Dr. Hiba Wazeer Al Zou’bi Neoplasia 3 Dr. Hiba Wazeer Al Zou’bi

Carcinogenesis: A MULTISTEP PROCESS Carcinogenesis resulting from the accumulation of multiple genetic alterations that collectively give rise to the transformed phenotype Tumor Progression : -Stepwise accumulation of mutations resulting in greater malignant potential - At the molecular level, tumor progression and associated heterogeneity are most likely to result from multiple mutations, generating subclones with different characteristics such as ability to invade, rate of growth, metastatic ability, karyotype, hormonal responsiveness, and susceptibility to antineoplastic drugs. - Most malignant tumors are monoclonal in origin, but by the time they become clinically evident their constituent cells may be extremely heterogeneous.

HALLMARKS OF CANCER Self-sufficiency in growth signals Insensitivity to growth-inhibiting signals Evasion of Cell death Limitless replicative potential: Telomerase Development of sustained Angiogenesis Invasive ability Metastatic ability Reprogramming Energy metabolism Evasion of immune system Genomic instability Tumor promoting inflammation

Growth signals Under physiologic conditions, cell proliferation can be readily resolved into the following steps: 1. The binding of a growth factor to its specific receptor on the cell membrane 2. Transient and limited activation of the growth factor receptor, which in turn activates several signal transducing proteins on the inner leaflet of the plasma membrane 3. Transmission of the transduced signal across the cytosol to the nucleus by second messengers or a cascade of signal transduction molecules 4. Induction and activation of nuclear regulatory factors that initiate and regulate DNA transcription 5. Entry and progression of the cell into the cell cycle,resulting ultimately in cell division

Growth signals Genes coding for growth: 1- Growth factors 2- Cell surface receptors 3- Signal transduction proteins 4- Nuclear transcription factors 5- Cell cycle proteins

Self Sufficiency in Growth Signals

1- Oncogenes coding Growth Factors Normally, cells that produce the growth factor do not express the cognate receptor. Many cancer cells acquire growth self-sufficiency by acquiring the ability to synthesize the same growth factors to which they are responsive. Glioblastomas secrete (PDGF) and express the PDGF receptor - many sarcomas make both transforming growth factor-α (TGF-α) and its receptor.

2- Oncogenes coding Growth Factor Receptors Mutant receptor protein  continuous signals even in the absence of GF…..OR Overexpressed receptors  hypersensitive to GF Epidermal GF receptor family: - ERbB1 overexpressed in 80% of squamous cell CA lung - ERbB2 ( HER 2) amplified in 25-30% of CA of breast

3- Oncogenes in Signal Transduction: 1- RAS - RAS proteins are inactive when bound to GDP Stimulation of cells by growth factors: exchange of GDP for GTP and generate active RAS. Intrinsic guanosine triphosphatase (GTPase) of RAS hydrolyzes GTP to GDP, releasing a phosphate group and returning RAS to its quiescent GDP-bound state. The GTPase protein is magnified dramatically by a family of GTPase-activating proteins (GAPs).

- The activated RAS stimulates downstream regulators of proliferation by two distinct pathways (RAF/MAP-K or PI3-K/AKT pathways) that converge on the nucleus and flood it with signals for cell proliferation. - Mutational activation of these “messengers” can mimic the growth promoting effects of activated RAS.

RAS protein most commonly activated by point mutations in amino acid residues that are either within the GTP-binding pocket or in the enzymatic region essential for GTP hydrolysis Active, GTP-bound form. Point mutations in codon 12, 13 are present in 30% of cancers, especially CA pancreas & Colon RAS is the Most commonly mutated proto-oncogene in human tumors

Loss-of function mutations in the GAPs Active, GTP-bound form. Disabling mutation of neurofibromin-1 (NF-1), a GAP familial neurofibromatosis type 1

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