Neoplasia Lec 6 PDF

 Neoplasia lec 6 Hallmarks of cancer: Self-sufficiency in growth signals Evasion of apoptosis Insensitivity to growth - Altered cellular metabolism inhibitory signals Sustained angiogenesis...

 Neoplasia lec 6 Hallmarks of cancer: Self-sufficiency in growth signals Evasion of apoptosis Insensitivity to growth - Altered cellular metabolism inhibitory signals Sustained angiogenesis Invasion and metastasis Limitless replicative potential (immortality) Accumulation af driver and passenger mutations. Self sufficiency in growth signals It stems from gain of function mutation that convert proto-oncogenes to oncogenes It has the ability to grow without needing growth factors to stimulate it because of the acquired mutation that give the cancer cell the ability to divide by itself Oncogenes will encode proteins called onto proteins that promotes the cell growth in the > next page Steps of normal cell proliferation Binding of growth factor to its specific receptor on the cell membrane Transient and limited activation of growth factor receptor → activation of several signal transducting proteins on the inner leaflet of the plasma membrane Transmission of the transduced signal across the cytosol to the nucleus by second messenger or a cascade of signals transduction molecules Induction and activation of nuclear regulatory factors that initiate and regulate DNA transcription and biosynthesis of other cellular components that are needed for cell division such as organelles ,membrane components, ribosomes. Entry and progression of the call into cell cycle → cell Division Growth factors: induce stromal cells to produce growth factors in the Cancer may tumor micro environment secrete their own growth factors paracrine action : Most of the soluble growth factors are made by one cell type and act on a neighboring cell to stimulate it to proliferate self sufficiency : Some cancer cells acquire growth self sufficiency by acquiring the ability to synthesize the same growth factors that they respond to For example: Gliablastomas secrete platelet - derived growth factors (PDGF) and express the PDGF receptor Many sarcomas make both transforming growth factor - alpha (TGF-a) and its receptor activate normal cells : In some cases tumor cells send signals to activate normal cells in the supporting stroma to produce growth factors that promote tumor growth Growth factor receptors Signal by Activating its intrinsic tyrosin kinase (by the gf binding) growth factor receptors Signal by stimulating the activity of downstream proteins  Many growth factor receptors function as oncoproteins when they are mutated or over expressed Examples: Epidermal growth factor Receptor family ERBB1 is over expressed in : HER2 (ERBB2) is amplified in: i ⑮ 80% of squamous cell carcinomas of the 20% of breast cancer lung Smaller fraction in adenocarinamas 50% or more in gliblastomas of lung, ovary ,stomach, slivary 80-100% of epithelial tumors in head and glands neck Notes: These tumors are exquisitely sensitive to the mitogenic effect of small amount of growth factors (contains cells with different HER2 is significant in treatment genes than the rest of the person, organ, or tissue.) (small) but functionally important changes in protein structure, or gene rearrangement that create fusion genes encoding chimeric receptors e 1) Tyrosine kinase activity is stimulated by point mutations that lead to subtle Examples: leukemia lymphomas, certine forms of sarcoma. 2) Downstream signal- transacting proteins: The signaling proteins that couple growth factor receptors to their nuclear targets are activated by ligand binding to growth factor receptors The signals are transmitted to the nucleus through various signals transduction molecules Two important oncoproteins in the category of signaling molecules are present: RAS ABL 1) RAS The most commonly mutated oncogenes in human turners 30% of all human tumors contain mutated RAS genes, The frequency is higher in some cancers e.g. Pancreatic adenocarcinoma RAS is a member of a family of small G proteins that bind GTP and GDP Sequential steps of signaling by RAS RAS normally flips back and forth between an excited signal transmitting state and quiescent state Inactive when bound to GDP Stimulation of cell growth factors (EGF and PDGF )→ exchange of GDP to GTP and conformational changes → activation of RAS (ras-gtp) Active RAS is short-lived because the activity of intrinsic GTPase activity RAS hydrolyze GTP to GDP releasing phosphate group and returning the protein to its quiescent GDP bound state The GTPase activity of activated RAS is magnified dramatically by a family of GTPase activating proteins (GAPs) GAPs act as molecular brakes that prevent uncontrolled RAS activation by favoring hydrolysis of GTP to GDP Activated RAS stimulates downstream regulators of proliferation by several interconnected pathways that act on the nucleus and alter the expression of genes that regulate growth such as MYC For example: BRAF which which lies in "RAF/ ERK /MAP kinase pathway " is mutated in more than 60% of melanomas → leading to unregulated cell proliferation RAS most commonly activated by point mutations in amino acid residues Se Within the GTP binding pocket In The enzymatic region that carries out GTP hydrolysis Examples Neurofibromatosis type 1 → the GAP neurofibromin -1 (nf1) is mutated Tumor suppressor gene called PTEN which is negative inhibitor of PI3 kinase is frequently mutated in carcinomas and certain leukemias Notes : Both mutations interfere with break down of GTP that is essential in inactivating RAS RAS remain in its activated,GTP-bound form → continuous cell proliferation Activating mutations in RAS can be mimicked by loss of function of GAPs → failure to stimulate GTP hydrolysis → RAS trapped in Activr state  2) ABL The ABL proto - oncoprotein has tyrosin kinase activity that is controlled by internal negative regulatory domains. Philadelphia chromosome : In chronic myeloid leukemia and certain acute leukemias a part of ABL gene is traslocated from it's normal site on chromosome 9 to chromosome 22 This fusion gene encodes as BCR-ABL hybrid protein that has tyrosin kinase activity. The BCR-ABL protein activates all of the signals is a potent stimulator of cell growth Imatinib mesylate (gleevec) :is BCR-ABL kinase inhibitors that has a dramatic clinical response in patients with chronic myeloid leukemia Nuclear transcription factors Mutated RAS or ABL → inappropriate and continuous stimulation of nuclear stimulation of transcription factors → the expression of growth-promoting nuclear genes MYC,MYB,JUN,FOS and REL oncogenes, function as transcription factors that regulate the expression of growth promoting genes, such as (cyclins) SMYC MYC is most commonly involved in human tumors Activates several growth promoting genes including cyclin- dependent kinases (cdk) Examples: MYC translocation 8→14 in Burkitt lymphoma ( aggressive b-cell tumor) MYC Amplified in breast, colon, lung cancers Neuroblastoma → NMYC gene amplification Carcinoma of lung → LMYC gene amplification Cyclins And cyclin-dependent kinases Progressin of cells through the cell cycle is controlled by cyclin- dependent kinases ( CDK ) CDK are activated by binding to cyclins. Cycling are characterized by cyclic nature of production and degradation More than 15 cyclins have been identified → C, D, A, B appear sequentially during the cycle and bind to one or more CDK mishaps affecting the expression of cyclin D or CDK4 seem to be a common event in Neoplastic transformation Cyclin D genes are over expressed in many cancers, including those affecting breast, esophagus, liver and lymphomas CDK 4 gene amplification occurs in Melanomas, sarcomas, glioblastemas Cyclin B, E mutations and others occur in much less frequency than cyclin D/CDK4 CDK inhibitors (cdki) silence the CDKs exert negative control over cell cycle The cdk-cyclin complex phosphorylate crucial target protein that drive the cell throw the cell cycle On completion → cyclin levels decline rapidly. Families of CDKI Inhibits the CDKs broadly Selective effect on cyclin D/ CDK4 and cyclin D/ 1-p21 [CDK1A] CDK6(also called INK4 )(A-D proteins ) 2-p27 [CDK1B] 1-p15 [CDKN2B] 3-p18 [CDKN2C] 3-p57 [CDK1C] 2-p16 [CDKN2A] 4-p19 [CDKN2D] Expression of these inhibitors is down regulated by mitogenic signaling pathways thus promoting the progression of cell cycle 4, e.g →p27 [CDKN1B] , CDKI that inhibits cyclin E is expressed throughout G1 Mitogenic signals inhibit p27 relieving inhibition of cyclin E-CDK2 → allowing the cell cycle to process The CDKIs are frequently mutated or other wise silenced in many malignancies Examples Germ-line mutations of p16(CDKN2A) are associated with 25% of melanoma. Acquired deletion or inactivation of p16(CDKN2A) is seen in: 75% of pancreatic carcinomas 40% to 70% of glioblastomas 50% of esophageal cancers 20% of non-small-cell lung carcinomas, soft tissue sarcomas, and bladder cancers. End of lec