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Hallmarks of Cancer - Sustained Proliferative Signaling

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Hallmarks of Cancer - Sustained Proliferative Signaling

  1. 1. Hallmarks of Cancer: Sustaining Proliferative Signaling
  2. 2. The Fundamentals of Cancer • The ability of cancer cells to sustain chronic proliferation is fundamental • Allows cancer cells to grow into tumors, metastasize, and invade other regions of the body (Hanahan and Weinberg, 2011)
  3. 3. Propagation of Normal Cells vs. Cancer Cells
  4. 4. The Big Question •How do cancer cells acquire the ability to replicate continuously?
  5. 5. Sustained Proliferative Signaling • Cancer cells maintain constant growth through sustaining proliferative signaling • Deregulation of cell signaling pathways allows cancers cells to upregulate growth signals and downregulate anti- growth signals
  6. 6. The Stages of Cell Signaling 1. Reception: Binding between a ligand molecule and receptor; highly specific 2. Transduction: conversion of a signal to a form that can bring about a specific response via phosphorylation cascade, protein kinases, and second messengers 3. Response: Regulation of gene expression or cytoplasmic activities
  7. 7. Stages of Cell Signaling
  8. 8. Mechanisms of Proliferative Signaling • Normal cells require mitogenic growth signals in order to proliferate • Cancer cells acquire growth signal autonomy in a variety of ways (Hanahan and Weinberg, 2011)
  9. 9. Production of Growth Signals • Cancer cells produce their own growth signals • Ability to synthesize growth factors and signaling molecules to which they are responsive (Fedi et al., 1997) • Creates positive feedback loop for cell growth • Example: Production of PDGT and TGF-alpha by glioblastomas and sarcomas (Fedi et al., 1997)
  10. 10. Overexpression of Receptors • Cancer cells over-express receptor proteins, in particular, growth factor receptors • Causes cancer cells to become hyper- responsive to external growth signals (Fedi et al., 1997) • Example: Epidermal GF receptor is up- regulated in stomach, brain, and breast tumors (Slamon et al.,1987)
  11. 11. Ligand-Independent Signaling • Over-expression of growth factor receptors induces ligand-independent signaling (DiFoire et al., 1987) • No need for signaling molecules to trigger cell division and growth • Same result achieved through structural alterations of receptor proteins • Example: Modified EGF receptor induces non- stop signaling (Fedi et al., 1997)
  12. 12. Downstream Alterations • Downstream alterations of intracellular circuits can trigger proliferative signaling • SOS-Ras-Raf-MAP Kinase growth pathway • Example: In 25% of tumors, Ras proteins are modified to induce mitogenic signals downstream of the GF receptor (Medema and Bos, 1993)
  13. 13. Recruitment of Normal Cells • Cancer cells recruit normal cells neighbors to supply growth factors and signals • Cancer cells stimulate normal cells to release growth factors into the tumor microenvironment (Cheng et al., 2008; Bhowmick et al., 2004) • Key role of fibroblasts and endothelial cells • Paracrine signaling vs. endocrine signaling
  14. 14. The Genetic Basis of Unregulated Growth: Mutation • Genetic mutation leads to cancer • Over-expression of oncogenes, under-expression of tumor suppressor genes • Mutations in oncogenes mimic growth signaling (Hanahan and Weinberg, 2000) • About half of human tumors have mutant Ras oncogenes (Kinzler and Vogelstein, 1996)
  15. 15. New Research • Somatic mutations activate additional downstream pathways • About 40% of human melanomas contain mutations affecting B-Raf proteins in the MAP- kinase pathway (Davies and Samuels, 2010) • Defects in negative-feedback loops promote proliferative signaling • Mutations in Ras oncogenes compromise GTPase activity, which regulates proliferative signaling (Hanahan and Weinberg, 2011)
  16. 16. Reference Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of Cancer: The Next Generation. Cell, 144, 646-674. Hanahan, D., & Weinberg, R.A. (2000). The Hallmarks of Cancer. Cell, 100, 57-70