Neoplasia 4 Molecular

8/6/2019 Neoplasia 4 Molecular

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NEOPLASIA:

molecular basis of cancer


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CANCER AND GENETICS


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CANCER: GENOME DISEASE

Changes in chromosomenumbers

- Aneuploidy

Loss of DNA

Gain of DNA

Changes in nucleotides

Epigenetic effects


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Chromosomal changes in the genome of cancer

cells: tip of the iceberg


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MOLECULAR BASIS OF CANCER

Non lethal genetic damage

Clonal expansion of a single precursor cell thathas incurred the genetic damage

Principal targets of genetic damage 4 classesof normal regulatory genes : Protooncogenes

Tumor suppressor genes

Apoptosis regulating genes DNA repair genes

Multistep process genetic and phenotypic


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In normal tissues, the ratesof new cell growth and old

cell death are kept inbalance

In cancer, this balance isdisrupted


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Post mitoticStem cell

Differentiated Normalsenescent

differentiated

cell

Benign

tumor

Grade 2malignancy

Grade 3 or 4

malignancy

Stem cells as the target of carcinogens


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Essential alterations for malignant

transformation: Self sufficiency in growth signals-oncogenes.

Insensitivity to growth signals-TSGs.

Evasion of apoptosis.

Defects in DNA repair.

Limitless replicative potential.

Sustained angiogenesis.

Ability to invade and metastasize.


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Flow chart depicting the molecular basis of cancer

Fig 7-27


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Cyclin A/ cdk 2

Cyclin B/cdk 1

Cyclin E/cdk 2

CyclinD/ cdk 4

G1 S

G2M


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What are the genes responsible for tumorigenic

cell growth?

Normal

Cancer

Proto-oncogenes Cell growth

and

proliferationTumor suppressor genes

+

-

Mutated or activated

oncogenes MalignanttransformationLoss or mutation of

Tumor suppressor genes

++


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ONCOGENES

Oncogenes : Genes that promote

autonomous cell growth in cancer cells mutated forms of cellular protooncogenes.

Protooncogenes code for cellular proteinswhich regulate normal cell growth and

differentiation.


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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

Five types of proteins encoded by proto-

oncogenes participate in control of cell growth:


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4. Nuclear

Proteins:

Transcription

Factors

5. Cell Growth

Genes

3. CytoplasmicSignal Transduction

Proteins

1. Secreted Growth Factors

2. Growth Factor Receptors

Functions of Cellular Proto-Oncogenes


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Role of proto oncogenes and oncoproteins

Protooncogenes function in regulating growth andproliferation of the cell.

Oncoproteins :Similar function, but endow the cell with self-sufficiency in growth

Devoid of regulatory elements


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Oncogenes

Proto-oncogene = ras

Oncogene = mutated ras

Always activated

Always stimulating proliferation


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TUMOR SUPPRESSOR GENES

The products ofthese genes regulate/ suppress furthercell proliferation

Involved in cell cyclecontrol, regulation ofapoptosis

If abnormal :INSENSITIVITY TO

GROWTH INHIBITORYSIGNALS

Daughter cell

Mitosis

DNA replication

Control Point

Gateway

GrowthFactors

Cell cycleinhibitors

CELL CYCLE


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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


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p53

Located on chromosome 17p13.1

Most common target for genetic alterations in

human tumorsLi Fraumeni syndrome :

Inherit 1 mutant p53 allelle

Younger age, multiple primary tumors Ca breast, adrenal cortex, sarcomas, brain

tumors and leukemias.


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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


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Other tumour suppressor genes

APC/b- catenin

NF-1, NF-2 genes

VHL


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DNA REPAIR DEFECTS AND GENOMIC

INSTABILITY

Hereditary Nonpolyposis Cancer syndrome

Xeroderma pigmentosum

Inherited loss ofnucleotide excision repair( NER)

Ataxia telangiectasia, Bloom Syndrome

BRCA-1 & BRCA-2 Genes

Mutations Breast & Ovary Ca


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IMPORTANCEOFDNAREPAIR


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Multiple mutations lead to colon cancer

Genetic changes --> tumor changes

Cellular

Tumor Progression


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Development of sustained angiogenesis

Neoplasia 4 Molecular

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