Carcinogenesis is a multistep process involving genetic mutations that cause cells to proliferate uncontrollably. There are four classes of regulatory genes involved: 1) growth promoters like proto-oncogenes that become activated oncogenes, 2) inhibitors like tumor suppressor genes, 3) genes regulating apoptosis, and 4) DNA repair genes. Genetic damage occurs through environmental and spontaneous mutations and fails to be repaired if the DNA damage response is defective. This can result in oncogene activation and tumor suppressor inactivation, leading to autonomous growth, evasion of growth inhibition, apoptosis resistance, limitless replication through telomerase expression, angiogenesis, invasion and metastasis. Cancer progression involves the accumulation of additional mutations that

1. Neoplasia-5
Carcinogenesis-
A Multistep process-
Hallmark of Cancer
Dr. Roopam Jain
Professor & Head, Pathology

2. Neoplasia Outline
 Tumor nomenclature
 Tumor characteristics
 Epidemiology
 Cancer pathogenesis
•Overview
•Genes
•Steps
•Chromosomes

3. Molecular Basis of Neoplasia:
Proto-oncogene
Oncogene

4. Gatekeepers and Caretakers
“Gatekeepers”
are the genes that directly
control cell birth and cell death.

5. Tumor growth kinetics is different
for gatekeepers and caretakers
Gatekeeper genes
is altered through mutation,
Oncogenes & tumor suppressor genes directly control
tumor growth. Regulate entry of cell into tumorigenic path
Caretaker genes
that do not directly control tumor growth but affect genomic
instability - DNA repair genes
Increased mutations of all genes
and the process of tumorigenesis is accelerated.

6. Molecular Basis of Carcinogenesis
 Four classes of regulatory genes.
1. Growth Promoters – Proto-oncogenes
2. Inhibitors – Cancer-suppressor genes
3. Genes regulating Apoptosis.
4. DNA repair genes.

7. Non-lethal Genetic damage lies at
the center of carcinogenesis.
 Loss/damage to suppressor genes,
 Duplication of promoter genes
 Loss/damage to Apoptosis genes
 Loss/damage of DNA repair genes.

8. Genes
Autonomous growth
Insensitivity to growth-inhibitory signals
Evasion of apoptosis
Limitless replication
Sustained angiogenesis
Invasion and metastasis
“Cancer genes” cause bad things in cells:

9. MOLECULAR BASIS OF
CANCER
Theories of Cancer

10.  1. Monoclonality of tumours
 2. Field theory of cancer
 3. Multi-step process of cancer growth and
progression
 4. Genetic theory of cancer
 5. Genetic regulators of normal and abnormal mitosis
 Four classes of regulatory genes.
1. Growth Promoters – Proto-oncogenes
2. Anti-Oncogenes – Cancer-suppressor genes
3. Genes regulating Apoptosis.
4. DNA repair genes.

11. Non-lethal, Genetic damage lies at the
center of carcinogenesis.
 i) Inactivation of cancer-suppressor genes (i.e.
inactivation of anti-oncogenes)
Loss/damage to suppressor genes,
 ii) Activation of growth-promoting oncogenes
(Duplication of promoter genes)
 iii) Abnormal apoptosis regulatory genes
(Loss/damage to Apoptosis genes)
 iv) Failure of DNA repair genes
(Loss/damage of DNA repair genes)

12. Basic concept of carcinogenesis at
molecular level

13. Basic concept of carcinogenesis at
molecular level

14. Major properties
of cancer in
terms of
molecular
carcinogenesis.

15. Genetic basis of cancer includes
major genetic properties
 1. Excessive and autonomous growth:
Activation of Growth-promoting oncogenes.
 2. Refractoriness to growth inhibition:
Inactivation of anti-oncogenes.
 3. Escaping cell death by apoptosis:
Abnormal apoptosis regulatory genes.
 4. Avoiding cellular ageing: Telomeres and
telomerase in cancer.
 5. Continued perfusion of cancer: Cancer
angiogenesis

16.  6. Invasion and distant metastasis: Cancer
dissemination.
 7. DNA damage and repair system: failure of
DNA repair genes, Mutator genes and cancer.
 8. Cancer progression and tumour
heterogeneity: Clonal aggressiveness.
 9. Cancer a sequential multistep molecular
phenomenon: Multistep theory.

17. Neoplasia Outline
 Tumor nomenclature
 Tumor characteristics
 Epidemiology
Cancer pathogenesis
•Overview
•Genes
•Steps
•Chromosomes

19. CANCER-RELATED GENES
AND CELL GROWTH
(HALLMARKS OF CANCER)

20. Genes
Autonomous growth
Insensitivity to growth-inhibitory signals
Evasion of apoptosis
Limitless replication
Sustained angiogenesis
Invasion and metastasis
“Cancer genes” cause bad things in cells:

21. Genes
Autonomous growth
Insensitivity to growth-inhibitory signals
Evasion of apoptosis
Limitless replication
Sustained angiogenesis
“Cancer genes” cause bad things in cells:

22. 1. Excessive and Autonomous Growth:
Growth Promoting Oncogenes
 Transformation of proto-oncogene (i.e. normal cell
proliferation gene) to oncogenes (i.e. cancer cell
proliferation gene) may occur by three mechanisms:
 i) Point mutations (RAS oncogene
 ii) Chromosomal translocations (Philadelphia
chromosome, translocation of c-MYC proto-oncogene)
 iii) Gene amplification (Neuroblastoma having n-MYC
HSR region. & ERB-B1 in breast and ovarian cancer.)

24. Mechanisms of activation of protooncogenes
to form growth promoting oncogenes.

26. Genes
Autonomous growth
Insensitivity to growth-
inhibitory signals
Evasion of apoptosis
Limitless replication
Sustained angiogenesis
“Cancer genes” cause bad things in cells:

27. 2. Refractoriness to Growth Inhibition:
Growth Suppressing Anti-Oncogenes
 Mutated anti-oncogenes behave like
growth-promoting oncogenes

28. Important tumour-suppressor anti-oncogenes
and associated human tumors

30. Genes
Autonomous growth
Insensitivity to growth-inhibitory signals
Evasion of apoptosis
Limitless replication
Sustained angiogenesis
“Cancer genes” cause bad things in cells:

31. 3. Escaping Cell Death by Apoptosis:
Genes Regulating Apoptosis and Cancer
 In cancer cells, the function of apoptosis is interfered due
to mutations in the genes (pro-apoptotic factors (BAD,
BAX, BID and p53) and apoptosis-inhibitors (BCL2,
BCL-X) , which regulate apoptosis in the normal cell.
 The examples of tumours by this mechanism are as under
a) BCL2 gene
b) CD95

32. Normal p53 pathway for control of cell apoptosis in breast
cancer

34. Damaged DNA
P 53
Rb
active
Rb
inactive

35. TWO MAJOR EFFECTS:
 i. Cell cycle arrest
 ii. Apoptosis
 Cell cycle arrest in late G1 phase-caused
by p53 dependent transcription of CDK
inhibitor p21- inhibits cyclin/CDK complexes.
 Thus prevents phosphorylation of RB
necessary for cells to enter S phase. So allows
cells the time to repair DNA damage.

36. Cell Cycle is controlled by genes.

37. 4. Avoiding Cellular Ageing: Telomeres
and Telomerase in Cancer
 Cancer cells in most malignancies have markedly
up-regulated telomerase enzyme, and hence
telomere length is maintained.
 Thus, cancer cells avoid ageing,
mitosis does not slow down or cease,
 thereby immortalising the cancer cells.

38. Genes
Autonomous growth
Insensitivity to growth-inhibitory signals
Evasion of apoptosis
Limitless replication
“Cancer genes” cause bad things in cells:

39. Limitless Replication
 Normal human cells: only 60-70 doublings
 Telomeres keep getting shorter…
 …leading to cell cycle arrest (via p53 check points,
causing proliferative arrest or apoptosis
 Stem cells and cancer cells use HIGH telomerase
activity to maintain telomere length and keep
replicating!

40. Genes
Autonomous growth
Insensitivity to growth-inhibitory signals
Evasion of apoptosis
Limitless replication
Sustained angiogenesis
“Cancer genes” cause bad things in cells:

41. 5. Continued Perfusion of
Cancer: Tumour Angiogenesis
 Cancers can only survive and thrive if the cancer cells
are adequately nourished and perfused, as otherwise
they cannot grow further.
 Neovascularisation in the cancers supplies oxygen and
nutrients to tumors.
 The stimulus for angiogenesis is provided by the release
of various factors:
 i) Promoters of tumour angiogenesis - (VEGF, bFGF)
 ii) Anti-angiogenesis factors – (thrombospondin-1,
angiostatin, endostatin and vasculostatin)

45. 6. Invasion and Distant
Metastasis: Cancer Dissemination
 One of the most important characteristic of
cancers is invasiveness and metastasis

46. 7. DNA Damage and Repair System:
Mutator Genes and Cancer
 small mutational damage to the dividing cell by
exogenous factors (radiation, chemical carcinogens etc) is
also repaired.
 p53 gene is held responsible for detection and repair of
DNA damage.
 However, if this system of DNA repair is defective
(mutator genes) --- cancer results.
 e.g. - Hereditary non-polyposis colon cancer, Ataxia
telangiectasia, Xeroderma pigmentosum , Bloom
syndrome

48. Neoplasia Outline
 Tumor nomenclature
 Tumor characteristics
 Epidemiology
 Cancer pathogenesis
•Overview
•Genes
•Steps
•Chromosomes

49. How do all these genetic mutations arise?
 We swim in a Sea of Carcinogens.
 mutagenic agents (sunlight, radiation, chemicals)!!
 We don’t get very many cancers because normal cells are
able to REPAIR DNA damage!!
 In addition to environmental damage, DNA of normal
dividing cells is susceptible to alterations resulting from
"Spontaneous Errors" occurring during DNA replication
 Many systems for DNA repair exist.
 If you inherit a defect in any of these systems, you’ll be more
likely to get cancer.
Failure of DNA repair

50. Carcinogenesis

51. Chromosomal Changes
 Genetic damage can be:
• small, invisible on a karyotype (point mutation)
• large, visible in a karyotype
 Some karyotypic abnormalities occur predictably in
certain tumors
• leukemias, lymphomas
• solid tumors

52. 1. Point mutation
2. Deletion
3. Chromosomal translocation
4. Gene amplification
5. Over expression of signaling proteins

54. Chromosome banding

55. Chromosomal Changes
 Balanced translocations
• Common!
• Either put proto-oncogene next to a
promotor…
• …or create a fusion gene that makes a bad,
growth-promoting product
• Most common in hematopoietic tumors
• Example: Ph chromosome

57. Chromosomal Changes
 Balanced translocations
 Deletions
• Deletion of part or all of a chromosome
• Usually: deletion of a tumor-suppressor gene
• Most common in solid tumors
• Example: del 13q14 in retinoblastoma

59. 8. Cancer Progression and
Heterogeneity:
Clonal Aggressiveness
 with passage of time cancers become more aggressive;
this property is termed tumour progression
 Clinical parameters of cancer progression are:
 increasing size of the tumour,
 higher histologic grade (as seen by poorer
differentiation and greater anaplasia),
 areas of tumour necrosis (i.e. tumour outgrows its
blood supply),
 invasiveness and distant metastasis

60. Gatekeepers and Caretakers
“Gatekeepers”
are the genes that directly
control cell birth and cell death.

61. Tumor growth kinetics is different
for gatekeepers and caretakers
Gatekeeper genes
is altered through mutation,
Oncogenes & tumor suppressor genes directly control
tumor growth. Regulate entry of cell into tumorigenic path
Caretaker genes
that do not directly control tumor growth but affect genomic
instability - DNA repair genes
Increased mutations of all genes
and the process of tumorigenesis is accelerated.

62. Inherited Conditions That Increase
Risk For Certain Cancers

63. Multi-step Theory
 Stage of initiation
 Latent stage
 Stage of promotion
 Stage of malignant transformation

64. Multi-step Process
 Tumor initiation and progression results from
stepwise accumulation of DNA mutations.
 Several characters of malignant neoplasm are
the result of multiple genetic defects.
 Initial steps reversible(e.g. dysplasia), but
final Malignant transformation is irreversible.
“Hit & Run”

65. Steps to Cancer
 Every tumor results from the accumulation of a
bunch of mutations
 Average: 90!
 Normally, body fixes or gets rid of mutated cells
(RB, p53)!
 For a tumor cell to grow, one of its mutations
must be within these checkpoint/guardian genes.

68. TUMOR PROGRESSION

69. Programmed cell death in carcinogenesis
TRANSFORMATION
Initial event
Immortalization
Inhibition of apoptosis
PROMOTION
Altered DNA
repair
Successive
accumulation of
mutations
Cell cycle
promotion
Inhibition of
apoptosis
PROGRESSION
Genomic instability
Other mutations
Irregular expression
of apoptosis
Drug resistance

71. Summary
 DNA damage - loss of control over cell
division.
 Radiation, Chemicals & Viral infections are
some known causes of cancers.
 Cancer evolves in multiple steps by
sequentially acquiring different DNA damages.
 Initiation, Latent stage, Promotion and
Malignant transformation are recognizable
stages in carcinogenesis.
 Each character of malignancy depends on
unique DNA alteration.