerogens. 4. Pathogenesis of tumors. 5. Stages of cancerogenesis. 6. Characteristic of tumor cells. 7. Mechanism of immunological response against tumor cells. 8. Treatment of tumors.
    2. 2. Actuality of the lecture By the prognoses of Worldwide health protection organization morbidity and death rate from oncologic diseases in the whole world will grow in 2 times for period from 1999 year for 2020: from 10 to the 20 million new cases and from 6 to the 12 million registered deaths. Taking into account that in the developed countries there is a tendency to deceleration of growth of morbidity and death rate from malignant tumors (due to the prophylaxis and due to the improvement of early diagnostics and treatment), clearly, that a basic increase will be at developing countries (countries of former USSR). That is why doctors have to expect serious increase of morbidity and death rate from oncopathology. From data of Committee of cancer prophylaxis 90% tumors are related to influencing of external factors, and 10% - depend on genetic factors.
    3. 3. Neoplasia – “new growth” & new growth is called a neoplasm.  Neoplasia is new tissue growth that is:  unregulated,  irreversible,  monoclonal. these features distinguish it from hyperplasia and repair  Monoclonal means that the neoplastic cells are derived from a single mother cell.  Cancer is an overgrowth of cells bearing cumulative genetic injuries that confer growth advantage over the normal cells. [Nowell’s Law]
    4. 4. • Oncology (Greek oncos = tumor) is the study of tumors or neoplasms. • Cancer is the common term for all malignant tumors. • Although the ancient origins of this term are somewhat uncertain, it probably derives from the Latin for crab, cancer — presumably because a cancer "adheres to any part that it seizes upon in an obstinate manner like the crab."
    5. 5.  Believe it or not, cancer has affected people for several centuries. It is not a new disease.  The word cancer came from the father of medicine, Hippocrates, a Greek physician. He used the Greek words, carcinos and carcinoma to describe tumors, thus calling cancer “karkinos.”  Hippocrates (460-377 BC) coined the term karkinos for cancer of the breast.  The word ‘cancer’ means crab, thus reflecting the true character of cancer since ‘it sticks to the part stubbornly like a crab’. He was certainly not the first to discover the disease.  The history of cancer actually begins much earlier. The History of Cancer, Lisa Fayed, About.com July,2008
    6. 6. • The world's oldest documented case of cancer hails from ancient Egypt, in 3000 b.c. • The details were recorded on a papyrus, documenting 8 cases of tumors occurring on the breast. • It was treated by cauterization. It was also recorded that there was no treatment for the disease, only palliative treatment. • There is evidence that the ancient Egyptians were able to tell the difference between malignant and benign tumors. • In ancient Egypt, it was believed cancer was caused by the Gods. The History of Cancer, Lisa Fayed, About.com July,2008
    7. 7. Ebers Papyrus treatment for cancer: recounting a "tumor against the god Xenus", it recommends "do nothing there against" Ancient Egyptian medical instruments depicted in a Ptolemaic period inscription on the Temple of Kom Ombo. http://en.wikipedia.org/wiki/Ancient_Egyptian_medicine
    8. 8. Terminology  Hyperplasia - increase in the number of cells,  Hypertrophy - increase in the sizes of individual cells.  Atrophy is an adaptive response in which there is a decrease in the size and function of cells.  Anaplasia - lack of differentiation.
    9. 9. Metaplasia : Transformation of a certain type of differentiated tissue into another type of differentiated tissue. Heteroplasia : Occurrence of non-neoplastic tissue at a location where it does not normally occur, either in a heterotopia or as a result of tissue dissemination.
    10. 10. All tumors, benign as well as malignant, have 2 basic components: “Parenchyma” comprised by proliferating tumor cells; parenchyma determines the nature and evolution of the tumor. “Supportive stroma” composed of fibrous connective tissue and blood vessels; it provides the framework on which the parenchymal tumor cells grow.
    11. 11. NOMENCLATURE Benign tumors are designated by attaching the suffix -oma to the cell of origin. Tumors of mesenchymal cells generally follow this rule. For example, a benign tumor arising from fibroblastic cells is called a fibroma, a cartilaginous tumor is a chondroma, a tumor of osteoblasts is an osteoma. Adenoma is the term applied to a benign epithelial neoplasm that forms glandular patterns as well as to tumors derived from glands but not necessarily reproducing glandular patterns. Benign epithelial neoplasms producing microscopically or macroscopically visible finger-like or warty projections from epithelial surfaces are referred to as papillomas Malignant tumours of epithelial origin are called carcinomas, while malignant mesenchymal tumours are named sarcomas (sarcos = fleshy) For example, fibrosarcoma, liposarcoma, leiomyosarcoma for smooth muscle cancer, and rhabdomyosarcoma for a cancer that differentiates toward striated muscle). However, some cancers are composed of highly undifferentiated cells and are referred to as undifferentiated malignant tumours. Teratomas (can be benign), in contrast, are made up of a variety of parenchymal cell types representative of more than one germ layer, usually all three.
    12. 12. "Knapsack” tumor: lipoma Pleural sarcomatosis: metastatic sarcoma of the uterus
    13. 13. CANCER CELLS AND NORMAL CELLS CANCER CELLS NORMAL CELLS Loss of contact inhibition Increase in growth factor secretion Increase in oncogene expression Loss of tumor suppressor genes Normal cell Few mitoses Oncogene expression is rare Intermittent or co-ordinated growth factor secretion Presence of tumor suppressor genes Frequent mitoses Nucleus Blood vessel Abnormal heterogeneous cells
    14. 14. Characteristics of Benign and Malignant Neoplasms Characteristics Benign Malignant Cell characteristics Well-differentiated cells that resemble normal cells of the tissue from which the tumor originated Cells are undifferentiated and often bear little resemblance to the normal cells of the tissue from which they arose Mode of growth Tumor grows by expansion and does not infiltrate the surrounding tissues; usually encapsulated by a fibrous capsule (exception – uterine leiomyomas do not have fibrous tissue capsule) Grows at the periphery and sends out processes that infiltrate and destroy the surrounding tissues Rate of growth Rate of growth usually is slow Rate of growth is variable and depends on level of differentiation; the more anaplastic the tumor, the more rapid the rate of growth Metastasis Does not spread by metastasis Gains access to the blood and lymph channels and metastasizes to other areas of the body General effects Usually is a localized phenomenon that does not cause generalized effects unless its location interferes with vital functions Often causes generalized effects such as anemia, weakness, and weight loss Tissue destruction Usually does not cause tissue damage unless its location interferes with blood flow Often causes extensive tissue damage as the tumor outgrows its blood supply or encroaches on blood flow to the area; also may produce substances that cause cell damage Ability to cause death Usually does not cause death unless its location interferes with vital functions Usually causes death unless growth can be controlled
    15. 15. Principal Pathways of Malignancy 1. Proliferation 2. Cell-Cycle Progression 3. DNA Repair 4. Immortalization 5. Apoptosis 6. Angiogenesis 7. Metastasis and Invasion
    16. 16.  1. Age > 55 years - more than 75% of cancers. 1)External factors: tobacco, alcohol, chemicals, radiation, pathogens 2) Internal factors: hormones, immune conditions, inheriled mutations  2. Causes: 3. Blacks a. Greatest risk for cancer and cancer-related deaths of any other racial group or ethnicity b. Applies to almost all cancers except malignant melanoma 4. Hispanics and Asians Lower incidence rates for all cancers combined than whites b. Exceptions are for cancers associated with infections – cervix (human papillomavirus), liver (hepatitis B and C), stomach (Helicobacter pylori) 5. Native Americans • Highest incidence and cancer-related deaths due to kidney cancer than all racial and ethnic populations. Cancer incidence 1. Cancers in children a. Second most common cause of death in children (accidents most common cause) b. Acute lymphoblastic leukemia (-33%), central nervous system (CNS) tumors (-21%), neuroblastoma (~7%), Wilms' tumor (-5%). • These are not common tumors in adults. 2. Cancers in men (in decreasing order) • Prostate, lung, colorectal 3. Cancers in women (in decreasing order) • Breast, lung, colorectal
    17. 17. Cancer Geography 1. Worldwide • Malignant melanoma is increasing at the most rapid rate of all cancers. 2. China • Nasopharyngeal carcinoma secondary to Epstein-Barr virus (EBV) 3. Japan • Stomach adenocarcinoma due t0 smoked foods 4. Southeast Asia • Hepatocellular carcinoma due to hepatitis B virus plus aflatoxins (produced by Aspergillus) in food Epidemiology of Endometrial Cancer 5. Africa • Burkitt's lymphoma due to EBV and Kaposi's sarcoma due t0 human herpes virus 8.
    18. 18. Causal Tumorigenesis  Cancer is a genetic disorder that arises from a single body cell (monoclonal disorder).  In humans and other animals, it may be triggered by noxious chemical, viral, and physical agents with mutagenic effects.  Cells acquire several characteristics during the course of this disease.
    19. 19. CARCINOGEN METABOLISM Three Main Categories: I. Chemical Carcinogens II. Physical Carcinogens III. Viral Agents Carcinogens Mutations Cancer Environmental ? factors
    20. 20. • Occupation related causes • Lifestyle related causes CARCINOGENS – Tobacco – Diet – Sexual practices • Multifactorial causes • Chemical carcinogens • Ionizing radiation • Viral carcinogens
    21. 21. CHEMICAL CARCINOGENESIS Direct-acting Carcinogens A. Alkylating agents • Anti-cancer drugs: cyclophosphamide (transitional cell carcinoma of urinary bladder), chlorambucil, busulfan, melphalan, nitrosourea etc. • β-propiolactone; • Epoxides B. Acylating agents: • Acetyl imidazole • Dimethyl carbamyl chloride Promoters  saccharine & cyclamates  Estrogen (endometrial carcinoma. Adenocarcinoma of the vagina is seen with increased frequency in adolescent daughters of mothers who had received estrogen therapy during pregnancy).  Anabolic steroids (↑ the risk of developing benign and malignant tumors of the liver)  Contraceptive hormones (↑ the risk of developing breast cancer. For long durations are benign tumors of the liver, and a few patients have been reported to have developed hepatocellular carcinoma. Gregg Valentino
    22. 22. Procarcinogens 1. Polyclic, aromatic hydrocarbons (in tobacco, smoke, fossil fuel, soot, tar, minerals oil, smoked animal foods, industrial and atmospheric pollutants) (Lung cancer, skin cancer, cancer of upper aerodigestive tract) • Anthracenes (benza-, dibenza-, dimethyl benza-) • Benzapyrene; • Methylcholanthrene 2. Aromatic amines and azo-dyes: • β-naphthylamine; Benzidine (Bladder cancer) • Azo-dyes (e.g. butter yellow, scarlet red) (hepatocellular carcinoma) 3. Naturally-occurring products  Aflatoxin B1 (Hepatocellular carcinoma in association with hepatitis B virus)  Actinomycin D; Mitomycin C; Safrole; Betel nuts 4. Miscellaneous  Nitrosamine & Amides  Asbestos (Bronchogenic carcinoma, pleural mesothelioma)  Vinyl chloride (Angiosarcoma, liver)  Chromium, nickel, other metals (Bronchogenic carcinoma)  Arsenic (Squamous cell carcinoma of skin, lung cancer, liver angiosarcoma) 3,4-benzopyrene This lady chews betel nuts the fruit of a palm
    23. 23. Stages: Initiation - primary exposure Promotion - transformation Progression - Cancer growth Cancer
    24. 24. Initiation  normal cells are exposed to a carcinogen  not enough to cause malignant transformation  requires one round of cell division  normal cells are exposed to a carcinogen 1. Direct-acting carcinogens 2. Indirect-acting carcinogens Procarcinogen Cytochrome P450 Ultimate carcinogen Promotion  initiated cells are exposed to promoters  promoters are not carcinogens !  properties of promoters  reversible  dose-dependent  time-dependent
    25. 25. Physical Carcinogenesis 1. Radiation 1). Ionizing radiation-induced cancers a. Mechanism: • Hydroxyl free radical injury to DNA b. Examples (1) Acute myelogenous or chronic myelogenous leukemia ( risk of leukemia in radiologists and individuals exposed to radiation in nuclear reactors); (2) Papillary thyroid carcinoma (3) Lung, breast, and bone cancers (4) Liver angiosarcoma (Due to radioactive thorium dioxide used to visualize the arterial tree) 2). UV light-induced cancers a. Mechanism • Formation of pyrimidine dimers, which distort DNA b. Basal cell carcinoma, squamous cell carcinoma, malignant melanoma 2. Physical injury 1). Squamous cell carcinoma may develop in third-degree burn scars. 2). Squamous cell carcinoma may develop at the orifices of chronically draining; sinuses (e.g., chronic osteomyelitis), PRE-IRRADIATION POST-IRRADIATION Chondrosarcoma
    26. 26. Ultraviolet Rays UV-A = 320 - 400 nm UV-B = 280 - 320 nm UV-C = 200 - 280 nm UV-C  filtered by ozone UV-B Inhibition of cell division inactivation of enzymes induction of mutations cell death at high doses Squamous cell cancer Basal cell cancer Melanocarcinoma
    27. 27. Viral Carcinogenesis Virus MECHANISM ASSOCIATED CANCER RNA Viruses HCV Produces postnecrotic cirrhosis Hepatocellular carcinoma HTLV-1 (human T-cell lympho-tropic virus) Activates TAX gene, stimulates polyclonal T-cell proliferation, inhibits TP53 suppressor gene T-cell leukemia and lymphoma DNA Viruses EBV (Epstein- Barr virus) Promotes polyclonal B-cell proliferation, which increases risk for t(8:14) translocation Burkitt's lymphoma, CNS lymphoma in AIDS, mixed cellularity Hodgkin's lymphoma, nasopharyngeal carcinoma HBV (hepatitis B virus) Activates proto-oncogenes, inactivates TP53 suppressor gene Hepatocellular carcinoma HHV-8 (human herpesvirus) Acts via cytokines released from HIV and HSV Kaposi's sarcoma in AIDS HPV types 16 and 18, 31, 33 (human papillomavirus) Type 16 (-50% of cancers); E6 gene product inhibits; TP53 suppressor gene Type 18 (-10% of cancers); E7 gene product inhibits; RB suppressor gene Squamous cell carcinoma of vulva, vagina, cervix, anus (associated with anal intercourse), larynx, oropharynx
    28. 28. Viruses (in brackets) in human tumors.
    29. 29. Viral carcinogenesis Burkitt's lymphoma Laryngeal papillomatosis Oral cancer Kaposi's sarcoma
    30. 30. A, Replication: Step 1. The DNA virus invades the host cell. Step 2. Viral DNA is incorporated into the host nucleus and T-antigen is expressed immediately after infection. Step 3. Replication of viral DNA occurs and other components of virion are formed. The new virions are assembled in the cell nucleus. Step 4. The new virions are released, accompanied by host cell lysis. B, Integration: Steps 1 and 2 are similar as in replication. Step 3. Integration of viral genome into the host cell genome occurs which requires essential presence of functional T-antigen. Step 4. A ‘transformed (neoplastic) cell’ is formed. Step 1. The RNA virus invades the host cell. The viral envelope fuses with the plasma membrane of the host cell; viral RNA genome as well as reverse transcriptase are released into the cytosol. Step 2. Reverse transcriptase acts as template to synthesise single strand of matching viral DNA which is then copied to form complementary DNA resulting in double-stranded viral DNA (provirus). Step 3. The provirus is integrated into the host cell genome producing ‘transformed host cell.’ Step 4. Integration of the provirus brings about replication of viral components which are then assembled and released by budding.
    31. 31. Lifestyle Risk Factors Tobacco-related:  Lung cancer  Pancreatic cancer  Bladder cancer  Renal cancer  Cervical cancer Lung carcinoma in situ Penetration of the vena cava: renal carcinoma
    32. 32. Diet-Related Risk Factors Nitrates Salt Low vitamins A, C, E Low consumption of yellow-green vegetables Gastric Cancer Esophageal Cancer
    33. 33. Diet-Related Risk Factors High fat Low fiber Low calcium High fried foods Colon Cancer Pancreatic Cancer Prostate Cancer Breast Cancer Uterine Cancer Carcinoma of the prostate Mycotoxins Liver Cancer
    34. 34. Sexual Practices Risk Factors Cervical Cancer Sexual promiscuity Multiple partners Unsafe Sex Human Papillomavirus
    35. 35. Multifactorial Factors Oral Cavity Cancer Esophageal Cancer Tobacco + Asbestos Tobacco + mining Tobacco + uranium + radium Respiratory Tract Cancer Lung Cancer Tobacco + Alcohol
    36. 36. CHARACTERISTICS OF CANCER • Clonality • Autonomy • Anaplasia • Metastasis
    37. 37. CHARACTERISTICS OF CANCER Clonality  Clonality can be determined by glucose-6- phosphate dehydrogenase (G6PD) enzyme isoforms.  1. Multiple isoforms (e.g., G6PDA, G6PDB, and G6PDC) exist; only one isoform is inherited from each parent.  2. In females, one isoform is randomly inactivated in each cell by lyonization (G6PD is present on the X chromosome).  3. Normal ratio of active isoforms in cells of any tissue is 1:1 (e.g., 50% of cells have G6PDA, and 50% of cells have G6PDG).  4. 1:1 ratio is maintained in hyperplasia, which is polyclonal (cells are derived from multiple cells).  5. Only one isoform is present in neoplasia, which is monoclonal.  6. Clonality can also be determined by androgen receptor isoforms, which are also present on the X chromosome.
    38. 38. CHARACTERISTICS OF CANCER Autonomy • Cancer cells are able to proliferate despite regulatory influences. • Unrestricted proliferation results in tumor formation. • Mechanisms: – Growth factor secretion – Increased number of cell receptors – Independent activation of key biochemical process • Proliferation depends on the cell cycle.
    39. 39.  A tumor usually is undetectable until it has doubled 30 times and contains more than 1 billion (10*9) cells. At this point, it is approximately 1 cm in size.  After 35 doublings, the mass contains more than 1 trillion (10*12) cells, which is a sufficient number to kill the host.
    40. 40. The Hayflick limit is the number of times a normal human cell population will divide until cell division stops.  The concept of the Hayflick limit was advanced by Leonard Hayflick in 1961, at the Wistar Institute in Philadelphia. Hayflick demonstrated that a population of normal human fetal cells in a cell culture will divide between 40 and 60 times. The population will then enter a senescence phase, which refutes the contention by Nobel laureate Alexis Carrel that normal cells are immortal.  Hayflick found that cells go through three phases:  The first is rapid, healthy cell division.  In the second phase, mitosis slows.  In the third stage, senescence, cells stop dividing entirely. Once a cell reaches the end of its life span, it undergoes a programmed cellular death called apoptosis.  Each mitosis slightly shortens each of the telomeres on the DNA of the cells.  Telomere shortening in humans eventually makes cell division impossible, and this aging of the cell population appears to correlate with the overall physical aging of the human body.  This mechanism also appears to prevent genomic instability.  Telomere shortening may also prevent the development of cancer in human aged cells by limiting the number of cell divisions.  However, shortened telomeres impair immune function that might also increase cancer susceptibility.
    41. 41. I) Epidermal growth factor (EGF) II) Fibroblast growth factor (FGF) III) Platelet-derived growth factor (PDGF) IV) Colony stimulating factor (CSF) V) Transforming growth factors-β (TGF-β) VI) Interleukins (IL) VII) Vascular endothelial growth factor (VEGF)
    42. 42. 1) Proto-oncogenes are growth-promoting genes i.e. they encode for cell proliferation pathway. 2) Anti-oncogenes are growth-inhibiting or growth suppressor genes. 3) Apoptosis regulatory genes control the programmed cell death. 4) DNA repair genes are those normal genes which regulate the repair of DNA damage that has occurred during mitosis and also control the damage to proto-oncogenes and antioncogenes. 1) Activation of growth-promoting oncogenes causing transformation of cell (mutant form of normal protooncogene in cancer is termed oncogene). Many of these cancer associated genes, oncogenes, were first discovered in viruses, and hence named as v-onc. Gene products of oncogenes are called oncoproteins. 2) Inactivation of cancer-suppressor genes (i.e. inactivation of anti-oncogenes) permitting the cellular proliferation of transformed cells. Anti-oncogenes are active in recessive form i.e. they are active only if both alleles are damaged. 3) Abnormal apoptosis regulatory genes which may act as oncogenes or anti-oncogenes. Accordingly, these genes may be active in dominant or recessive form. 4) Failure of DNA repair genes and thus inability to repair the DNA damage resulting in mutations.
    43. 43. MOLECULAR CARCINOGENESIS Mutation  the molecular hallmark of cancer Gene Families in Cancer Development 1 - Oncogenes 2 - Tumor Suppressor genes 3 - Mutator genes
    44. 44. + oncogenes Oncogenes  promote cell proliferation  dominant & highly conserved  types: viral oncogenes [v-oncs] cellular oncogenes [c-oncs] Proto-oncogene  “Mutation”  Oncogene
    45. 45. Classification of Oncogenes c-sis, hst erb B, fms, ret, trk, fes, fms c-src, c-abl, mst, ras E. Regulators of the Cell Cycle Components of signal transduction pathways A. Secreted Growth Factors B. Cell Surface Receptors C. Intracellular Transducers D. DNA-binding Nuclear Proteins myc, jun, fos bcl, bax, bad
    46. 46. PROTO-ONCOGENE FUNCTION MUTATION CANCER ABL Nonreceptor tyrosine kinase activity Translocation t(9:22) Chronic myelogenous leukemia (chromosome 22 is Philadelphia chr.) HER (ERBB2) Receptor synthesis Amplification Breast carcinoma (marker of aggressiveness) MYC Nuclear transcription Translocation t(8:14) Burkitt's lymphoma N-MYC Nuclear transcription Amplification Neuroblastoma RAS Guanosine triphosphate signal transduction Point mutation Leukemia; lung, colon, pancreatic carcinomas RET Receptor synthesis Point mulation Multiple endocrine neoplasia lla/llb syndromes SIS’ Growth factor synthesis Overexpression Osteogenic sarcoma, astrocytoma
    47. 47. Mechanisms of Oncogene Activation H-ras GTP Perpetual cell division 1. Point Mutation H-ras [codon 12] Normal CGC  Gly Bladder ca CTC  Val 2. Gene Amplification Double minutes HSRs Normal copy Multiple copies
    48. 48. Mechanisms of Oncogene Activation 3. Gene Translocation Ex. Chronic Myelogenous Leukemia [CML]
    49. 49. Mechanisms of Oncogene Activation 4. Viral Gene Integration promoter Viral promoter
    50. 50. ONCOGENS Categories of oncogenes include growth factors, growth factor receptors, signal transducers, nuclear regulators, and cell cycle regulators Mechanisms of activation of protooncogenes to form growth promoting oncogenes.
    51. 51. Tumor Suppressor Genes  Synonym: anti-oncogenes  Definition: Collective term for genes whose products physiologically inhibit cell proliferation, promote cell differentiation, and also suppress certain steps in tumorogenesis and metastasis.  A. Regulate cell growth and, hence, decrease ("suppress") the risk of tumor formation;  p53 and Rb (retinoblastoma) are classic examples.  B. p53 regulates progression of the cell cycle from G1 to S phase,  1. In response to DNA damage, p53 slows the cell cycle and upregulates DNA repair enzymes.  2. If DNA repair is not possible, p53 induces apoptosis.  a). p53 upregulates BAX, which disrupts Bcl2.  b). Cytochrome c leaks from the mitochondria activating apoptosis,  3. Both copies of the p53 gene must be knocked out for tumor formation (Knudson two-hit hypothesis).  a). Loss is seen in > 50% of cancers.  b). Germline mutation results in Li-Fraumeni syndrome (2nd hit is somatic), characterized by the propensity to develop multiple types of carcinomas and sarcomas.
    52. 52. TUMOR SUPPRESSOR GENE FAMILY Retinoblastoma gene [RB1 gene]  rare form of childhood malignancy  forms: hereditary & sporadic pRb  location: 17p13.1  105-KDa nuclear protein  function: induces DNA repair or apoptosis; inhibits E2F [prevents G1  S transition]  inhibited by: phosphorylation, viral oncoproteins [E1A, E1B, HPV E6, E7]  mutation: point mutation > deletion  results to: loss of function & extended lifespan of p53  Clinical conditions: carcinomas, Li Fraumeni Syndrome
    53. 53. Cell Cycle Regulation ► Process assures that cell accurately duplicates its contents. ► Important checkpoints are present at G1 and G2 and are regulated by protein kinases called cyclins (cdk). ► Checkpoints determine whether the cell proceeds to next phase of the cycle.
    54. 54. The role of p53 in maintaining the integrity of the genome. Activation of normal p53 by DNA-damaging agents or by hypoxia leads to cell-cycle arrest in G1 and induction of DNA repair, by transcriptional up-regulation of the cyclin-dependent kinase inhibitor p21, and the GADD45 genes, respectively. Successful repair of DNA allows cells to proceed with the cell cycle; if DNA repair fails, p53-induced activation of the BAX gene promotes apoptosis. In cells with loss or mutations of p53, DNA damage does not induce cell-cycle arrest or DNA repair, and hence genetically damaged cells proliferate, giving rise eventually to malignant neoplasms.
    55. 55. SOME TUMOR SUPPRESSOR GENES, THEIR FUNCTIONS, AND ASSOCIATED CANCERS GENE FUNCTION ASSOCIATED CANCERS APC (adenomatous polyposis coli) Prevents nuclear transcriplion (degrades catenin, an activator of nuclear transcription) Familial polyposis (colorectal carcinoma) BRCA1/BRCA2 (breast cancer) Regulates DNA repair Breast, ovary, prostate carcinomas RB (retinoblastoma) Inhibits G1 to S phase Relinoblastoma, osteogenic sarcoma, breast carcinoma TGF-β (transforming growth factor-β) Inhibits G1 to S phase Pancreatic and colorectal carcinomas TP53 Inhibits G1 to S phase. Repairs DNA, activates BAX gene (initiates apoptosis) Lung, colon, breast carcinomas. Li- Fraumeni syndrome: breast carcinoma, brain tumors, leukemia, sarcomas VHL (Von Hippel-Lindau ) Regulates nuclear transcription Von Hippel-Lindau syndrome: cerebellar hemangioblasloma, retinal angioma, renal cell carcinoma (bilateral), pheochromocytoma (bilateral) WT1 (Wilms' tumor) Regulates nuclear transcription Wilms' tumor
    56. 56.  Antiapoptosis genes; BcL2 family of genes  Prevent apoptosis in normal cells, but promote apoptosis in mutated cells whose DNA cannot be repaired (e.g., Bcl2)  a. Protein products prevent cytochrome c from leaving mitochondria. • Cytochrome c in the cytosol activates caspases initiating apoptosis. b. Mutation causes increased gene activity (e.g., over expression), which prevents apoptosis; e.g.. B-cell follicular lymphoma.  (1) BcL2 gene family (chromosome 18) produces gene products that prevent mitochondrial leakage of cytochrome c (signal for apoptosis).  (2) Translocation t(14; 18) causes over expression of the BcL2 protein product. • Prevents apoptosis of B lymphocytes causing B-cell follicular lymphoma  Apoptosis genes a. Regulate programmed cell death (ex. BAX apoptosis gene)  (1) Activated by a TP53 suppressor gene product if DNA damage is excessive  (2) BAX protein product inactivates the BcL2 antiapoptosis gene.  (3) Mutation inactivating TP53 suppressor gene renders the BAX gene inoperative, which prevents apoptosis.
    57. 57. Anaplasia The third characteristic feature of tumor cells – is anaplasia, which is cells structural and biochemical organization simplification, coming back to embryonic state. Neoplastic cells lose a capacity for differentiation and can not form the specific tissue complexes. Tumor arises from one mutational maternal cell. However such cells differ from their general ancestor by much parameters. These distinctions consearn the cell structure, its organelles, metabolism, specific properties and functions. Therefore the following kinds of anaplasia are distinguished:  morphological,  biochemical,  physical and chemical,  functional,  immunological.
    58. 58. The essence of morphological anaplasia is in appearance of atypic cultural and tissue.  Description of cultural atypic – lays in:  cellular polymorphism,  nuclear size increase,  polynuclear state,  nuclear hyperchromatosis,  nucleoluses amount increase, mitochondrias changes – quantative size decrease,  crests disappearance Tissue atypism – is sizes and shapes of tissue structures change, sometimes is the total loss of morphological tissue signs. Conjunctival melanoma
    59. 59.  Biochemical anaplasia – is the tumor cells metabolism peculiarities. Its are arose their genetic system changes, enzymic spectrum of such cells gets changed. All cells get alike by enzymic admission (unification of isoenzymic spectrum).  The most typical biochemical feature of neoplastic cells concern proteins and carbohydrates metabolism. Proteins metabolism peculiarities are:  synthesis activation of nucleic acids,  DNA-polymerase inactivation,  increase of proteins synthesis,  decrease of proteins disintegration.  Carbohydrates metabolism and energetic of tumor cells is also differ of norm. The main energy sources in normal cells are anaerobic and aerobic carbohydrates disintegration, that is glycolysis and Krebs cycle. Neoplastic cell also receives the energy owing to glycolysis and Krebs cycle. However glycolysis role in tumor cell is more, than in normal one.  The tumor cells energetic supply include:  anaerobic glycolysis activation,  aerobic glycolysis presence,  oppression of Krebs cycle by powerful glycolytical enzymes system.
    60. 60.  Functional anaplasia displays in loss or perversion of tumor cells function.  For example, in neoplastic thyroid cells a surplus amount of hormones thyroxine and triiodothyronine can be synthesized, thyrotoxicosis arises.  In other cases separate functions of tumor cells fall out, for example, bilirubin does not get conjugated in hepatocyte.  In very malignant neoplastic cells functions are totally lost. Sometimes such cells begin doing the functions, which are not specific for them (bronchus cancer synthesizes the gastrointestinal hormones).
    61. 61.  Immunological anaplasia – is change of tumor cell antigen properties. In such cells antigen admission is changed. Several deviation kinds of antigen out of norm admission are distinguished antigen simplification, antigen divergence and antigen reversion.  Antigen simplification – is the general number of neoplastic cells antigens diminution. For example, the cells of normal tissue synthesize up to 7 typical antigens, while same tissue tumor cells synthesize only 2-3 antigens.  The idea of antigen divergence is in the fact of neoplastic cells starting to synthesize heterologous antigens. For example, hepatoma (liver tumor) begins synthesizing organospecific spleenic antigens, or other organs antigens.  Antigen reversion means neoplastic embryonic antigens synthesis. For example, human liver cancer synthesizes a special embryonic protein, which is a-fetoprotein.
    62. 62. Invasion and Metastasis • The defining characteristic of a malignancy. • Invasion: active translocation of neoplastic cells across tissue barriers. • Critical pathologic point: local invasion and neovascularization. These events may occur before clinical detection.
    63. 63. Metastasis • 1. Benign tumors do not metastasize. • 2. Malignant tumors metastasize. • 3. Pathways of dissemination: • a. Lymphatic spread to lymph nodes (usual mechanism of dissemination of carcinomas) • b. Hematogenous spread: 1) Usual mechanism of dissemination for sarcomas 2) Cells entering the portal vein metastasize to the liver. 3) Cells entering the vena cava metastasize to the lungs.
    64. 64. Metastasing  The final progression stage of any tumor is its transformation into the malignant neoplasm. The major criteria of malignant tumor is its ability to generalisation, that is – to metastasing.  Metastasing includes three stage:  neoplastic invasion into the surrounding tissues,  tumor cells transport with the blood and lymphatic vessles,  their implantation in different organs and tissues.  Separate cells evacuation out of the neoplastic node takes place in case of intercellular contacts relaxation.  Tumor loses calcium, which must turn intercellular spaces cementated in malignisation process. Diminished amount of desmosomes, which create the intercellular contacts arises in pernicious neoplasms. The amount of gangliosides is disranked on the cellular surface of malignant tumor.
    65. 65. ATTRIBUTES OF CANCER Metastasis  Two basic steps: Destruction of the BM Attachment to the laminin of distant BM  Genes up-regulated among good metastasizers: EDGF receptor Basic Fibroblast Growth Factor Type IV Collagenase -Cathepsin (under-expressed) Cathepsin B (a lamininase) Heparanase
    66. 66. STAGING OF CANCER • A. Assessment of size and spread of a cancer • B. Key prognostic factor; more important than grade • C. Determined after final surgical resection of the tumor • D. Utilizes TNM staging system • 1. T—tumor (size and/or depth of invasion) • 2. N—spread to regional lymph nodes; second most important prognostic factor • 3. M—metastasis; single most important prognostic factor
    67. 67. Metastasis: cervical lymph node Lymph node metastasis Tissue destruction: carcinoma of the maxillary sinus Cancer "crater”: liver metastases
    68. 68. ANGIOGENESIS  Formation of new blood vessels from existing vascular bed  Carried out by endothelial cells (EC) and extra cellular matrix (ECM)  Regulated by angiogenic factors (inducers and inhibitors) * A tumor is unable to grow larger than 1 mm3 w/o developing a new blood supply
    69. 69. Components of Angiogenesis 1) ENDOTHELIAL CELLS  Fenestrated  Increased cell adhesion molecules (E-selectin)  Increased integrins αγβ3 essential for viability during growth  Activated ECs release: bFGF PDGF IGF-1
    70. 70. Components of Angiogenesis 2) INDUCERS OF ANGIOGENESIS VEGF – main inducer TGF- β TNF-α low concentration - inducer high concentration - inhibitor PDGF/thymidine phosphorylase TGF-α EGF IL-8
    71. 71. Components of Angiogenesis 3) CELL ADHESION MOLECULES (CAM)  Mediate cell-cell adhesion processes  Selectins  IG Supergene family- ICAM, VCAM  Cadherins  Integrins- vitronectin receptor 4) PROTEASES  Degrade ECM to provide suitable environment for EC migration thru adjacent stroma Ex: Metalloproteinases (MMP)
    72. 72. Components of Angiogenesis 5) ANGIOGENESIS INHIBITORS  Interferon  TSP-1  Angiostatin  Endostatin  Vasostatin CLINICAL SIGNIFICANCE: Tumor angiogenesis switch is triggered as a result of shift in the balance of stimulators to inhibitors
    73. 73. Immune system and neoplastic growth  Tumor cells are heterologous for the organism. They synthesizethe proteins, which are not character for normal cells. Neoplasms product specific swelling antigen. Their specificity is conventional, but it is still sufficient for immune reaction development. A final result depends on immune attack intensity greatly: that means, if the transformed cell is going to reproduct or not; is the tumor going to arise, or not.  Neoplasms are observed in people with congenital immunodeficiency 10000 times more often, than in persons with normal immune system. The malignant neoplasms arise in patients, with transplanted organ (for example, kidney) very often. Immunodepressive drugs are being prescribed with the purpose of transplanted organ rejection prophylaxy in such patients. Tumors in are observed in such cases 100 times more frequent, than in the rest of population.  These facts testify, that the transformed cells underlie the organism immune system supervision. In most people they eliminate in time. A transformed cell exists, reproducts, and produces the neoplasm in a fact of immune supervision insolvency.  Tumor renders an oppressive action upon the organism immune system in its own way. Immunodepression gets developed.  The matters, which render immunodepressive action are produced in neoplastic cells. Low-molecular metabolites (oligopeptides, unsaturated fatty acids), embryonic antigens (a-fetoprotein), glucocorticoids belong to them.  Т-suppressors activity in patients with tumors is increased. They slow down antineoplastic immunity. One more reason of immunodepression in oncologic patients is the disparity between neoplastic growth speed and immune answer development speed. Lymphoid cells reproduct slower, than tumor cells do. Adequate immune answer is late.
    74. 74. Systemic neoplastic action upon the organism Tumor is not locally isolated process. It renders an influence upon the diverse organism functions. This is concerning the malignant neoplasms especially. Their systemic action displays the cancer cachexy. There are a few components of its development. Tumor absorbs the glucose reinforcely. Chronic hypoglycaemia tendency arises. Glycogen disintegrates in liver and muscles reinforcely. Glyconeogenesis gets increased. However, this compensatory mechanism has the negative characteristics. Firstly, glucocorticoids cause the albumens disintegration of immunocompetence organs (thymus, spleen, lymphoid tissue of other organs). Secondly, of big amount of amino acids in glyconeogenesis usage gets the organic albumens synthesis limited. Diverse organs dystrophy develops, muscles – first of all. Neoplastic growth can be described with the intensive synthetic processes. Plastic material (amino acids, nucleic acids) is very important for this. Neoplasm absorbs these matters not only nutritional, but from other organs also. It is named as nitrogen snare. all of other tissues are having amino acid deficiency. They can not synthesize their own proteins in a necessary volume. This is one more link of cancer cachexy pathogens.
    75. 75. Neoplastic Tumors
    76. 76. Tumor Complications  The lesions described below complicate the simple growth of the tumor. The combination of such lesions with tumor expansion and metastasis constitute neoplastic disease that extends beyond the tumor as such. Local Complications  Stenosis: Tumors can lead to several compression syndromes.  — Expansion of the tumor compresses the surrounding tissue (A1) and causes stenosis in hollow organs (A2), compression of the small bowel by a mesenterial liposarcoma; Complications may include difficulties in swallowing, impaired micturition, disruption of intestinal motility, and also increased intracranial pressure.  — Infiltration of the tumor can cause congestion in a hollow organ. Complications may include prestenotic dilation of the duct, stasis and congestion of secretions or excretions, and bacterial infestation of the congested area. 1 A 2 Tumor compression (mesenterial liposarcoma) Budd-Chiari Syndrome
    77. 77. Tumor Complications Circulatory Disruption: Tumor growth that compromises or infiltrates vascular structures produces a variety of lesions. — Obstruction of venous drainage is common and successively leads to varicose changes in the walls of the veins and thrombosis. — Vascular thrombosis may result from vascular stenosis and/or substances produced by the tumor itself that promote coagulation.  — Bleeding due to erosion of vascular structures may lead to spitting of blood from the lungs or bronchi (hemoptysis), vomiting of blood (hematemesis), passage of bloody stools (melena), blood in the urine (hematuria), acyclic bleeding from the uterus (metrorrhagia), and hemorrhagic effusions (B). B Hemorrhagic effusion (lung cancer)
    78. 78. Tumor Necrosis (C): occurs as a result of the interplay of several factors. These include:  — Thrombotic arterial obstruction;  — Vascular compression by the tumor;  — Twisting of the tumor pedicle;  — Cytokines (macrophagic TNF-a);  — Aggressive tumor therapy. Complications of tumor necrosis:  – Ulceration of the inner or outer body surface may occur, primarily in gastrointestinal, skin, and breast cancer (D).  – Perforation of the tumor necrosis may occur into hollow organs or through the surface of the skin (E).  – Fistulas may form that communicate with adjacent organs.  Disruption of Organ Function: occurs especially in tumors that not only mechanically alter the organ parenchyma and its supporting tissue but also destroy them.  Particularly susceptible tissues include:  — Neurovascular structures;  — Urinary tract,  — Intestinal tract;  — Skeletal system, where bone tumors can cause pathologic fractures (F). C D Necrosis: uterine sarcoma Perforation of the cheek: cancer of the tongue E F Bone destruction: Ewing sarcoma Skin ulceration: breast cancer
    79. 79. Systemic Complications Advanced neoplastic disease regularly produces four types of systemic lesions.  Tumor Metastases: occasionally occur even in the early phases of neoplastic disease.  Cancer Cachexia: involves weight loss in cancer patients. Causes include: — Impaired swallowing due to the tumor; — Impaired digestion due to the tumor; — Generation of TNF-a by macrophages stimulated by tumor-associated antigens. — Generation of leptin (fat-cell hormone). This results in loss of appetite (anorexia), reduced intake of nutrients, decreased body fat, and increased energy consumption.  Tumor Anemia: produces the characteristic pale skin of cancer patients. It is due to several factors, including: — Blood loss due to internal bleeding; — Lack of substances that promote maturation of blood cells; — Autoreactive antibodies against erythrocytes; — Displacement of bone marrow by tumorous infiltrates.
    80. 80. Paraneoplastic Syndromes Definition: Collective term for a group of generalized pathologic manifestations that are not attributable to the local effects of a tumor but are linked to the existence of a tumor and can regress after the tumor has been removed. Pathogenesis: Often unclear. — Cell destruction occurs due to formation of autoreactive antibodies against tumor antigens and “self” antigens and as a result of apoptosis caused by certain tumor proteins. — Dysfunction results from synthesis of peptides with endocrine and enzymatic effects. Endocrinopathies General pathogenesis: Tumors synthesize ectopic hormones of substances similar to hormones. The most important forms are as follows: — Cushing’s syndrome is caused by formation of ACTH and occurs in patients with bronchial cancer. — Flush’s syndrome is caused by formation of serotonin and leads to facial erythema, diarrhea, colic, and bronchospasm. It occurs in patients with bronchial or ileal carcinoid. — Schwartz-Bartter’s syndrome is caused by formation of proteins resembling ADH and leads to hyponatremia. It occurs in patients with small cell bronchogenic carcinoma. — Hypercalcemia syndrome is caused by formation of parathormone-like protein. It occurs in patients with squamous cell bronchogenic carcinoma or renal cell carcinomas.
    81. 81. PARANEOPUSTIC SYNDROMES SYNDROME ASSOCIATED CANCER COMMENT Acanthosis nigricans Stomach carcinoma Black, verrucoid-appearing lesion Eaton-Lambert syndrome Small cell carcinoma of lung Myasthenia gravis-like symptoms(e.g., muscle weakness); antibody directed against calcium channel Hypertrophic osteoarthropathy Bronchogenic carcinoma Periosteal reaction of distal phalanx (often associated with clubbing of nail) Nonbacterial thrombotic endocarditis Mucus-secreting pancreatic and colorectal carcinomas Sterile vegetations on mitral valve Seborrheic keratosis Stomach carcinoma Sudden appearance of numerouspigmenled seborrheic keratoses (Lescr-Trdlat sign) Superficial migratory thrombophlebitis Pancreatic carcinoma Release of procoagulants (Trousseau's sign) Nephrotic syndrome Lung, breast, stomach carcinomas Diffuse membranous glomerulopathy
    82. 82. DISORDER ASSOCIATED CANCER ECTOPIC HORMONE Cushing syndrome Small cell carcinoma of lung, medullary carcinoma of thyroid ACTH (adrenocorticotropic hormone) Gynecomastia Choriocarcinoma (testis) hCG (human chorionic gonadotropin) Hypercalcemia Renal cell carcinoma, primary squamous cell carcinoma of lung, breast carcinoma. Malignant lymphomas (contain 1α-hydroxylase) PTH-relaled protein (parathyroid hormone) Calcitriol (vilamin D) Hypocalcemia Medullary carcinoma of thyroid Calcitonin Hypoglycemia Hepatocellular carcinoma Insulin-like factor Hyponatremia Small cell carcinoma of lung Antidiuretic hormone Secondary polycythemia Renal cell and hepatocellular carcinomas Erythropoietin
    83. 83. Nerve and Muscle Syndromes Pathogenesis: Nerve cells and/or muscle fibers are destroyed by autoimmune processes and by tumor-induced apoptosis. The most important forms are as follows: • — Myasthenia gravis occurs in patients with thymus tumors (thymomas). • — Limbic encephalopathy occurs in patients with small cell bronchogenic carcinoma. • — Degeneration of the cerebellar cortex occurs in patients with small cell bronchogenic carcinoma, breast cancer, or ovarian carcinoma. Vascular and Hematologic Changes • — Hemolysis: The tumor synthesizes cytotoxic substances and/or autoreactive antibodies, damaging the bone marrow and leading to hemolytic anemia. This occurs in patients with leukemias or Hodgkin’s • disease’s lymphoma. • — Erythrocyte proliferation: The tumor synthesizes substances that stimulate erythropoiesis (erythropoietin), leading to polyglobulism (an overabundance of erythrocytes). This occurs in patients with renal cell carcinoma. • — Leukocyte proliferation: The tumor synthesizes substances that stimulate myelopoiesis, leading to a leukemoid reaction. This occurs in patients with stomach cancer or large cell bronchogenic carcinoma. • — Macroscopic coagulopathy: The tumor synthesizes thromboplastic substances that lead to thrombosis. This occurs in patients with pancreatic or adenoid carcinomas. • — Disseminated intravascular coagulation: The tumor synthesizes thromboplastic and fibrinolytic substances that consume the clotting factors. This occurs in patients with leukemias. • Note: Coagulopathy is characterized by thrombotic vascular occlusion (primarily in the lung), whereas disseminated intravascular coagulation is characterized by hyalin microthrombi (primarily in the microvasculature of the lung).
    84. 84. Dermatologic Disorders  — Acanthosis nigricans manifests itself as thickening of the skin with clearly discernible papillary lines, hyperpigmentation, and wart-like papillomas. It occurs in patients with stomach cancer or squamous cell bronchogenic carcinoma. (А)  — Bazex’s syndrome (paraneoplastic acrokeratosis) manifests itself as reddish purple plaques of calcification on the hands, feet, nose, and ears. It occurs in patients with carcinoma of the tongue or tonsils. (B)  — Erythema gyratum repens is a rare skin rash resembling zebra stripes that changes daily. It occurs in patients with various carcinomas. (C, D)  — Hypertrichosis lanuginosa is a rare manifestation involving excessive growth of the head and body hair. It occurs in patients with various carcinomas. (Е, F) А B C D F E
    85. 85. 7 warning signs of cancer  C change in bowel or bladder habit  A a sore that doesn’t heal  U unusual bleeding or discharge  T thickening or lump  I indigestion  O obvious change in wart or mole  N nagging cough or hoarseness
    86. 86. Literature  Handbook of general and Clinical Pathophysiology/ Edited by prof.A.V.Kubyshkin, CSMU, 2005. – p. 130-138  Pathophysiology/ Edited by prof.Zaporozan, OSMU, 2005 – p.105-114  General and clinical pathophysiology/ Edited by Anatoliy V. Kubyshkin – Vinnytsia: Nova Knuha Publishers – 2011. p. 166-183  Pathophysiology, N.K. Symeonova. Kyiv, AUS medicine Publishing, 2010, p. 142-160.  General and clinical pathophysiology. Workbook for medical students and practitioners. – Odessa. – 2001.  J.B.Walter I.C.Talbot General pathology. Seventh edition. 1996.  Stephen J. McPhee, William F. Ganong. Pathophysiology of Disease, 5th edition. 2006.  Robbins and Cotran Pathologic Basis of Disease 7th edition / Kumar, Abbas, Fauto 2006.  Pathophysiology, Concepts of Altered Health States, Carol Mattson Porth, Glenn Matfin.- New York, Milwaukee- 2009 p 156-197.
    87. 87. THANK YOU !