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Evading Growth Suppressors
• Cancer cells must circumvent powerful programs that negatively regulate cell proliferation
• Many of these programs depend on the actions of tumor suppressor einberg R. Hallmarks of Cancer: The Next Generation.
Cell, 2011,144( 5): 646-674.
Dept. Medical Oncology, 1st Affiliated Hospital ****University
• Normal tissues ensuring a homeostasis by carefully control thing the production and release of growthpromoting signals
• Cancer cells, by deregulating these signals, become masters of their own destinies.
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• Cancer cells can produce growth factor ligands
• Send signals to stimulate normal cells within the supporting tumor-associated stroma
• Elevating the levels of receptor proteins displayed at the cancer cell surface
• Cancer cells with defects in RB pathway function are missing the services of a critical gatekeeper of cell-cycle progression whose absence permits persistent cell proliferation.
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• The enabling signals are conveyed in large part by growth factors that bind cell-surface receptors
• Cancer cells can acquire the capability to sustain proliferative signaling in a number of alternative ways
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• TP53 receives inputs from stress and abnormality sensors
• If the degree of damage to the genome is excessive, or if the levels of nucleotide pools, growth-promoting signals, glucose, or oxygenation are suboptimal, TP53 can call a halt to further cell-cycle progression until these conditions have been normalized.
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Six hallmarks of cancer proposed in 2000
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Emerging hallmarks
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Sustaining Proliferative Signaling
• The most fundamental trait of cancer cells involves their ability to sustain chronic proliferation
• Structural alterations in the receptor molecules
• Somatic mutations activate additional downstream pathways. EGFR mutation in NSCLC, B-Raf mutation in melanoma.
• Alternatively, in the face of alarm signals indicating overwhelming or irreparable damage to such cellular subsystems, TP53 can trigger apoptosis.
• Two prototypical tumor suppressors encode the RB and TP53 proteins
• To remove contact Inhibition • Corruption of the TGF-b Pathway Promotes Malignancy,
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• Disruptions of negative-feedback mechanisms that attenuate proliferative signaling
• Excessive proliferative signaling can trigger cell senescence: RAS,MYC.
more elaborate than simple shutdown of its antiproliferative signaling circuitry activate EMT
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• The RB protein integrates signals from diverse extracellular and intracellular sources and, in response, decides whether or not a cell should proceed through its growth-and-division cycle