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Hallmarks of Cancer Biology A) Definition and Historical Background 1) What is cancer? Before the 19th century, cancer was often portrayed as a foreign body. In the 19th century, two key discoveries changed the way we think about human development and the definition of cancer: a) all tissues are composed of cells b) all cells arise from pre-existing cells that can be traced back to the fertilized egg Cancer is a group of cells (tumor) that are derived from a normal cell, but have lost the ability to form normal tissues with normal function. Instead, cancer cells gain new functions: a) the primary tumor can spread to distant sites to form a metastasis b) primary tumor or metastasis can invade normal structures, which may cause pain, bleeding, neurological dysfunction c) para-neoplastic syndromes: cachexia 2) Benign vs. Malignant Tumor (growth of cells): a) Benign—Tumor that does not invade adjacent tissues and metastasize. Benign tumors follow some of the rules that normal cells follow b) Malignant (Cancer) —Tumors that grow uncontrollably, invade, and metastasize B) Cancers Can be Classified According to Their Tissue of Origin a) Carcinomas—derived from epithelial cells • Lung, Breast, Prostate, GI, Head & Neck, Cervix b) Sarcomas—derived from mesenchymal cells • Osteosarcoma, Undifferentiated Pleomorphic Sarcoma, Rhabdomyosarcoma c) Hematopoietic Malignancies • Leukemia, Lymphoma d) Neuroectodermal Malignancies • GBM, Neuroblastoma, Medulloblastoma DO NOT COPY OR USE THIS MATERIAL WITHOUT PERMISSION 8/31/16 David Kirsch, M.D., Ph.D. and Elaine Zeman, Ph.D 1 Hallmarks of Cancer Biology C) How does cancer develop? Cancer develops from normal cells over many years, through a process termed tumorigenesis. In some types of cancers, such as colon cancer, normal cells become adenomas (benign tumors), which can then progress through a series of genetic and epigenetic changes to become adenocarcinomas (malignant tumors). Adenoma to Carcinoma Progression Why so long? Multiple mutations must arise within the same cell and may need a promoting microenvironment. DO NOT COPY OR USE THIS MATERIAL WITHOUT PERMISSION 8/31/16 David Kirsch, M.D., Ph.D. and Elaine Zeman, Ph.D 2 Hallmarks of Cancer Biology Molecular Basis for Colon Cancer Progression Genetic differences between normal and tumor cells help determinethe therapeutic ratio of cancer therapy. Not every colon cancer has the same mutations: Genome scale analysis: 276 human colon and rectal cancers July18,2012 - whole exome sequence - 97 whole genome sequencing 276 human colon and rectal cancers -whole exome sequencing -97 whole genome sequencing Findings: 16% hypermutated -3/4 silencing of MLH1 by promoter methylation -1/4 mismatch-repair gene or DNA Pole mutation 84%: 24 genes significantly mutated over background: APC, p53, SMAD4, PI3KCA, Ras DO NOT COPY OR USE THIS MATERIAL WITHOUT PERMISSION 8/31/16 David Kirsch, M.D., Ph.D. and Elaine Zeman, Ph.D 3 Hallmarks of Cancer Biology The genes mutated in human cancer form molecular circuits that regulate the behavior of normal cells. July 31, 2014 230 untreated tumors: Analyzed at the DNA, RNA and protein levels DO NOT COPY OR USE THIS MATERIAL WITHOUT PERMISSION 8/31/16 David Kirsch, M.D., Ph.D. and Elaine Zeman, Ph.D 4 Hallmarks of Cancer Biology Whole Exome Sequencing: 18 Significantly Mutated Genes in Human Lung Adenocarcinoma Pathway Alterations in Lung Adenocarcinoma: 1) 2) 3) 4) 5) 6) RTK/RAS/RAF (76%) PI3K-mTOR activation (25%) p53 pathway alteration (63%) Cell cycle regulators altered (64%) Oxidative stress pathways (22%) Chromatin and RNA splicing (49%) DO NOT COPY OR USE THIS MATERIAL WITHOUT PERMISSION 8/31/16 David Kirsch, M.D., Ph.D. and Elaine Zeman, Ph.D 5 Hallmarks of Cancer Biology April 18, 2012 First 1000 tumors applied copy number, gene expression & clinical outcome -10 Integrative Subgroups: DO NOT COPY OR USE THIS MATERIAL WITHOUT PERMISSION 8/31/16 David Kirsch, M.D., Ph.D. and Elaine Zeman, Ph.D 6 Hallmarks of Cancer Biology Different parts of the same renal cell carcinoma or metastases from the same patient share some, but not all mutations. DO NOT COPY OR USE THIS MATERIAL WITHOUT PERMISSION 8/31/16 David Kirsch, M.D., Ph.D. and Elaine Zeman, Ph.D 7 Hallmarks of Cancer Biology The bad news for students (but the good news for patients): The genetic differences between various cancers may determine how aggressively individual cancers behave and may help determine the efficacy of cancer therapies. Therefore the details of the pathways matter, but for now the list of clinically relevant genetic differences is short: a) Breast cancer: ER/PR status, Her2 amplification, gene expression profiles b) Gastrointestinal Stromal Tumors: c-kit mutations The good news for students: most of the gene mutations that cause cancer appear to regulate 6 pathways, which have been termed the Hallmarks of Cancer (Hanahan and Weinberg Cell 2000): ras mutation p53 mutation Apc mutation DO NOT COPY OR USE THIS MATERIAL WITHOUT PERMISSION 8/31/16 David Kirsch, M.D., Ph.D. and Elaine Zeman, Ph.D 8 Hallmarks of Cancer Biology TianSetal.BiomarkerInsights2010 DO NOT COPY OR USE THIS MATERIAL WITHOUT PERMISSION 8/31/16 David Kirsch, M.D., Ph.D. and Elaine Zeman, Ph.D 9 Hallmarks of Cancer Biology We will focus on the 6 Hallmarks of Cancer: 1. Insensitivity to anti-growth signals (Tumor Supressor Genes) 2. Self-sufficiency in growth signals (Oncogenes) 4. Sustained angiogenesis 5. Tumor invasion and metastasis 6. Limitless replicative potential 3. Evading apoptosis or cell death Hallmarks of Cancer: The Next Generation (Hanahan and Weinberg Cell 2011): DO NOT COPY OR USE THIS MATERIAL WITHOUT PERMISSION 8/31/16 David Kirsch, M.D., Ph.D. and Elaine Zeman, Ph.D 10 Hallmarks of Cancer Biology Boss M-K et al. Radiation Research 2014 DO NOT COPY OR USE THIS MATERIAL WITHOUT PERMISSION 8/31/16 David Kirsch, M.D., Ph.D. and Elaine Zeman, Ph.D 11 Hallmarks of Cancer Biology Examples from the molecular basis of colon cancer progression: 1) Insensitivity to anti-growth signals: APC mutation Familial adenomatous polyposis Normal Colon APC functions in the cytoplasm of epithelial cells of the colon to relay growth inhibiting signals to the nucleus by regulating the levels of b-catenin. At high levels, b-catenin binds to TCF in the nucleus and “turns on” genes that create a stem-cell-like state— the cells self-renew and do not differentiate. APC is a large protein that brings GSK-3b and b-catenin together, so that b-catenin can be phosphorylated by GSK-3b and can be targeted for degradation by the proteosome. At the base of the crypts, stromal cells secrete Wnts, which suppress GSK-3b function. As cells move away from the crypt, the levels of Wnts decreases; this anti-growth signal activates GSK-3b and the level of b-catenin decreases. APC is required for GSK-3b to interact with b-catenin. 90% of all sporadic colon cancers have mutations in APC. Without APC, b-catenin levels accumulate in cells in which Wnts (the anti-growth signal) is absent, and these cells do not migrate up the crypt and differentiate. Over time, these cells form a benign polyp. DO NOT COPY OR USE THIS MATERIAL WITHOUT PERMISSION 8/31/16 David Kirsch, M.D., Ph.D. and Elaine Zeman, Ph.D 12 Hallmarks of Cancer Biology What about the other 10% of colon cancers? Many have mutations in b-catenin. This mutant b-catenin can not be phosphorylated by GSK-3b. This is an alternative mechanism to activate b-catenin in the absence of Wnts. 2) Self-sufficiency in growth signals: Ras mutation Tyrosine kinase (TK) receptors, such as the epidermal growth factor receptor (EGFR), bind to extra-cellular growth factors. Then they become active and phosphorylate targets that convert inactive Ras (GDP bound) to active Ras (GTP bound). Active Ras, in turn, “turns on” several different signaling cascades, such as the MAP kinase pathway. In the absence of growth factors, Ras is converted back into an inactive (GDP bound) state. Mutant Ras (*) is locked in the GTP-bound state even when there is no signal from the growth factor receptor. Clinical Correlation: Colon cancers with K-ras mutations do not respond to cetuximab. Response Rate to Cetuximab Wild-type Ras 40% Mutant Ras 0% Lievre et al. J Clin Oncol 2008 Blocking EGFR with a monoclonal antibody (cetuximab) is not able to block the growth of colon cancer cells when the signaling pathway downstream of EGFR is constitutively active as a result of Ras mutations. DO NOT COPY OR USE THIS MATERIAL WITHOUT PERMISSION 8/31/16 David Kirsch, M.D., Ph.D. and Elaine Zeman, Ph.D 13 Hallmarks of Cancer Biology 3) Evading apoptosis The tumor suppressor protein p53 is induced by a variety of stimuli, including hypoxia. As a benign tumor grows, areas of hypoxia can undergo p53dependent apoptosis. Mutations in p53 prevent apoptosis and can allow tumor cells to survive in regions of hypoxia. 4) Sustained Angiogenesis (Dr. Palmer) 5) Tumor Invasion and Metastasis (Dr. Metheny-Barlow) DO NOT COPY OR USE THIS MATERIAL WITHOUT PERMISSION 8/31/16 David Kirsch, M.D., Ph.D. and Elaine Zeman, Ph.D 14 Hallmarks of Cancer Biology 6) Limitless replicative potential • Macroscopic tumor growth requires § Growth signal autonomy § Insensitivity to antigrowth signals § Resistance to cell death § Disruption of program that limits multiplication • Cell autonomous • Cancer cells become immortalized Number of population doublings in the absence of cell death required to reach tumors of various sizes Many cells within a tumor die or may not be clonogenic (i.e., may not be able to divide into daughter cells). Therefore, the number of population doublings needed to generate a macroscopic tumor is much higher than 40. DO NOT COPY OR USE THIS MATERIAL WITHOUT PERMISSION 8/31/16 David Kirsch, M.D., Ph.D. and Elaine Zeman, Ph.D 15 Hallmarks of Cancer Biology Normal human fibroblasts display the Hayflick Phenomenon: after a certain number of population doublings, the cells undergo a process termed “replicative senescence,” and stop dividing. Senescence correlates with increased levels of cyclin-dependent kinase inhibitors (p21 and p16): NormalCells Ectopicp16 Replicative Senescence Senescence has been identified in benign nevi (moles) by the staining of senescence-associated bgalactosidase (blue cells in figure): DO NOT COPY OR USE THIS MATERIAL WITHOUT PERMISSION 8/31/16 David Kirsch, M.D., Ph.D. and Elaine Zeman, Ph.D 16 Hallmarks of Cancer Biology Cells can acquire additional mutations and bypass of senescence: • Senescence can be bypassed by loss of Rb and p53 • These cells are Not immortalized • After an additional 10 to 20 population doublings the cells enter “crisis” Crisis: result of dicentric chromosomes that undergo mitotic catastrophe (dicentric) DO NOT COPY OR USE THIS MATERIAL WITHOUT PERMISSION 8/31/16 David Kirsch, M.D., Ph.D. and Elaine Zeman, Ph.D 17 Hallmarks of Cancer Biology Why is there telomere erosion? DNA replication occurs from a short RNA primer that must bind to complementary DNA. At the end of the DNA molecule, there is no place for the RNA Primer to bind. With each round of cell division, the end of the chromosome (telomere) shortens. The solution to this end problem: telomerase—an enzyme made up of proteins and RNA, which contains its own RNA primer to syntheize DNA at the end of the chromosome. To avoid crisis, rare cells that have by-passed senescence by losing the Rb and p53 tumor suppressor pathways, express high levels of telomerase. These cells are now immortalized (can divide with infinite replicative potential). DO NOT COPY OR USE THIS MATERIAL WITHOUT PERMISSION 8/31/16 David Kirsch, M.D., Ph.D. and Elaine Zeman, Ph.D 18 Hallmarks of Cancer Biology Poremba et al J Clin Oncol 2000 Ohali et al J Clin Oncol 2003 Clinical Correlation: Telomerase levels correlate with outcome in some pediatric cancers To summarize: Limitless Replicative Potential results as a consequence of: 1) Senescence (as a result of increased cyclin-dependent kinase inhibitors) 2) Crisis (as a result of telomere erosion) By-pass of senescence requires loss of p53 and Rb pathways, and to prevent crisis telomerase can be overexpressed. This results in immortalization of the cells. Take Home Points • Cancer develops through a variety of mutations that alters 6 conserved pathways o Self-sufficiency in growth signals o Insensitivity to anti-growth signals o Evading apoptosis o Angiogenesis o Metastasis o LimitlessReplicativePotential DO NOT COPY OR USE THIS MATERIAL WITHOUT PERMISSION 8/31/16 David Kirsch, M.D., Ph.D. and Elaine Zeman, Ph.D 19