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&apos;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&apos;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 tumors. – 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: monoazobenzene, benzidine, 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 &apos;being Taiwanese&apos;, 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&apos;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&apos;s &apos;green gold&apos;. 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 &apos;betel nut&apos;. 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 &apos;high&apos; 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 &apos;green gold&apos; 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 &apos;nearly 100 billion NT dollars&apos;, 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. Promotion 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&quot;. 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 &gt; thyroid ca &gt; 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&apos;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 genes. — 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.
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.
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
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
From data of Committee of cancer prophylaxis 90%
tumors are related to influencing of external factors,
and 10% - depend on genetic factors.
“new growth” & new
growth is called
Neoplasia is new tissue growth that is:
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]
• Oncology (Greek oncos = tumor) is the
study of tumors or neoplasms.
• Cancer is the common term for all
• 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."
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
• 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
• There is evidence that the ancient Egyptians were
able to tell the difference between malignant and
• In ancient Egypt, it was believed cancer was
caused by the Gods.
The History of Cancer, Lisa Fayed, About.com July,2008
Ebers Papyrus treatment
for cancer: recounting a
"tumor against the god
Xenus", it recommends
"do nothing there against"
depicted in a Ptolemaic
period inscription on
the Temple of Kom
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.
of a certain
another type of
tissue at a
it does not
occur, either in
a heterotopia or
as a result of
All tumors, benign as well as
malignant, have 2 basic components:
proliferating tumor cells;
determines the nature
and evolution of the
composed of fibrous
and blood vessels; it
provides the framework
on which the
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
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 =
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.
"Knapsack” tumor: lipoma
metastatic sarcoma of the uterus
CANCER CELLS AND NORMAL
CANCER CELLS NORMAL CELLS
Loss of contact inhibition
Increase in growth factor secretion
Increase in oncogene expression
Loss of tumor suppressor genes
Oncogene expression is rare
Intermittent or co-ordinated
growth factor secretion
Presence of tumor suppressor
Characteristics of Benign and Malignant Neoplasms
Characteristics Benign Malignant
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
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
Usually is a localized phenomenon that
does not cause generalized effects
unless its location interferes with vital
Often causes generalized effects such as
anemia, weakness, and weight loss
Usually does not cause tissue damage
unless its location interferes with blood
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
Usually does not cause death unless its
location interferes with vital functions
Usually causes death unless growth can be
Principal Pathways of
2. Cell-Cycle Progression
3. DNA Repair
7. Metastasis and Invasion
1. Age > 55 years - more than 75% of cancers.
1)External factors: tobacco,
2) Internal factors: hormones,
immune conditions, inheriled
a. Greatest risk for cancer
deaths of any other racial
group or ethnicity
b. Applies to almost all
4. Hispanics and Asians
Lower incidence rates for all
cancers combined than
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
due to kidney cancer
than all racial and
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
Cancer Geography 1. Worldwide
• Malignant melanoma is
increasing at the most rapid
rate of all cancers.
carcinoma secondary to
Epstein-Barr virus (EBV)
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
• Burkitt's lymphoma due to EBV and
Kaposi's sarcoma due t0 human
herpes virus 8.
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.
Three Main Categories:
I. Chemical Carcinogens
II. Physical Carcinogens
III. Viral Agents
Carcinogens Mutations Cancer
• Occupation related causes
• Lifestyle related causes
– Sexual practices
• Multifactorial causes
• Chemical carcinogens
• Ionizing radiation
• Viral carcinogens
A. Alkylating agents
• Anti-cancer drugs: cyclophosphamide
(transitional cell carcinoma of urinary bladder),
chlorambucil, busulfan, melphalan,
B. Acylating agents:
• Acetyl imidazole
• Dimethyl carbamyl chloride
saccharine & cyclamates
Estrogen (endometrial carcinoma.
Adenocarcinoma of the vagina is seen with
increased frequency in adolescent daughters of
mothers who had received estrogen therapy
Anabolic steroids (↑ the risk of
developing benign and malignant tumors of the
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
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-)
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
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)
This lady chews betel nuts the fruit of a palm
Initiation - primary exposure
Promotion - transformation
Progression - Cancer growth
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
initiated cells are exposed to promoters
promoters are not carcinogens !
properties of promoters reversible
1). Ionizing radiation-induced cancers
• Hydroxyl free radical injury to DNA
(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
• Formation of pyrimidine dimers, which distort DNA
b. Basal cell carcinoma, squamous cell carcinoma,
2. Physical injury
1). Squamous cell carcinoma may develop in third-degree
2). Squamous cell carcinoma may develop at the
orifices of chronically draining;
sinuses (e.g., chronic osteomyelitis),
UV-A = 320 - 400 nm
UV-B = 280 - 320 nm
UV-C = 200 - 280 nm
UV-C filtered by ozone
Inhibition of cell division
inactivation of enzymes
induction of mutations cell
death at high doses
Squamous cell cancer
Basal cell cancer
Virus MECHANISM ASSOCIATED CANCER
HCV Produces postnecrotic cirrhosis Hepatocellular carcinoma
Activates TAX gene, stimulates
polyclonal T-cell proliferation,
inhibits TP53 suppressor gene
T-cell leukemia and lymphoma
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,
HBV (hepatitis B
inactivates TP53 suppressor gene
Acts via cytokines released from
HIV and HSV Kaposi's sarcoma in AIDS
HPV types 16
and 18, 31, 33
Type 16 (-50% of cancers); E6 gene
product inhibits; TP53 suppressor
Type 18 (-10% of cancers); E7 gene
product inhibits; RB suppressor
Squamous cell carcinoma of vulva,
vagina, cervix, anus (associated
with anal intercourse), larynx,
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.
Lifestyle Risk Factors
Penetration of the vena cava:
Diet-Related Risk Factors
Low vitamins A, C, E
Low consumption of
High fried foods
Carcinoma of the prostate
Mycotoxins Liver Cancer
Oral Cavity Cancer
Tobacco + Asbestos
Tobacco + mining
Tobacco + uranium +
Tobacco + Alcohol
CHARACTERISTICS OF CANCER
CHARACTERISTICS OF CANCER
Clonality can be determined by glucose-6-
phosphate dehydrogenase (G6PD) enzyme
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
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.
CHARACTERISTICS OF CANCER
• Cancer cells are able to proliferate despite
• Unrestricted proliferation results in tumor
– Growth factor secretion
– Increased number of cell receptors
– Independent activation of key biochemical process
• Proliferation depends on the cell cycle.
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
After 35 doublings,
the mass contains
more than 1 trillion
(10*12) cells, which
is a sufficient
number to kill the
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
1) Proto-oncogenes are growth-promoting genes i.e. they encode for cell proliferation
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
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
the molecular hallmark of cancer
Gene Families in Cancer Development
1 - Oncogenes
2 - Tumor Suppressor genes
3 - Mutator genes
Classification of Oncogenes
erb B, fms, ret, trk, fes, fms
c-src, c-abl, mst, ras
E. Regulators of the Cell Cycle
A. Secreted Growth Factors
B. Cell Surface Receptors
C. Intracellular Transducers
D. DNA-binding Nuclear Proteins
myc, jun, fos
bcl, bax, bad
FUNCTION MUTATION CANCER
22 is Philadelphia chr.)
HER (ERBB2) Receptor synthesis Amplification
MYC Nuclear transcription Translocation t(8:14) Burkitt's lymphoma
N-MYC Nuclear transcription Amplification Neuroblastoma
Leukemia; lung, colon,
RET Receptor synthesis Point mulation
Mechanisms of Oncogene Activation
Perpetual cell division
1. Point Mutation
H-ras [codon 12]
Normal CGC Gly
Bladder ca CTC Val
2. Gene Amplification
Normal copy Multiple copies
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.
Tumor Suppressor Genes
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
TUMOR SUPPRESSOR GENE FAMILY
Retinoblastoma gene [RB1 gene]
rare form of childhood malignancy
forms: hereditary & sporadic
105-KDa nuclear protein
function: induces DNA repair or apoptosis; inhibits E2F [prevents G1 S
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
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.
The role of p53 in
maintaining the integrity of
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,
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
SOME TUMOR SUPPRESSOR GENES, THEIR
FUNCTIONS, AND ASSOCIATED CANCERS
GENE FUNCTION ASSOCIATED CANCERS
Prevents nuclear transcriplion
(degrades catenin, an activator of
Familial polyposis (colorectal carcinoma)
Regulates DNA repair Breast, ovary, prostate carcinomas
Inhibits G1 to S phase
Relinoblastoma, osteogenic sarcoma, breast
Inhibits G1 to S phase Pancreatic and colorectal carcinomas
Inhibits G1 to S phase. Repairs
DNA, activates BAX gene (initiates
Lung, colon, breast carcinomas. Li-
Fraumeni syndrome: breast carcinoma,
brain tumors, leukemia, sarcomas
Regulates nuclear transcription
Von Hippel-Lindau syndrome: cerebellar
hemangioblasloma, retinal angioma, renal
cell carcinoma (bilateral),
Regulates nuclear transcription Wilms' tumor
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
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.
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
physical and chemical,
The essence of morphological anaplasia is in
appearance of atypic cultural and tissue.
Description of cultural atypic – lays in:
nuclear size increase,
nucleoluses amount increase,
mitochondrias changes –
quantative size decrease,
Tissue atypism – is sizes and shapes of tissue
structures change, sometimes is the total loss
of morphological tissue signs.
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
synthesis activation of nucleic acids,
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.
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
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
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
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
Antigen reversion means neoplastic embryonic antigens
synthesis. For example, human liver cancer synthesizes a
special embryonic protein, which is a-fetoprotein.
Invasion and Metastasis
• The defining
characteristic of a
• Invasion: active
neoplastic cells across
• Critical pathologic point:
local invasion and
These events may occur
before clinical detection.
• 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
3) Cells entering the vena cava metastasize to the
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
tumor cells transport with the blood and
their implantation in different organs
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.
Two basic steps:
Destruction of the BM
Attachment to the laminin of distant BM
Genes up-regulated among good metastasizers:
Basic Fibroblast Growth Factor
Type IV Collagenase
Cathepsin B (a lamininase)
STAGING OF CANCER
• A. Assessment of size and spread of a cancer
• B. Key prognostic factor; more important than
• C. Determined after final surgical resection of
• 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
Metastasis: cervical lymph node
Lymph node metastasis
carcinoma of the maxillary sinus
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
5) ANGIOGENESIS INHIBITORS
Tumor angiogenesis switch is triggered as
a result of shift in the balance of
stimulators to inhibitors
Immune system and
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.
Systemic neoplastic action upon
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
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.
Stenosis: Tumors can lead to several
— 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
— 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.
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
— 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).
Hemorrhagic effusion (lung cancer)
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
– 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
Disruption of Organ Function: occurs especially in
tumors that not only mechanically alter the organ
parenchyma and its supporting tissue but also destroy
Particularly susceptible tissues include:
— Neurovascular structures;
— Urinary tract,
— Intestinal tract;
— Skeletal system, where bone
tumors can cause pathologic
Necrosis: uterine sarcoma
Perforation of the cheek:
cancer of the tongue
Advanced neoplastic disease regularly produces four types of systemic
Tumor Metastases: occasionally occur even in the early phases of
Cancer Cachexia: involves weight loss in cancer patients. Causes
— Impaired swallowing due to the tumor;
— Impaired digestion due to the tumor;
— Generation of TNF-a by macrophages stimulated by tumor-associated
— 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.
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
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
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.
SYNDROME ASSOCIATED CANCER COMMENT
Acanthosis nigricans Stomach carcinoma Black, verrucoid-appearing lesion
Small cell carcinoma of
symptoms(e.g., muscle weakness);
antibody directed against calcium
Periosteal reaction of distal phalanx
(often associated with clubbing of
and colorectal carcinomas
Sterile vegetations on mitral valve
Seborrheic keratosis Stomach carcinoma
Sudden appearance of
keratoses (Lescr-Trdlat sign)
Release of procoagulants
Lung, breast, stomach
DISORDER ASSOCIATED CANCER ECTOPIC HORMONE
Small cell carcinoma of lung,
medullary carcinoma of thyroid
Gynecomastia Choriocarcinoma (testis)
hCG (human chorionic
Renal cell carcinoma, primary
squamous cell carcinoma of lung,
breast carcinoma. Malignant
lymphomas (contain 1α-hydroxylase)
Calcitriol (vilamin D)
Hypocalcemia Medullary carcinoma of thyroid Calcitonin
Hypoglycemia Hepatocellular carcinoma Insulin-like factor
Hyponatremia Small cell carcinoma of lung Antidiuretic hormone
Renal cell and hepatocellular
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
• — 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
• 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).
— 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
— 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)
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
O obvious change in wart or mole
N nagging cough or hoarseness
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