Neoplasia 4

					Epidemiology & Molecular basis of cancer

Epidemiology:
1. Cancer incidence:

– Males: prostate, lung & colorectal. – Females: breast, lung & colorectal. 2. Geographic incidence: – Ca stomach: 7-8 x Japan cf US. – Ca lung: 2 x US cf Japan. – Ca skin: 6 x New Zealand cf Iceland. Environmental influences, UV rays, asbestos, obesity, alcohol, cigarette smoking. Almost everything one does to gain a livelihood or for pleasure is fattening, immoral, illegal or even worse ONCOGENIC.

Epidemiology contd..
3. Age:
– – – – > 55 yrs. of age. Females: 40-79 yrs. Males: 60-79 yrs. Children: < 15 yrs.

4. Genetic predisposition to cancer:
– Autosomal dominant inherited cancer syndromes. – Defective DNA repair syndromes. – Familial cancers.

Genetic predisposition to cancer:
Autosomal dominant inherited cancer syndromes:  Point mutation in single allele of a tumor suppressor gene. 2nd allele: chromosome deletion or recombination.
– – – – Retinoblastoma- 40% inherited. Familial adenomatous polyposis- Colonic Ca. MEN 1 & 2. HNPCC Syndrome.

 Characteristics : – Tumors involve specific sites in each syndrome. – Within each group, a/w specific marker phenotype. – Incomplete penetrance and variable expressivity.

Defective DNA repair Syndromes: DNA instability Autosomal recessive inheritance Xeroderma pigmentosum, ataxia telangiectasia, Bloom syndrome, HNPCC ( autosomal dominant): inactivation of DNA MMR gene.

Familial cancers:
 Ca colon, breast, ovary, brain, melanomas.  Characteristic features : – Early age at onset. – Occur in 2/ more close relatives of index case. – Multiple or bilateral cancers. – No specific marker phenotypes.

5. Nonhereditary predisposing conditions:
 Regenerative, hyperplastic and dysplastic

proliferations are fertile soil for the origin of a malignant tumor.  Chronic inflammation:
– Virchow proposed that cancer develops at sites of chronic inflammation. – Ulcerative colitis, Crohn disease, H.pylori gastritis, viral hepatitis, chronic pancreatitis. – Cytokines →stimulate growth of transformed cells. – Chronic infl. → ↑ pool of tissue stem cells → effect of mutagens. – Reactive O2 Species → genomic instability. ?COX-2.

5. Nonhereditary predisposing conditions:
Precancerous conditions: – Chronic atrophic gastritis, chronic ulcerative colitis, solar keratosis, leukoplakia- oral, vulva, etc.. – Majority: no malignancy emerges. – Cancers arising in benign tumors:
• Villous adenoma- colon (50%). • Leiomyosarcoma in leiomyoma. • Carcinoma ex pleomorphic adenoma.

Chronic atrophic gastritis:
 Atrophic gastritis.  Autoantibodies against parietal cells.  Pernicious anemia.  Gastric carcinoma and carcinoid tumor.

Ulcerative colitis:
 Ulceroinflammatory disease of mucosa and

submucosa, involving colon.  Islands of regenerating mucosa forming pseudopolyps.  Dysplasia and frank carcinoma.  Caused by DNA damage d/t DNA repair deficiency and genomic instability.

Leukoplakia:
 White patch that cannot be scraped off and
 Cannot be characterized as any other

disease.  5-25% of these are pre-malignant.  Hyperkeratosis overlying a thickened, acanthotic epithelium, with marked dysplastic changes.

CANCER AND GENETICS

MOLECULAR BASIS OF CANCER
 Nonlethal genetic damage  Clonal expansion of a single precursor cell

that has incurred the genetic damage  Principal targets of genetic damage – 4 classes of normal regulatory genes :
– – – – Protooncogenes Tumor suppressor genes Apoptosis regulating genes DNA repair genes

 Multistep process – genetic and phenotypic

• In normal tissues, the rates of new cell growth and old cell death are kept in balance • In cancer, this balance is disrupted

Cancer Cell Do Not Grow Faster Than Normal Cells.
Rather, Their Growth is Just Uncontrolled.

Acquired (environmental) DNA damaging agents: Chemicals Radiation viruses

Normal cell
DNA Damage

Successful DNA repair

Failure of DNA repair Mutations in the genome of somatic cells

Inherited mutations in: Genes affecting DNA repair Alterations of genes that regulate apoptosis

Activation of growthpromoting oncogenes

Inactivation of suppressor genes

tumor

Unregulated cell proliferation decreased apoptosis

and

Clonal expansion
Additional mutations (progression) Heterogeneity

Malignant neoplasm

Flow chart depicting the molecular basis of cancer

 Fig 7-27

Essential alterations for malignant transformation:
 Self-sufficiency in growth signals-oncogenes.  Insensitivity to growth signals-Tumor

Suppressor Genes.  Evasion of apoptosis.  Defects in DNA repair.  Limitless replicative potential.  Sustained angiogenesis.  Ability to invade and metastasize.

Oncogenes

Cell cycle

Apoptosis

Tumor Suppressor

Angiogenesis

Inv. and Mets

Hanahan and Weinberg, Cell 100: 57, 2000

CELL CYCLE
Daugther cell

Mitosis

Gateway
Growth Factors

S
DNA replication

CELL CYCLE

Cell cycle inhibitors

Control Point

• CyclinD / cdk 4

• Cyclin E /cdk 2

G1 M
• Cyclin B /cdk 1

S G2
• Cyclin A / cdk 2

External signals (growth factors, integrins)

MYC, RAS..

DNA damage, cell sress Feedback reg.

Cyclin D

+ CDK4 Cyclin D/CDK4 (active c) p16INK4
RB phosphorylation

p53

MDM2

p21

Active E2F

Cyclin E transcription

CYCLIN E CDK2 Cyclin E/CDC2

G1

S

What are the genes responsible for tumorigenic cell growth?
Normal
Proto-oncogenes Tumor suppressor genes

+

++

Cell growth and proliferation

Cancer
Mutated or “activated” oncogenes

Loss or mutation of Tumor suppressor genes

Malignant transformation

ONCOGENES
 Oncogenes are mutated forms of cellular

protooncogenes.
 Protooncogenes code for cellular proteins

which regulate normal cell growth and differentiation.

Five types of proteins encoded by protooncogenes participate in control of cell growth:
Class I: Growth Factors

Class II: Receptors for Growth Factors Class III: Intracellular Signal Transducers
Class IV: Nuclear regulatory proteins

Class V: Cell-Cycle regulators

Functions of Cellular Proto-Oncogenes
1. Secreted Growth Factors

2. Growth Factor Receptors

3. Cytoplasmic Signal Transduction Proteins

4. Nuclear Proteins: Transcription Factors
5. Cell Growth Genes

Role of proto-oncogenes and oncoproteins
 Protooncogenes function in regulating growth and

proliferation of the cell. – Growth factor ligands & receptors – Signal transducers – Transcription factors – Cell cycle components  Oncoproteins : Similar function, but endow the cell with selfsufficiency in growth

Oncogenes are usually dominant (gain of function)
• cellular protooncogenes that have been mutated (and “activated”)

• cellular protooncogenes that have been captured by retroviruses and have been mutated in the process (and “activated”)
• virus-specific genes that behave like cellular protooncogenes that have been mutated to oncogenes (i.e., “activated”)

The result:
 Overproduction of growth factors  Flooding of the cell with replication signals  Uncontrolled stimulation in the intermediary

pathways  Cell growth by elevated levels of transcription factors

Oncogenes
Proto-oncogene = ras Oncogene = mutated ras Always activated Always stimulating proliferation

TUMOR SUPPRESSOR GENES
 The products of these genes regulate / suppress

further cell proliferation  Involved in cell cycle control, regulation of apoptosis etc. Function as : Transcription factors Cell cycle inhibitors Signal transduction molecules Cell surface receptors Regulators of cell response to DNA damage  If abnormal : INSENSITIVITY TO GROWTH INHIBITORY SIGNALS

TUMOR SUPPRESSOR GENES
Disorders in which gene is affected Gene (locus) DCC (18q) Function cell surface interactions transcription Familial unknown Sporadic colorectal cancer lung cancer

WT1 (11p)

Wilm’s tumor

Rb1 (13q)

transcription

retinoblastoma

small-cell lung carcinoma

p53 (17p)

transcription

Li-Fraumeni syndrome
breast cancer

breast, colon, & lung cancer
breast/ovarian tumors

BRCA1(17q)

transcriptional

BRCA2 (13q)

regulator/DNA repair

Differences:
Dominant oncogenes Alleles in normal cells Two Tumor suppressor genes Two

Alleles mutated to produce effect Function of protein Germline mutations identified
Mutations

One Enhanced Rare- RET
Activating, gain in function, dominant

Two Reduced Many-RB, p53
Inactivating, loss of function, recessive

RB Gene
 Product of RB gene is a nuclear

phosphoprotein that plays a key role in regulating the cell cycle  In quiescent cell : ACTIVE, HYPOPHOSPHORYLATED STATE  G1/S : INACTIVE HYPERPHOSPHORYLATED STATE

KNUDSON TWO HIT HYPOTHESIS IN FAMILIAL CASES
Familial RB (%30)

RB

rb

Normal cells

RB LOH

rb

RB

rb

Inactivation of a tumor suppressor gene requires two mutations, inherited mutation and somatic mutation.
Normal cells

Tumor cells

KNUDSON TWO HIT HYPOTHESIS IN SPORADIC CASES
Normal Cells
RB

RB

RB

RB

RB LOH

RB Mutation

Tumor cells

Inactivation of a tumor suppressor gene requires two somatic mutations.



E2F-RB (hypo) – inhibitor, brake S Increased Cyclins (D,F) RB ( hyper): E2F released

G1  Growth factors

Increased transcription factors (E2F)  Mutation at any step somatic/ inherited
 Unregulated progression to S phase  NO cell cycle control: MALIGNANCY

External signals (growth factors, integrins)

MYC, RAS..

DNA damage, cell sress Feedback reg.

Cyclin D

+ CDK4 Cyclin D/CDK4 (active c) p16INK4
RB phosphorylation

p53

MDM2

p21

p53
 Located on chromosome 17p13.1
 Most common target for genetic alterations

in human tumors Li Fraumeni syndrome :  Inherit 1 mutant p53 allelle  Younger age, multiple primary tumors  Ca breast, adrenal cortex, sarcomas, brain tumors and leukemias.

 MOLECULAR POLICEMAN  Prevents propagation of genetically damaged cells
 It acts in the cell cycle only when DNA is damaged

 DNA damage :

Rapid increase in p53, protein kinases & ATM (which phosphorylate p53): Apoptosis  Important in therapy Tumors with normal p53 respond well to chemo and radiotherapy

APC-ß catenin pathway
 Down regulation of growth promoting signals  Eg : APC, NF-1.  APC loss : Pathogenesis of colon tumours, hepatoblastoma,

hepatocellular carcinoma  Component of WNT signalling pathway  Downregulates ß catenin in cytoplasm  Loss of APC
 Increased ß catenin – binds to TCF in nucleus  Upregulates cell proliferation ( incr transcr of c-myc etc)  ß catenin- E cadherin axis defects – Reduced cell adhesion

APC-ß catenin pathway

Other tumour suppressor genes
 NF-1, NF-2 genes
 VHL

 PTEN  WT-1  Cadherins  PTCH

BRCA-1 & BRCA-2 Genes
 Involved in :

Transcriptional regulation Homologous recombination of DNA repair Chromatin remodelling Compo of G1/S checkpoint  Mutations of either – Breast & Ovary Ca  Mutation of BRCA-1 –Ca: prostate, colon  Mutation of BRCA-2 – Ca : male breast, pancreas, melanoma

Genes that regulate apoptosis
Inhibit apoptosis: Bcl-2 gene (18q21), Bc1-x
Favor apoptosis: BAX (p53), BID (p53): chemotherapy MYC : triggers proliferation; Bcl-2 : prevents cell death.

IMPORTANCE OF DNA REPAIR

Tumor Progression
Cellular

Multiple mutations lead to colon cancer Genetic changes --> tumor changes

Development of sustained angiogenesis
Tumors stimulate the growth of host blood vessels : Angiogenesis. TUMORS

Angiogenic switch
Incr Production of angio factors/ loss of angio inhibitors (eg : wild p53). VEGF, bFGF (tumor cells, stromal cells, infl cells) Recruit endoth cell precursors / sprouting of existing capillaries NEOVASCULARISATION Leaky vessels ( VEGF ) Tortuous, irregularly shaped. Anti angiogenic factors

 Dual effect of neovas on tumor cells
GFs secreted : PDGF
 

Stimulate growth of tumor cells, Supplies nutrients and oxygen

 Important for metastasis  Currently important modalities of therapy :

Angiogenic inhibitors Abs to VEGF, VEGF-R2,


				
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