Neo3

Question 1

Mechanisms of carcinogenesis

Answer 1

Cancer as a multistep process:
Initiation: DNA alteration or cell change
Tumor-promotion: from single mutated cell to formation of tumor
Tumor-progression: development of malignancy

Question 2

Results from mutation of DNA to activate a proto-oncogene or inactivate a tumor suppressor gene

Answer 2

Initiation

• Initiation alone does not result in tumors

Question 3

complete carcinogens”).

Answer 3

Some initiators can subsequently act as promoters (are “complete carcinogens”).

Question 4

are usually substances that produce cell activation and proliferation

Answer 4

Promotors
#Effects of promotors are reversible.

Question 5

Promotors cannot induce neoplasia if

Answer 5

i) alone
ii) if applied before initiator
iii) if applied in too small amount
iv) if too much time elapses between applications

Question 6

does not cause mutation, but it leads to clonal expansion of the initiated (mutated) cells

Answer 6

Promotion

Ex : hormones (estrogen) , growth factors

Question 7

: Progression

Answer 7

Karyotypic instability:
Increased growth rates
Increased invasiveness
Increased hormonal response
Anaplasia

Question 8

multiple genetic alterations involving activation of several oncogenes and loss of two or more cancer suppressor genes.

Answer 8

Progression

Question 9

colon cancer:

Progression

Answer 9

Colon epithelial hyperplasia
Formation of adenomas
Malignant transformation

Question 10

Karyotypic Changes in Tumors

Answer 10

Point mutation: e.g. ras oncogene
Balanced translocations
Gene amplification 
Deletions 
Whole chromosomes may be gained or lost.

Question 11

Molecular Basis of Multistep Mechanism
Genes that regulate entry of cells into the multi-step carcinogenesis are called…..

E.g. mutations of ….

Answer 11

gatekeepers

Rb, NF-1, VHL, or APC gives rise to retinoblastoma, schwannomas, renal cell cancer, and colon cancer

Question 12

In contrast to gatekeeper genes, those that affect genomic stability are called…… genes
E.g…

Answer 12

caretaker

the DNA repair genes

Question 13

A) Chemical Carcinogens

Answer 13

Direct agents:
They require no metabolic conversion to become carcinogenic
Indirect agents:
They become active after metabolic conversion
These agents react with RNA, cellular proteins, and DNA
Some chemical carcinogens are augmented by certain agents that are called promoters

Question 14

Direct-Acting Carcinogens

Answer 14

1. Alkylating agents
Anticancer drugs (cyclophosphamide , chlorambucil ,    nitrosoureas, and others)
2. Acylating agents
  1-Acetyl-imidazole
  Dimethylcarbamyl chloride

Question 15

Indirect Acting Agents

Answer 15

Polycyclic and heterocyclic aromatic hydrocarbons

Aromatic amines, amides, azo dyes

2-Naphthylamine (β-naphthylamine)

bladder cancer in workers exposed to aniline dye & rubber industry

Natural plant and microbial products

Aflatoxin B1 hepatocellular carcinoma

Others
Asbestos, nickel, chromium lung cancer

Question 16

HPV (types 1, 2, 4, 7): cause

Answer 16

benign squamous papillomas (warts in human)

Question 17

HPV (types 16, 18, 31)

Answer 17

involved in the genesis of oropharyngeal, cervical, anal, perianal, and penile cancers

Question 18

Epstein-Barr Virus:

• Involved in the pathogenesis of several human tumors

Answer 18

– Burkitt lymphoma
– AIDS-related lymphomas
– Nasopharyngeal carcinoma

Question 19

Helicobacter Pylori
• gram negative spiral bacteria
• associated with 90% of duodenal ulcers,and 70-90% of gastric ulcers
• the likely cause for gastric carcinoma & lymphoma (MALToma: marginal zone associated lymphoma)

Answer 19

.

Question 20

Four classes of genes are targets of genetic damage

Answer 20

1. The growth promoting proto-oncogenes
2. The growth-inhibiting tumor-suppressor genes
   (anti-oncogenes)
3. Genes that regulate apoptosis
4. The DNA repair genes

Question 21

Six fundamental changes in cell physiology that together dictate malignant phenotype

Answer 21

1. Self-sufficiency in growth signals (oncogenes)
2. Insensitivity to growth-inhibitory signals (Cancer
   Suppressor Genes)
3. Evasion of apoptosis
4. Limitless replicative potential
5. Sustained angiogenesis
6. Ability to invade and metastasize

Question 22

Mutations and pathologic overexpression of normal forms of growth factor receptors have been detected in several tumors. e.g

Answer 22

the epidermal growth factor (EGF) receptor is overexpressed in 80% of squamous cell carcinomas of the lung.

Question 23

Knudson (two hit theory):
• In hereditary retinoblastoma, children are born with one normal and one defective copy of the Rb gene (first hit).
• They lose the normal copy by some somatic mutation
(second hit).

Answer 23

,

Question 24

Tumor Suppressor Genes: p53
• located on chromosome 17
• It’s the most common Tumor Suppressor Gene target for genetic alterations in human tumors
• More than 50% of human tumors contain mutations in this gene
• Familial loss causes Li-Fraumeni syndrome (multiple tumors) includes sarcomas, breast cancer, leukemia,
brain tumors, and carcinomas of the adrenal cortex

Answer 24

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Question 25

Tumor Angiogenesis • Angiogenesis is required for: 1. continued tumor growth 2. metastasis • Tumors can not enlarge beyond 1-2 mm in diameter or thickness unless they are vascularized • The 1-2 mm zone represents the maximal distance across which oxygen and nutrients can diffuse from blood vessels. Beyond this distance the tumor fails to enlarge without vascularization. Hypoxia will induce apoptosis by activation of p53

Answer 25

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Question 26

How Do Growing Tumor Develop a Blood Supply • Tumor growth is controlled by the balance between angiogenic factors, & antiangiogenesis molecules. • Examples of angiogenic factors: – Vascular endothelial growth factor (VEGF) – Basic fibroblast growth factor (bFGF) • Examples of antiangiogenesis are: – thrombospondin-1, angiostatin, endostatin, & vasculostatin.

Answer 26

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Question 27

Hypoxia within the growing tumor favors angiogenesis by release of hypoxia-inducibale factor–1 (HIF-1). HIF-1 controls transcription of VEGF Transcription of VEGF is under the control of Ras oncogene Ras oncogene activation upregulates the production of VEGF Proteases are involved in regulating the balance between angiogenic and antiangiogenic factors

Answer 27

. Hypoxia within the growing tumor favors angiogenesis by release of hypoxia-inducibale factor–1 (HIF-1). HIF-1 controls transcription of VEGF Transcription of VEGF is under the control of Ras oncogene Ras oncogene activation upregulates the production of VEGF Proteases are involved in regulating the balance between angiogenic and antiangiogenic factors

Question 28

P53 inhibits angiogenesis by inducing the synthesis of the antiangiogenic molecule thrombospondin-1 With mutational inactivation of both p53 alleles, the level of thrombospondin-1 drop markedly tilting the balance in favor of angiogenic factors Some success in the treatment of cancer has been achieved through the use of angiogenesis inhibitors such as endostatin

Answer 28

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Question 29

Metastatic process can be divided into two phases: Invasion of the extracellular matrix Vascular dissemination and homing of tumor cells E-cadherins acts as intercellular glue that bind cells together. E-cadherin function is lost in almost all epithelial cancer

Answer 29

Invasion of the cellular matrix in 4 steps: Detachment of tumor cells from each other Attachment of tumor cells to matrix components Degradation of ECM Migration of tumor cells

Question 30

Attachment of tumor cells to ECM proteins such as laminin and fibronectin Local degradation of the basement membrane and interstitial connective tissue Tumor cells either secrete proteolytic enzymes themselves or induce the host cells fibroblasts to elaborate proteases Several of metalloproteinases including gelatinases, collagenases, and stromelysins, cathepsin-D are involved Benign tumors show little type IV collagenase activity, whereas their malignant counterpart overexpresses this enzyme

Answer 30

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