Six hallmarks of cancer proposed in 2000
Emerging hallmarks
Sustaining Proliferative Signaling
• The most fundamental trait of cancer cells involves their ability to sustain chronic proliferation
more elaborate than simple shutdown of its antiproliferative signaling circuitry
activate EMT
• 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
• Disruptions of negative-feedback mechanisms that attenuate proliferative signaling
• Excessive proliferative signaling can trigger cell senescence: RAS,MYC.
• 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
at the cancer cell surface • Structural alterations in the s activate additional downstream
pathways. EGFR mutation in NSCLC, B-Raf mutation in melanoma.
Paper sharing:
Hanahan D, Weinberg R. Hallmarks of Cancer: The Next Generation.
Cell, 2011,144( 5): 646-674.
Dept. Medical Oncology, 1st Affiliated Hospital ****University
• 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
• Normal tissues ensuring a homeostasis by carefully control thing the production and release of growth-promoting signals
• Cancer cells, by deregulating these signals, become masters of their own destinies.
• Two prototypical tumor suppressors encode the RB and TP53 proteins
• To remove contact Inhibition • Corruption of the TGF-b Pathway Promotes Malignancy,
• 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.
• Alternatively, in the face of alarm signals indicating overwhelming or irreparable damage to such cellular subsystems, TP53 can trigger apoptosis.
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 genes
• 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, growthpromoting signals, glucose, or oxygenation are suboptimal, TP53 can call a halt to further cellcycle progression until these conditions have been normalized.