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Cancer is a genetic disease o gene dysfunction is implicated in initiating and driving cancerous changes in all tissues o heritable (genetic) cancer syndrome genes are linked to sporadic cancer development o analysis and documentation of common mutations in cancer tissue (signature or profile) o genomic studies identify changes associated with cancer o no two cancers will be the same (although many have mutations in common) personalized medicine---tumor’s gene signature---may provide prognosis candidate drugs to target specific cellular processes—tyrosine kinases not a single disease, name used to describe the rapid and uncontrolled cellular proliferation that produces a mass/tumor must be malignant o cell growth is no longer controlled by normal boundaries of cellular function o capable of progression by invading neighboring tissues o capable of invasion of more distant tissue Three types o Sarcoma: originates in mesenchymal tissue o Carcinoma: originates in epithelial tissue o Hematopoetic/lymphoid: originate in bone marrow, lymphatic system and peripheral blood o Within each type classified based on site, tissue type, histological appearance and degree of malignancy (stage) Development of cancer: oncogenesis o Multi-step process resulting from gene dysregulation o process that produces genetic mutations induced by chemicals or physical agents (initiation promotion progression localized tumor metastasis) initiation-irreversible genetic change in single cell promotion-increased proliferative ability in initiated cell (clonal growth) progression-acquisition of more genetic damage that allows cell(s) to proceed to malignant phenotype o General scheme for mechanisms of oncogenesis by proto-oncogene activation, loss of tumor-suppressor gene expression, activation of antiapoptotic genes, or loss of pro-apoptotic gene expression o Tumor formation is driven by accumulation of mutations (drivers) in key genes that encode functions of cell cycle regulation, cell growth, and programmed cell death (clonal evolution) o Oncogene co-operativity: cells divide without regulation Important terms o Hereditary cancer syndrome: first cancer causing gene mutation inherited; therefore present in every cell in the body followed by a somatic mutation at a second point in time (ex: Lynch Syndrome) o Sporadic Cancer: a mutation occurs in a single cell; progression to tumor via accumulation of other mutations and clonal evolution o Oncogene (Onc): mutation of a proto-oncogene(normal cellular protein coding genes) that are involved in growth or cell survival that when altered stimulate cell division and proliferation o Tumor-Suppressor Gene (TSG): encode proteins that protect the transition of cells through checkpoints (gatekeepers)or proteins that protect cell division or integrity/stability of the genome (caretakers) o Loss of Function of caretakers: gene mutation that allows the accumulation of deleterious mutations in proto-oncogenes and gatekeepers that can initiate or promote cancer o Tumor Initiation: irreversible genetic alterations that allow dysfunction in a single cell Fearon- Vogelstein Adenoma- Carcinoma Model o Classic model for mutli-stage progression of colorectal cancer Cancer cell phenotypes o Immortality Replication of telomeres protected Loss of growth control via loss of tumor suppressor activity o Decreased dependence on growth factors for proliferation Tumor cells can autocrine signal with GF o Loss of anchorage dependent growth /altered cell adhesion Allows for metastasis through protealitic cleavage of BM MPPs (matrix metalloproteins)not normally expressed in adult cells but are over-expressed in tumor cells o Loss of cell cycle control (mitosis) CDKs control progression through cell cycle Controlled by oncogene and tumor suppressor gene products Invalid or abnormal checkpoints can produce genome instability and increased mutation frequency Cip/Kip family members: p21/ Cip1/ waf1/Sdi1, p21/Kip1, p57/Kip2 Proteins in this family ---broad specificity---bind and inactivate most of the cyclin/cdk complexes that are needed for the progression of the cell cycle o P53 when DNA damage detected—halts cell cycle for DNA repair (serious problem if this is mutated) INK4 Family members: p16/INK4a, p15/INK4b, p18/INK4c, p19/INK4d restricted binding to cdk4/6---primary function to regulate phosphorylation of Rb critical cell cycle checkpoint o Reduced sensitivity to apoptosis o Critical effectors: caspases o Death receptor mediated apoptosis examples: P38 promotes Bim/Bax>> caspase 9, inhibits Bcl-2 Fas/FasL (death inducing signaling complex= DISC)>> caspase 8 o Cancer overcomes these through overexpression of Bcl-2 and mutated Fas receptor o increased genetic instability chromosomal aneuploidy—gain or loss of one or more chromosomes chromosomal polyploidy---accumulation of extra set(s) of chromosomes Translocation and re-arrangements can provide growth advantages Examples: Burkitt’s lymphoma –t(8,14) translocation where c-myc protooncogene expressed from IgH promoter/enhancer due to chromosome re-positioning resulting in transcriptional fusion protein Philadelphia chromosome (CML)-- t(9;22) translocation where c-Abl+Bcr kinase +GAP are spliced to form constitutively active chimeric kinase that drives cell proliferation Gene amplification: multiple rounds of DNA replication at a single site o Angiogenesis (neo-vascularization with cancer cell proliferation) “angiogenic switch” up-regulation of angiogenesis and down-regulation of of anti-angiogenic factors significant transformation that leads to more lethal tumors VEGF—(vascular endothelial growth factor) first identified as a factor secreted from tumor cells caused normal blood vessels to become hyperpermeable Cancer genes o Oncogenes: derived from cellular genes (proto-oncogenes/c-onc) that become dysregulated as a result of mutation contribute to cell proliferation or decrease sensitivity to cell death o 7 classes of prot-oncogenes (Mutant forms alter intracellular cascades conferring selective growth advantage that allow tumors to develop) GF GF receptors GF and receptors autocrine signal up-regulating unregulated proliferation G proteins Activated by mutation and go on to activate further oncogenes RAS functions in cell proliferation, cell survival, and remodeling of the actin cytoskeleton Ser-Tyr kinases RAF recruited by ras and then activates one of mitogen-induced protein kinases (MAPKs) action invokes activation of transcription factors in nucleus containing “Elk-1” response elements can also activate protein kinase C that signals other kinases to activate –c-jun Non-receptor Tyr Kinase SRC o SH1 has kinase activity o SH2 and SH3 involved in protein-protein interactions intracellular signaling function---mutations may generate constitutive signaling within cell Bcr-Abl (Philadelphia chromosome) o chimeric fusion derived from t(9;22) in chronic myelogenous leukemia (CML)—Ph chromosome o c-Abl (chromosome 9) is a tyrosine kinase o Bcr (chromosome 22) is a GTPase activating (GAP) protein---fusion protein causes unregulated cell growth by initiating ras signaling---reduces growth factor dependence, alters cell adhesion properties, enhances cell viability Nuclear proteins Transcription factors o c-myc transcription factor Burkitt’s Lymphoma The c-myc gene is a central oncogenic switch for oncogenes and the tumor suppressor APC. o c-jun transcription factor (AP-1) osetosarcoma o c-fos transcription factor (AP-1) sarcoma o cellular functions include: cell proliferation and metastasis AP-1 nuclear target for growth factor induced signaling also regulates genes like the MMPs and gene products that aid in cell migration through connective tissue Telomerases o Telomerase activity has been observed to be active in cancer cells; allowing tumor cells to proliferate indefinitely mutation in telomerase gene up-regulated via other pathways or oncogene products uncharacteristic end to end fusions of chromosomes---disrupt mitosis important step in progression of cancer Cytoplasmic proteins engaged in cell survival o bcl-2 oncogene disrupts apoptotsis increased expression seen in variety tumor cells --associated with poor prognosis o Tumor Suppressor Genes For tumor suppressor product to generate a tumor both copies must be lost/ mutated---recessive effect! Two types: caretakers and gatekeepers Example Rb is first tumor suppressor gene identified---loss of RB protein produces cancer. Protein active in cell nucleus; when unphosphorylated binds to E2F transcription factor--- thus preventing transcription of E2F associated gene targets. When RB protein function disrupted ---deregulated cell cycle and uncontrolled cell division---E2F can keep activating its target genes. Dysregulated function requires loss of both Rb alleles Loss of Heterozygosity Tumor Suppressor Gene Inactivation "Loss of heterozygosity” (LOH) describes inactivation of the 2ndcopy of a tumor suppressor gene Mutations that inactivate tumor suppressor genes= “loss-of-function” mutations: point mutations or small indels that disrupt the protein function(s) Another example p53 tumor suppressor gene: activated in many cell functions DNA damage, hypoxia, ribonucleotide depletion, cell adhesion and cell stress created by activation cellular oncogenes Loss of function via three paths: o mutant p53 gene---seen in approx. 53% sporadic tumors and Li-Fraumeni Syndrome o viral transforming antigens—SV40 Large T antigen form inactive p53 complex o cytoplasmic sequestration—can’t enter nucleus to activate target genes APC mutations occur early in colon carcinogenesis---initiating event leads to activation of c-myc (an oncogene) since wildtype APC suppresses c-myc APC also assist in maintaining crypt migration of cells in intestine and apoptosis PTEN induces cell cycle cessation and apoptosis---negative regulator of Akt activation suppresses blood vessel growth (opposing VEGF) Heritable cancer syndromes o Li-Faumeni: germline p53 gene o Breast and ovarian cancer: BRCA, BRCA 2, RAD51C RAD51D o Lynch Syndrome (HNCCT): MSH2 and MLH1 mutation o Xeroderma Pigmentosum: XPC mutation o Franconi’s Anemia: FRACB genes o Bloom’s Syndrome: BLM mutation (recQ kinase) miRNAs and cancer o miRNAs can be tumor suppressors or modulate other genes with oncogenic o or tumor suppressor roles o miRNAs can increase expression to initiate cell processes contributing to cancer or they can decrease expression that leads to mis-regulation and cancer Chemical Carcinogenesis (DNA adducts) o Planar chemical---integrated into DNA forming an adduct can introduce mutations when DNA replicates during mitosis Summary o Cancer is a molecular genetic disease o Derived from a single cell by clonal expansion and co-operativity o Mutations in proto-oncogenes (c-myc, etc.) dominant o Mutations in tumor suppressor genes (Rb, etc.) recessive o Chemicals (benzene) and physical agents (radiation) can induce errors in DNA repair leading to cancer o Many cellular processes are disrupted as genome mutations accumulate and alter “normal” cell functioning o miRNA can alter cell functions that can cause cancer o Cancer can be predisposed/inherited in families: “two hit” hypothesis (Cancer Syndromes) o Chromosomal translocation: create fusion proteins or create transcriptional hybrids that alter cell function proteins that dysregulate cell function o Cancer cells can evade many critical cell activities: apoptosis, mitotic checkpoints, growth arrest, transcriptional controls, hormonal controls, etc. o Cancer is a multiple stage process: initiation, progression, metastatic transformation o Cancer therapies are being “custom” designed to block critical cancer cell activities (kinase Inhibitors) o Genetic signatures (profiles) of cancer tissue are used to estimate prognosis and recurrence rates