Cancer arises from mutations in genes that control cell growth. These include proto-oncogenes, which promote growth, and tumor suppressor genes, which slow growth. Cancer develops in stages - initiation causes DNA damage, promotion involves continued cell division, and progression leads to uncontrolled growth. Cancer cells evade programmed cell death, self-stimulate growth, and invade other tissues. Doctors use tumor markers in blood and tissues to detect and monitor cancer.

1. CHAPTER 2.
2. CANCER BIOLOGY AND GENETICS

2. 2.1. Definition of cancer
 Cancer is a term used to describe a large group of diseasesthat
are characterized by a cellular malfunction.
 Healthy cells are programmed to “know what to do and when to
do it”.
 Cancerous cells do not have this programming and therefore
grow and replicateout of control.
 They also serve no physiological function. These cells are now
termed a neoplasm
 Medically cancer is known Malignant neoplasm.
 It is a broad group of disease involving unregulated cell growth.
 The unregulated cell growth forms a tumor.

3. Celluler Basis Of Cancer
 Cancer arises when multiple control systems within a single
cell are corrupted.
 These are of two basic types:
 systems that promote cell growth (proliferation),and
 safe-guard systems that protect against “irresponsible” cell
growth.
 Controlled cell proliferation is a good thing.
 a lot of proliferation must take place between the time we are
a single fertilized egg and the time we are fullgrown.

4. Cont.,
 All this cell proliferation, must be carefully controlled to
insure that the right amount of proliferation occurs at the
right places in the body and at the right time.
 Usually, the growth-promoting systems within our cells work
just fine
 However, occasionally one of these systems may malfunction,
and a cell may begin to proliferate inappropriately.
 When this happens, that cell has taken the first step toward
becoming a cancer cell.

5. Cont.,
 Because these growth-promoting systems are made up of proteins,
malfunctions occur when gene expression is altered, usually as a
result of a mutation.
 A gene which, when mutated, can cause a cell to proliferate
inappropriately is called a proto-oncogene.
 And the mutated version of such a gene is called an oncogene.
 The important point here is that uncontrolled cell growth can
result when a normal cellular gene is mutated.

6. Cont.,
 To protect against malfunctions in the control systems that
promote cell proliferation, our cells are equipped with
internalsafeguard systems.
 These safeguards are of two general types:
systems that help prevent mutations and
systems that deal with mutations once they occur.
 Cells have a number of different repair systems that can fix
damaged DNA, helping safeguard against mutations.

7. Cont.,
 These DNA repair systems are especially important, because
mutations occur continuously in the DNA of all our cells.
 In fact, it is estimated that, on average, each of our cells
suffers about 25,000 mutational events every day.
 Fortunately, repair systems work nonstop, and if the DNA
damage is relatively small, it can be repaired immediately as
part of the “maintenance” repair program.

8. Cont.,
 Sometimes, however, the maintenance repair systems may miss a
mutation, especially when there are many mutations and the repair
systems are overwhelmed.
 When this happens, a second safeguard system comes into play –
one that monitors unrepaired mutations.
 If the mutations are not extensive, this safeguard system stops the
cell from proliferating to give the repair systems more time to do
their thing.
 However, if the genetic damage is severe, the safeguard system will
trigger the cell to commit suicide, eliminating the possibility that
it will become a cancer cell.

9. Cont.,
 One of the important components of such a safeguard
system is a protein called Nuclear phosphoprotein /p53.
 Proteins like p53, which help safeguard against uncontrolled
cell growth, are called tumor suppressors, and the genes
that encode them are called anti-oncogenes or tumor
suppressor genes.
 Mutations in the gene for p53 have been detected in the
majority of human tumors, and scientists have created mice
with mutant p53 genes.

10. Cont.,
 Every normal cell has both proto-oncogenes and tumor
suppressor genes.
 Where things get dangerous is:
 When proto-oncogenes are mutated, so that the cell proliferates
inappropriately, and
 Tumor suppressor genes are mutated, so that the cell can’t
defend itself against proto-oncogenes “gone wrong.”

11.  Tumor
 Neoplasmic mass often forms a clumping of cells known as a tumor .
 Tumor is a any abnormal proliferation of cell.
 Tumer’s are two types
 Benign tumor (non-cancerous)
 Malignant tumor (cancerous)

12. a) Benign Tumor (Non-cancerous)
 Benign tumors are those tumor, which grow only in one
place.
 They cannot spread or invade other parts of the body.
 Enclosed in fibrous shell or capsule.
 They can be dangerous if they press on vital organs such
as brain.
 It stay confined to its original location.

13. b) Malignant Tumor (Cancerous)
 This type of tumor are capable of invading
surrounding tissue or invading the entire body.
 Invade and emit claw like protrusions that disrupt the
RNA and DNA of normal cells (these cancerous cells
act like a virus).
 Most malignant cells become metastatic.

14. 14
Metastasis

15. 15

16. 2.2. Types and classification of cancer
 Cancers may be classified
1. By their primary site of origin
2. By their histological or tissue types
3. Classification by grade
4. Classification by stage.
1. Classification by site of origin
 By primary site of origin, cancers may be of specific types like
breast cancer, lung cancer, prostate cancer, liver cancer , renal cell
carcinoma (kidney cancer), oral cancer, brain cancer etc.

17. 2. Classification by tissue types
 The international standard for the classification and
nomenclature of histologies is the International Classification of
Diseases for Oncology, Third Edition (ICD-O-3). This
classification is based on the ICD-O-3.
 Based on tissue types cancers may be classified into six major
categories
 Carcinoma
 Sarcoma
 Myeloma
 Leukemia
 Lymphoma
 Mixed types

18. a) Carcinoma
 This type of cancer originates from the epithelial layer of
cells that form the lining of external parts of the body or
the internal linings of organs within the body.
 Carcinomas, malignancies of epithelial tissue, account
for 80 to 90 percent of all cancer cases
 since epithelial tissues are most abundantly found in
the body from being present in the skin to the covering
and lining of organs and internal passageways, such as
the gastrointestinal tract.

19. b) Sarcoma
 It is a type of cancer that arises from transferred cells or
mesanchymal origin
 These cancers originate in connective and supportive tissues
including muscles, bones, cartilage and fat.
 Bone cancer is one of the sarcomas termed osteosarcoma.
 It affects the young most commonly.
 Sarcomas appear like the tissue in which they grow.
 Other examples include chondrosarcoma (of the cartilage),
leiomyosarcoma (smooth muscles), rhabdomyosarcoma (skeletal
muscles), Mesothelial sarcoma or mesothelioma (membranous
lining of body cavities), Fibrosarcoma (fibrous tissue) etc..

20. c) Myeloma
 These originate in the plasma cells of bone marrow.
 Plasma cells are capable of producing various antibodies in
response to infections.
 Myelomais a type of blood cancer.
d) Leukemia
 This a group of cancers that are grouped within bloodcancers.
 These cancers affect the bone marrowwhich is the site for blood
cell production.
 When cancerous, the bone marrow begins to produce excessive
immature white blood cells that fail to performtheir usual actions
and the patient is often prone to infection.

22. e) Lymphoma
 These are cancers of the lymphatic system.
 Lymphomas may be of two types
 Hodgkin’s lymphoma and Non-Hodgkin’s lymphomas.
 In Hodgkin lymphoma there is characteristic presence of Reed-
Sternberg cells in the tissue samples which are not present in Non-
Hodgkin lymphoma.
f) Mixed types
 These have two or more components of the cancer.
 Some of the examples are:
 mixedmesodermal tumor
 Carcinosarcoma
 adenosquamous carcinoma and
 teratocarcinoma.

23. 2.3. Phases of Carcinogenesis
 Carcinogenesis or oncogenesis or tumorigenesis means
mechanismof induction of tumours (pathogenesis of cancer)
 Agents which can induce tumours are called carcinogens
(etiology of cancer).
 Cell division-physiologic process –occurs in almost all cells
 Homeostasis-balance b/w proliferating and programmed cell
death-tightly regulated processes
 Mutations in DNA –disrupt the programming of regulation of
the process

25. 7
1. Latent period
 Usually lapse up to 20 years or more, between the initiating
insult and the appearance of a clinically detectable tumor.
 During the latent period cellular proliferation occurs, limited by
host defenses and/or lack of access to the host’s blood supply.
2. Initiation stage
 Can occur after a single exposure to chemical or physical
carcinogen
 Involves genetic mutation
 Appears irreversible
 Is heritable within the cell population because the initiated cell
conveys the malignant alteration to its daughter cells.

26. 3. Promotion Stage
 It is a slow and gradual process; usually takes years
 Requires a more prolonged exposure to carcinogenic agent.
 It is partially irreversible
 can be arrested by certain anti-carcinogenic agents
4. Progression Stage
 Requires continuous clonal proliferation of altered cells, during
which a loss of growthcontrol and an escape from host defense
mechanisms become prominent phenotypic traits.
 Allows progressive growthto clinically detectable tumor.
 It is irreversible due to pronounced changes in the genome.

27.  The progression stage of carcinogenesis is an extension of the
tumor promotion stage, and results from it in the sense that the
cell proliferation caused by promoting agents allows the cellular
damage inflicted by initiation to be propagated, and the
initiated cells are clonally expanded.

28. 2.4. Causes of cancer: Exogenous carcinogens and
Endogenous carcinogens
1. Mutations and cancer
 Cancer development is based on the accumulation of somaticmutations over
lifetime.
 Germline mutations are typically not involved, but in very rare cases of
inherited cancer predisposition, they are contributing to disease progression.
 Typically the basal mutation rate is low in humans, but it may be enhanced
through one of the three following groups of environmental carcinogens:
chemical mutagens, radiation and tumor viruses.
 Exposure to mutagens or radiationgreatlyincreases the mutation rate and
thus the probability of developing cancer.

29.  Chemical mutagens
 comprise a quite disparate group of chemicals that
modify DNA through a range of mechanisms, such as
alkylation or deamination of DNA bases, or through
intercalation between base pairs and formation of DNA
adducts (e.g. aromatic hydrocarbons).
 Oxidative damage may also affect DNA integrity.
 X-rays andradioactive radiation
 tend to induce DNA double-strand breaks, whereas UV
radiation results in the formation of pyrimidine dimers,
by cross-linking of adjacent pyrimidine bases.

30.  Viral causes of cancer
 Certain viruses, derived from quite different taxonomic groups are
able to induce cancer development.
 We distinguish the highly oncogenic viruses, which contain viral
oncogenes in their genomes that are in most cases derived from
cellular proto-oncogenes, whereas slowlytransforming viruses do
not contain such genes.
 They tend to use one of the following mechanisms to stimulate
proliferation of their host cells:
 Insertion of a strong promoter in the vicinity of a host cell proto-oncogene
 Expression of proteins that neutralise host cell tumour suppressor proteins
 Expression of proteins that prevent or delay apoptosis

31.  Characteristics of viral carcinogenesis include:
 Tumour viruses often establish persistent infections in the human host
 Host factors are important determinants of virus-induced
carcinogenesis
 Viruses are rarely complete carcinogens; they require additional factors
to fully activate carcinogenesis.

33. 2.5. Oncogenes and Cancer Induction
 Oncogenes
 The genes involved in the development of cancer.
 Normal cells do contain DNA sequence similar to viral oncogenes.
 To distinguish these two genes: Viral gene (V-src) and Cellular gene (C-src).
 Protooncogenes
 Normal constituents of cells whose function is to promote proliferation or cell survival.
 These genes can code for growthfactors, growthfactor receptors, signal
transduction proteins, intracellular kinases and transcriptionfactors.
 Tumor suppressor genes(normal growthsuppressor genes)
 Encode proteins that slow proliferation, promote cell death or repair DNA.

34.  Protooncogenes
 Protooncogenes are regulatory genes.
 Products of many protooncogenes are polypeptide growth
factors.
 e.g.- sis gene produce PDGF- normal wound healing.
 Product act as receptor for growth factor.
 e.g.- erb-B produces receptor for EGF.
 Protooncogenes are under the control of regulatory genes and
expressed only when required.
 When virus enters, an extra oncogene is inserted so as to produce
continuous expression of gene leading to uncontrolledcellular
activity & malignant transformation.

35. 35

36.  Factors Affecting Protooncogenes
 Tumor Virus
 Chemical carcinogens
 Chromosomal translocation
 Radiations
 Spontaneous mutation
 Because neoplasia is a multistep process, more than one of these
mechanisms often contribute to the genesis of human tumors by
alteringa numberof cancer-associated genes.
 Full expression of the neoplastic phenotype, including the capacity for
metastasis, usually involves a combination of protooncogene activation
and inactivation of tumor suppressor gene.
All such factors may converge
into one biochemical
abnormalities “Activation of
protooncogenes” leading to
malignancy

37. 37
 Mechanisms Of Activation
 5 mechanisms of activation
 Promoter insertion
 Enhancer insertion
 Chromosomal translocation
 Gene amplification
 Pointmutations

39. 2.6 Characteristic andproperties of cancers and cancer cells
 Characteristics of a Cancer Cell
1. Self-sufficiency in growth signals: cancer cells acquire an
autonomous drive to proliferate - pathological mitosis -
by virtue of the activation of oncogenes such as ras or myc.
2. Insensitivity to growth-inhibitory (antigrowth) signals: cancer cells
inactivate tumor suppressor genes, such as Rb,
that normally inhibit growth.
3. Evasion of programmed cell death (apoptosis): cancer cells
suppress and inactivate genes and pathways that
normally enable cells to die.

40. 4. Limitless replication potential: cancer cells activate specific gene
pathways that render them immortal even after generations of
growth.
5. Sustained angiogenesis: cancer cells acquire the capacity to draw
out their own supplyof blood and blood vessels - tumor
angiogenesis.
6. Tissue invasion and metastasis: cancer cells acquire the capacity
to migrate to other organs, invade other tissues, and colonize
these organs, resulting in their spread throughout the body.

42.  Properties Of Cancer Cells:
 It shows uncontrolled mitoticdivisions
 Due to uncontrolled growth – tumor is formed
 They are less adhesive than normal cells
 They exhibits number of alterations
 Lack differentiation
 They loss ability to communicate with other cells

43. Tumor Markers
 Cancer can be detected and monitored using biologic tumor
markers.
 Tumor markersare produced either directly by the tumor or
as an effect of the tumor on healthy tissue (host).
 Tumor markers encompass an array of diverse molecules
such as:
Serum proteins Metabolites
 Enzymes Oncofetal antigens
 Receptors Hormones

44. Applications of Tumor Marker Detection
 Ideally, a tumor marker would be:
1. Tumor specific
2. Absent in healthy individuals
3. Readily detectable in body fluids.
 Unfortunately, all of the presently available tumor markers do not
fit this ideal model.
 However, a host of tumor markers have been identified that have
a high enough specificity & sensitivity to be used in:
1. screening populations at risk & diagnosis
2. Prognosis
3. Detection of recurrence & monitoring response to treatment.

45. Sensitivity and Specificity
 Ideal tumor marker for screening asymptomatic population should be:
100%sensitive: Always positive in patients with the disease
100%specific: Always negative in individuals who do not have the disease
Example
 If a test gives positive results in 199 patients out of 200 patients: its
sensitivity is 99.5%
 If a test gives negative results in 90 normal individuals out of 100 normal
individuals: its specificity is 90%

46. 1- Screening & diagnosis
 With the possible exception of Prostate-Specific Antigen (PSA), no tumor
marker identified to date can be used to adequately screen asymptomatic
populations
 because most of the clinically used tumor markers are found in normal
cells and benign conditions in addition to cancer cells.
 Screening asymptomatic populations would therefore result in detection
of false-positives-(patients without disease with detectable tumor
marker), leading to undue alarm and cost to patients.

47. 2- Prognosis
 Tumor marker concentration generally increases with tumor progression,
reaching their highest levels when tumors metastasize.
 Therefore, serum tumor marker levels at diagnosis can reflect the
aggressiveness of a tumor and helppredict the outcome for patients.
 High serum tumor markers at diagnosis might indicate the presence of
malignancyand possible metastasis associated with a poorer prognosis.

48. 3- MonitoringEffectiveness of Therapy and Disease Recurrence
 One of the most useful applications of tumor markers is monitoring
therapy efficacy and detecting disease recurrence.
 After surgical resection, radiation, or drug therapy of cancer
(chemotherapy), tumor markers are routinely followed serially.
 In patients with elevated tumor markers at diagnosis, effective therapy
results in a dramatic decrease or disappearance of the tumor marker.
 If the initial treatment is effective, the appearance of circulating tumor
markers can then be used as a highly sensitive marker ofrecurrence.

49. Common Tumor Markers
Alphafetoprotein(-FP)
– Oncofetal antigen
– abundant serum protein normally synthesized by the fetal liver
– Re-expressed in certain types of tumors
 Clinical Applications:
 Diagnosis, prognosis, and treatment monitoring of hepatocellular carcinoma (HCC; hepatoma)
 Screening (High-risk; HBV or HCV patients)
 AFP is not completely specific for HCC
 AFP might be increased in pregnancy & benign liver disease

50. • A tumor marker for classification and monitoring therapy for
nonseminomatous testicular cancer “in combination with -human
chorionicgonadotropin (-hCG)”
Testicular cancer

51. Cancer Antigen 125 (CA-125)
 Detection of ovarian tumors at an early stage
 CA-125 is not specific for ovarian cancer, as it may be
elevated in:
 Menstruation
 First trimester of pregnancy
 Endometriosis
 Currently, CA-125 is the only clinically accepted serologic
marker of ovarian cancer

53. Carcinoembryonic Antigen (CEA)
 CEA is an oncofetal antigen
 It is expressed during development and then re-expressed in tumors
 It is the most widely used tumor marker for colorectal cancer
Clinical Applications:
 The main clinical use of CEA is as a tumor marker for colorectal cancer
 In colon cancer, CEA is used for prognosis, in postsurgery surveillance
and to monitor response to chemotherapy

54. colorectal cancer

55. Prostate Specific Antigen (PSA)
 PSA is a glycoprotein produced by the epithelial cells of the acini
and ducts of the prostatic ducts in the prostate
 PSA is a serine protease
ElevatedPSA can be found also in:
 Prostate infection
 Pelvic congestion
 Benign prostatic hyperplasia (enlargement)

56. Prostate cancer

57. Human epidermal growth factor receptor 2 (HER-2)
Encodes an Epidermal Growth Factor Receptor (EGF-R)
A proto-oncogene that is converted to oncogene by:
 Mutation(especially pointmutation) or
 Altered(over) expression
Marker for breast and ovarian cancers
It is now routinely measured in breast cancerto determine the type
of therapy:
 Breast cancer positive for HER-2/NEUis responsive to treatment
(Herceptin)

59. 1.7 Diagnosis and Treatment of cancer
 Diagnosis of cancer
• The presenting signs and symptoms of cancer vary widely and
depend on the type of cancer.
• The presentation in adults may include any of cancer's warning
signs as well as pain or loss of appetite.
• The definitive diagnosis of cancer relies on a sample of the tissue
or cells suspected of malignancy and pathologic assessment

60. Cont.,
 Mainmethods of cancer diagnosis
1. Radiological diagnosis
2. Cytological diagnosis
3. Histological diagnosis
4. Frozen section
5. Heamatological diagnosis
6. Immunohistochemistry
7. Molecular diagnosis
8. Tumour markers

61. Staging and workup
 Tumors should be staged to determine the extent of disease before
any definitive treatment is initiated.
 Staging provides information on prognosis and guides treatment
selection.
 After treatment, the staging is usually repeated to evaluate the
effectiveness.
 Some cancers produce tumor markers

62. Goals of cancer treatment
1- Primary goal
 Cure the patient
 Render him clinically and pathologically free of disease and return their
life expectancy to that of healthy individuals of the same age and sex.
 Current therapies do not offer cures for all patients
2- Thebest alternativegoal
 To prolong survival while maintaining the patient's functional status and
quality of life.
3- The3rd goal
 Relive symptoms such as pain for patients in whom the likehood of cure
or prolonged survival is very low

63.  Treatment of cancer
1. Surgery
 It is used for both diagnosis and therapy.
 Surgical removal of cancer is the oldest and most classical method
of treatment.
 Curativesurgery is performed on a primary neoplastic lesion,
whether it is benign or malignant.
 If metastatic lesion are present, surgery may be carried out to
remove the tumor(s)in order to reduce the amount of cancer in
body, this if surgery is followed by other modification (radiotherapy
and chemotherapy).
 It is also carried out in order to remove the bulksof tumorsthat
may obstruct or press on vital organs and passages.

64. 2. Radiotherapy
 It is very effective whether used after surgery or alone with
chemotherapy.
 Different types of radiation are used.
 Their mechanism depends on damaging the dividing cells, but it
also affects normal tissue.
 Malignant lymphomas, leukemias and most carcinomas are
relatively sensitive to radiation.
 Sarcomas are more resistant.

65. 3. Immunotherapy
 It depends on the stimulation of the host’s own immune defense
or, the treatment of the host with antibodies specific for the
tumor, especially after treatment with drugs.
4. Hormone therapy
 It depends on:
a) lowering the plasma hormones,
b) blocking the action of circulating hormones through blocking
certain receptors (e.g. tamoxifen) and
c) additive hormone therapies (used mainly in breast cancers).

66. 5. Chemotherapy
 Once metastasis occurs, surgical and most probably radiation
therapy are not curative.
 Although complete cure is difficult in this stage, chemotherapy, is
used for increasing the useful life-time of many patients.
 There are some cancers in advanced stages that respond well to
chemotherapy
 e.g. acute lymphocytic leukemia, Hodgkin’s disease (a
lymphoma), Burkitt’s lymphoma, Ewing’s sarcoma of bone, and
Wilm’s tumer of the kidney.
 All these tumors are characterized by rapid growth.

67.  Successive chemotherapy is related to the growth fraction of the
tumor, that is, the percentage of cells undergoing cell division at
any one time.
 Rapidly growing cancers have large growth fractions; therefore,
the drugs affect greater proportion of the cell population.
 The search for and development of new drugs is very difficult
and takes a long time.
 A drug goes through several stages such as;
 selection of the compound
 screening its effectiveness in animals
 study how the body handles it, and
 finally trials on patients.

68. 6. Combination chemotherapy
 Is used to improve the results of treating cancer patients.
 Each drug is chosen for its ability to attack cells at a certain point in their
life cycle.
 When properly combined, several drugs (2-6) may be more effective in
treating a particular cancer than 1single drug.
7. Adjuvant chemotherapy
 Doctors sometimes use chemotherapy as a precautionary measure when
they are uncertain if a cancer has spread.
 This use of drugs is called ‘adjuvant chemotherapy’.
 The drugs are intended to destroy cancerous cells that may be alive but
undetected, in the body.
 Adjuvant chemotherapy is commonly used when cancer has been
discovered in several lymph nodes.