L9: Carcinogenesis

Question 1

What is the etiology of Carcinogenesis?

Answer 1

 These are the possible causes of cancer and the mechanisms involved in the transformation of a normal cell into a neoplastic cell.

 No single factor is responsible for the development of tumors alone.

 The role of some carcinogenic factors in carcinogenesis is established
while others are still unknown.

Question 2

What does the etiology of Carcinogenesis include?

Answer 2

A.Carcinogenic agents (carcinogens).

B. Preneoplastic (precancerous, premalignant) lesions.

Question 3

What are the carcinogenic agents?

Answer 3

These are agents which can produce malignancy

Question 4

What are carcinogenic agents classified into?

Answer 4

1. Internal
2. External:
   a) Physical (radiation)
   b) Chemical
   c) Infectious agents (viral, bacterial, and parasitic)

Question 5

What are the internal carcinogens?

Answer 5

A. Smegma: in uncircumcised males may produce penile carcinoma.

B. Hormones: The tumor growth is affected by hormones (hormone dependant tumors), in these cases, hormones act as promotors (second step in carcinogenesis).
E.g: Estrogen dependant hormones as Breast, ovarian, endometrial carcinoma.

Question 6

What are physical carcinogens?

Answer 6

A. Non-ionizing radiation

• (ultraviolet rays, UVR): Cause skin tumors especially in faired skin as squamous cell carcinoma, basal cell carcinoma, and melanoma
  b. Ionizing radiation
• cause Leukemia, thyroid carcinoma, lung carcinoma, and osteosarcoma.

Question 7

What are chemical carcinogens classified into?

Answer 7

a. Direct-acting agents

B. Indirect acting agents that need metabolic convergence

Question 8

What are the direct chemical carcinogens?

Answer 8

 As alkylating agents (chemotherapy for malignancy)

 As cyclophosphamide, chlorambucil, busulfan may cause leukemia.

Question 9

What are indirect chemical carcinogens?

Answer 9

1. Tar (tobacco products)
2. Azo dyes
3. Aflatoxins
4. Nitrosamine
5. Asbestos

Question 10

Effect of tar

Answer 10

may cause carcinoma of the lung, urinary bladder, oral cavity, larynx, and esophagus.

Question 11

Effect of Azo dyes

Answer 11

Food coloring agents (scarlet red, butter yellow) may cause liver malignancy (hepatocellular carcinoma).

Question 12

Effect of aflatoxins

Answer 12

The product of Aspergillus flavus fungus that contaminates grains and peanuts, may cause hepatocellular carcinoma.

Question 13

Effect of nitrosamine

Answer 13

converted to nitrosamine by bacterial flora in the stomach with achlorhydria may cause stomach carcinoma.

Question 14

Effect of asbestos

Answer 14

used in industries may lead to mesothelioma (malignant mesothelial tumor)

Question 15

What are the biological (infectious) carcinogens?

Answer 15

I. Bacterial carcinogens: Helicobacter pylori may cause gastric carcinoma or gastric B-cell lymphoma.

II. Parasitic carcinogens: Bilharzial cystitis may cause urinary bladder carcinoma.

III. Viral carcinogens: Examples:
 Human papillomavirus (HPV): Types 16 & 18 cause cancer cervix.
 Epstein Barr virus (EBV) causes Burkitt’s lymphoma or Nasopharyngeal
carcinoma.
 Hepatitis B virus causes Hepatocellular carcinoma.

Question 16

What are pre-neoplasia lesions?

Answer 16

These are non-malignant lesions that are well-recognized predispositions for malignancy.

Question 17

What do preneoplastic lesions include?

Answer 17

A) Hereditary premalignant Lesions (disorders)

B) Acquired preneoplastic lesions (disorders)

Question 18

What are hereditary premalignant disorders? (inherited cancer syndromes)

Answer 18

1) Autosomal dominant as Familial adenomatous polyps of the colon
2) Autosomal recessive syndromes of defective DNA repair (Xeroderma pigmentosa).
3) Familial cancers as breast, ovarian, colonic carcinomas

Question 19

What are acquired preneoplastic disorders? (Give examples)

Answer 19

1. Chronic irritation as chronic ulcers and scars
2. Hyperplastic proliferation: atypical endometrial hyperplasia and atypical mammary hyperplasia.
3. Metaplastic lesions: as squamous metaplasia.
4. Some benign tumors as adenomatous polyps of the colon.
5. Dysplastic proliferation (as dysplastic bronchial mucosa in smokers) and Carcinoma in situ.

Question 20

What accompanies dysplasia?

Answer 20

 It often accompanies metaplasia or hyperplasia.

Question 21

What does dysplasia involve?

Answer 21

If involves the whole thickness, this is usually associated with changes similar to that of malignancy but the basement membrane is intact and no invasion of underlying connective tissue.

Question 22

What are other names for dysplasia?

Answer 22

It is called carcinoma-in-situ or intra-epithelial carcinoma pre-invasive carcinoma.

Question 23

What are preneoplastic lesions classified according to?

Answer 23

They are classified according to their malignant potential

Question 24

What are premalignant lesions classified into?

Answer 24

High-risk lesions:
 In which the development of cancer is invariable (100%)
 e.g. Multiple familial polypses, Xeroderma pigmentosa

Low-risk lesions
 : In which the incidence of malignancy is so low (3-5 %)
 e.g. Leukoplakia, endometrial hyperplasia, dysplasia.

Question 25

What is the definition of Carcinogenesis?

Answer 25

Carcinogenesis is a complex multistep process leading to the transformation of a normal cell to a neoplastic one capable of producing a mass ( conversion of a normal cell to malignant cell) by the action of carcinogens

Question 26

What are the steps of Carcinogenesis?

Answer 26

Carcinogenesis is a multistep process, it passes through 3 steps:

1. Initiation
2. Promotion
3. Progression and heterogeneity.

Question 27

What is initiation in Carcinogenesis?

Answer 27

This is the first step in carcinogenesis, induced by irreversible, nonlethal genetic material change (gene mutation) of the affected cell. This mutation may be inherited in germ cells or acquired by carcinogens.

Question 28

Are multiple mutations needed in initiation?

Answer 28

Multiple mutations are required usually affecting genes that regulate cell proliferation.

Question 29

What are cell cycle regulatory genes?

Answer 29

I. Proto-oncogenes and oncogenes
II.Tumor suppressor genes
III. Genes controlling apoptosis
IV. DNA repair genes

Question 30

Proto-oncogenes and oncogenes

Answer 30

• Proto-oncogenes are genes found in normal cells and are responsible for controlling normal growth and proliferation
• When they are mutated, they are active called oncogenes.
• Proto-oncogenes are dominant genes and changes that affect them are usually acquired.

Example: Epidermal Growth factor receptor: EGFR in breast carcinoma

Question 31

Tumor suppressor genes

Answer 31

• These genes code the production of proteins that inhibit cell proliferation.
• The gene damage inactivates it.
• Tumor suppressor genes act as recessive genes and the absence of both copies is required for transformation, Mutations of tumor suppressor genes may be inherited or acquired
• Examples: P53 in most tumors, BRCA-1 & BRCA-2 in breast & ovary carcinoma.

Question 32

p53.

Answer 32

 It is called the guardian of the genome.

 Mutated in more than 50% of malignant tumors.

 When there’s damage to the DNA, P53 causes cell cycle arrest at G1 providing time for DNA repair then the cell re-enters the cell cycle again.

 If DNA repair is not successful, P53 activates BAX the proapoptotic gene and the cell dies by apoptosis, thus preventing the mutated cell from growth.

 Loss or mutation in P53 is common in urinary bladder, lung, breast, and ovarian carcinoma

Question 33

Genes controlling apoptosis

Answer 33

-Cell survival is regulated by genes that initiate and inhibit apoptosis. Normally, the BAX gene (proapoptotic) stimulates apoptosis while the bcl2 gene (anti-apoptotic) prevents programmed cell death.

Examples: Activation of antiapoptotic genes as Bcl2 leads to prolongation of the life span of genetically mutated cells and development of malignant tumors as in
Follicular B cell lymphoma.

Question 34

DNA repair genes

Answer 34

• Normal human DNA is subjected to daily minor damage by body heat & ultraviolet rays, repair of this damage takes place by a group of DNA repairing enzymes called DNA ligases.
• Mutation in genes that control the expression of DNA ligases lead to the development of tumors as in Xeroderma Pigmentosa → frequent skin malignancies.

Question 35

What does promotion (colonial expansion) in Carcinogenesis mean?

Answer 35

Promotion means the proliferation of the initiated cells resulting in monoclonal expansion from a single initiated progenitor cell ( formation of tumor mass by replication of the initiated cells).

Question 36

What does the promotion of the tumor depend on?

Answer 36

Depends on 2 factors:

• Intrinsic factors (kinetics of tumor cell growth).
• Host factors (angiogenesis).

Question 37

What are the intrinsic factors that affect the promotion of the tumor?

Answer 37

The time is taken by a single transformed cell to appear clinically as a mass depends on Increased Cell production/cell loss ratio due to:

a) Increase in proliferation,
b) increase in telomerase activity and decreased apoptosis

Question 38

What are the host factors that affect the promotion of tumors?

Answer 38

Formation of new blood vessels for the nourishment of the tumor cells as the tumor can’t grow beyond 2 mm without vascularity.

 Angiogenesis occurs due to angiogenic Growth Factors:
- produced by Tumor cells
 FGF (fibroblast growth factor)
 VEGF “vascular endothelial growth factor”.
- produced by macrophages invading the tumor
 TGFα “transforming growth factor-alpha”
 TNF “tumor necrosis factor”

Question 39

What are tumor progression and heterogeneity?

Answer 39

• Tumor progression means that the aggressiveness of tumors increases with time & acquire more malignant characters (as more invasiveness)
• Although the tumor is monoclonal, by the time it is clinically evident, its constituent cells are very heterogeneous due to multiple mutations of different tumor cells.