Hallmarks of Cancer Cells, Part 1 PDF

Video 45: Hallmarks of Cancer Cells, Part I Cancer versus a Corporation 1. Fuels its own growth 2. Counteracts growth-inhibiting factors 3. Resists to, and survives, adverse conditions from outside and inside 4. Grows without limits 5. Builds its own infrastructure to support functions 6. Acquires...

Video 45: Hallmarks of Cancer Cells, Part I Cancer versus a Corporation 1. Fuels its own growth 2. Counteracts growth-inhibiting factors 3. Resists to, and survives, adverse conditions from outside and inside 4. Grows without limits 5. Builds its own infrastructure to support functions 6. Acquires new resources and spaces (markets) The Six Basic Properties of Cancer Self-sufficiency in growth signals Insensitivity to anti-growth signals Evasion of apoptosis Sustained angiogenesis Limitless replicative potential Tissue invasion and metastasis Role of Mutations: Causing the Hallmarks Driver gene mutations: those crucial for the initiation, progression, and viability of the cancer Passenger mutations: mutations that may occur in cancer, but that do not contribute to cancer development Oncogenes: mutated, activated versions of proto-oncogenes, genes that normally control cell growth (Ras as an example) Tumor suppressor genes: genes that control cell growth, but when are mutated and lost, cancer results Oncogenic activation typically require mutation of one allele – one hit Tumor suppressor mutations typically require mutation of both alleles – the “two-hit hypothesis” Retinoblastoma is an example of cancer caused by the two-hit loss of the Rb tumor suppressor Most hereditary cancer syndromes are due to inheritance of one mutated allele of a tumor suppressor, the second hit occurs later (autosomal dominant) Most cancers require a series of mutations in different genes – the “multiple-hit hypothesis” – colorectal cancer is an example Cancer Cell Metabolism and Other Hallmarks The altered metabolism of cancer cells was recognized by Otto Warburg in the 1920s. Most cancers are glycolytic; however, there are additional deregulated metabolic pathways that contribute to uncontrolled proliferation. Video 45: Hallmarks of Cancer Cells, Part I Basic Properties of Cancer Cells: Self-sufficiency in Growth Signals Mitogens: diffusible growth factors, extracellular matrix components, cell-to-cell adhesion, and interaction molecules. Cancer cells exhibit reduced dependence upon exogenous growth stimulation, and this is based on different “strategies.” Strategies for Growth Signal (GS) Autonomy Alterations in the extracellular GS: normal cells are instructed to grow by their neighbors (paracrine signals) or via systemic (endocrine signals); however, in cancer cells, autocrine signaling is predominant. Alterations in the receptors of the GS: overexpression or structural changes of these receptors. Alterations in the types of extracellular matrix (ECM) receptors – integrins; the type of integrins influences the decisions of the cells to commit to quiescence, apoptosis, or proliferation. Alterations in the intracellular cascades that transmit the extracellular signals initiated by ligand-receptor binding; these are the most complex mechanisms of acquired GS autonomy. Growth Signal (GS) Autonomy through Alterations in the Intracellular Cascades In 25% of human tumors, the structurally altered RAS proteins are active without the need for ongoing stimulation from upstream regulators (i.e., receptors and mitogens). The RAS proteins activate the intracellular MAP kinase pathway. Accomplices to the Growth Signal (GS) Autonomy of Cancer Cells “Normal bystanders” such as fibroblasts, endothelial, immune, and fat cells may drive the proliferation of cancer cells by supplying growth and transformation signals. Video 45: Hallmarks of Cancer Cells, Part I Basic Properties of Cancer Cells: Insensitivity to Antigrowth Signals Insensitivity to Antigrowth Signals pRB: Almost all antigrowth signals are funneled through pRB and its related proteins (p107 and p130). E2F: Transcriptional factors; when bound by pRB, they are inactive. pRB-E2F: Blocks progress from G1 to S phase. Mechanisms of resistance to antigrowth signals: 1. Mutations in pRB or downstream/upstream factors. 2. Sequestration of pRB (e.g., in papillomavirus-induced cervical carcinomas, pRB is sequestered by the viral oncoprotein E7). 3. Modulated phosphorylation of pRB (only hypophosphorylated pRB is active and binds to the E2F transcription factors). Video 45: Hallmarks of Cancer Cells, Part I Basic Properties of Cancer Cells: Evading Apoptosis The overexpression of oncogenes or loss of tumor suppressors frequently results in high apoptosis. Tumor growth takes place only if the cells acquire resistance to apoptosis. How does resistance to apoptosis develop: There are sensors and effectors of the apoptotic machinery. The sensors are responsible for monitoring the extracellular and intracellular cues of whether the cell should live or die. Examples: cell surface receptors bind to survival or death signals (FAS ligand binds the FAS receptor, TNF-alpha binds the receptor TNF-R1). Intracellular sensors respond to abnormalities such as DNA damage, increased proliferation signaling, and hypoxia. The sensors regulate the effectors of apoptotic death (e.g., caspases, intracellular proteinases). The Major Sensor of Apoptotic Signals – p53 p53 is mutated in more than 50% of the human cancers. p53 senses DNA damage, hypoxia, and oncogene overexpression. p53 induces an apoptotic effector cascade. Apoptotic Pathways: an Example Most apoptotic signals converge on the mitochondria that release cytochrome C, a catalyst of apoptosis. The release of cytochrome C is modulated by members of the BCL-2 family of proteins, some of which are: - Pro-apoptotic (e.g., BAX, BAK). - Anti-apoptotic (e.g., BCL-2, BCL-XL). The apoptotic cascade (simplified): p53 upregulates BAX expression in response to DNA damage → BAX stimulates the release of cytochrome C from mitochondria →cytochrome C in the cytosol activates caspases. Putting It Together Cancer cells have six basic properties and cancer typically exhibits altered metabolism. Cancer cells are self-sufficient for growth signaling. Cancer cells are insensitive to anti-growth signaling. Cancer cells evade apoptosis.