Essential Alterations for Malignant Transformation

Self sufficiency in growth and cell division

Protooncogenes - genes in normal cells which encode proteins that have normal function in cells. Protooncogenes are physiologic regulators of cell proliferation and differentiation

Oncogenes - genes that promote autonomous cell growth in cancer cells. Oncogenes are characterized by the ability to promote cell growth in the absence of normal mitogenic signals

Oncogene products, called oncoproteins, resemble the normal products of protooncogenes with the exception that oncoproteins are devoid of important regulatory elements

Functional Category of Oncogenes

1) Growth Factors - neoplastic cells acquiries the ability to synthesize the same growth factors to which they are responsive. eg platelet-derived growth factor (PDGF) and transforming growth factor α (TGF-α)

2) Growth Factor Receptors - Mutations and pathologic over expression of normal forms of growth factor. Mutant receptors give signals to the cell evenb in absecence of growth factors. Eg EGF – epidermal growth factor overexpressed in 80% of squamous cell carcinoma of lung. HER2 is amplified in 25% to 30% of breast cancers and adenocarcinomas of the lung, ovary, and salivary glands.

3)Proteins Involved in Signal Transduction - RAS and ABL

RAS – gets activated by exchanging GDP for GTP. RAS when activated induce signal to nucleus for cell prolifration by inducing mitogenic cascade. RAS is short lived, GTPase inactivate GTP there by deactivates RAS but in mutant RAS protein GTPase activity fails to be augmented. – uncontrlooed cell proliferation.

ABL - ABL protooncogene has tyrosine kinase activity. In chronic myeloid leukemia and certain acute leukemias, the ABL gene is translocated from its normal abode on chromosome 9 to chromosome 22, where it fuses with part of the breakpoint cluster region (BCR) gene. The BCR-ABL hybrid gene has potent tyrosine kinase activity and it activates several growth stimulating pathways.

4) Nuclear Regulatory Proteins - Growth autonomy may occur as a consequence of mutations affecting genes that regulate transcription of DNA. A host of oncoproteins, including products of the MYC, MYB, JUN, FOS, and REL oncogenes, localised on the nucleus and there mutant varitey may lead to sustained proliferation of cells.

5) Cell-Cycle Regulators – cyclin, CDK and CDK inhibitors

Designer drugs- why do we need to know about the growth signalling pathway

Cetuximab: antibody against EGFR

Imatinib mesylate: inhibitor of Abr-bcl chimeric protein which acts as a tyrosine kinase; DOC in CML

Gefitinib, Erlotinib: inhibitor of EGFR tyrosine kinase activity

Bevacizumab: antibody against VEGF

Rituximab: CD20 antibody, used in B cell NHL

Gemtuzumab: CD33 antibody, used in AML

Alemtuzumab: CD52 antibody, used in CLL

IFNα used in leukemia, melanoma to increase the tumor immunity

Trastuzumab/ Herceptin: Ab against ERB B2/ HER/ Neu growth factor receptors on breast cancer cells

Insensitivity to Growth-Inhibitory Signals

Implies mutation in tumor suppressor genes

Unlike oncogenes, the tumor suppressor genes are recessive, so both the genes should be mutated( Knudson’s two hit hypothesis)

Main examples are

RB gene causing Retinoblastoma

TP53 gene mutation causing many cancers

APC gene mutation causing Adenomatous Polyposis Coli, and finally colon cancer

Pathogenesis of Retinoblastoma;

Note the Knudson’s two hit hypothesis

p53 Gene: Guardian of the Genome

p53 is the central monitor of stress in the cell and can be activated by anoxia, inappropriate oncogene signaling, or DNA damage. Activated p53 controls the expression and activity of genes involved in cell cycle arrest, DNA repair, cellular senescence, and apoptosis

If DNA damage cannot be repaired, p53 induces cellular senescence or apoptosis. Of human tumors, 70% have homozygous loss of p53. Patients with the rare Li-Fraumeni syndrome inherit one defective copy

Apoptosis : There is activation of a proteolytic cascade of caspases that destroys the balance between pro-apoptotic (e.g., BAX, BAK) and anti-apoptotic molecules (BCL2, BCL-XL)

p53 can be incapacitated by binding to proteins encoded by oncogenic DNA viruses like HPV, and possibly EBV and HBV

Telomerase and limitless replicative potential of cancer cell

In normal cells, which lack expression of telomerase, the shortened telomeres generated by cell division eventually activate cell cycle checkpoints, leading to senescence and placing a limit on the number of divisions a cell may undergo

Tumor cells reactivate telomerase, thus staving off mitotic catastrophe and achieving immortality.

Function of telomerase in cancer causation

Evasion of Apopotosis

reduced levels of Fas in hepatocellular carcinomas render the tumor cells less susceptible to apoptosis by FasL.

Overexpression of BCL2 protects lymphocytes from apoptosis and allows them to survive for long periods

Some tumors have high levels of FLIP, a protein that can bind death-inducing signaling complex and prevent activation of caspase 8

Certain melanoma cells show loss of APAF-1, blocking the mitochondrial-cytochrome c pathway.

Defective DNA repair

Genomic Instability-Enabler of Malignancy

Hereditary Nonpolyposis Colon Cancer Syndrome

Xeroderma Pigmentosum

autosomal recessive disorders comprising

Bloom syndrome, ataxia-telangiectasia, and Fanconi anemia

Development of Sustained Angiogenesis

pro-angiogenic cytokines, such as vascular endothelial growth factor (VEGF)

Anti- angiogenic protein produced by VHL gene( Von Hippel Lindau): VHL acts as a tumor suppressor gene, and its is associated with cell cancers, pheochromocytomas, hemangiomas of the CNS and retina (VHL syndrome).

Ability to Invade and Metastasize

Invasion of Extracellular Matrix (ECM)

Detachment of tumor cells from each other

Degradation of ECM

Attachment to novel ECM components

Migration of tumor cells

Vascular Dissemination and Homing of Tumor Cells