Hallmarks of Cancer - Sustained Proliferative Signaling
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Transcript of Hallmarks of Cancer - Sustained Proliferative Signaling
Hallmarks of Cancer: Sustaining Proliferative Signaling
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)
Propagation of Normal Cells vs. Cancer Cells
The Big Question
• How do cancer cells acquire the ability to replicate continuously?
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
The Stages of Cell Signaling1. 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
Stages of Cell Signaling
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)
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)
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)
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)
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)
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
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)
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)
ReferenceHanahan, 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