Hallmarks of Cancer I (Jahn).pdf

The Hallmarks of Cancer Stephan C. Jahn, Ph.D. So… What IS cancer? Cancer is essentially a cell gone rogue. What makes a cell go rogue? Cells normally only grow when told to  Gas pedal Cells normally stop when they need to  Brakes DNA mutations make incorrect proteins...

The Hallmarks of Cancer Stephan C. Jahn, Ph.D. So… What IS cancer? Cancer is essentially a cell gone rogue. What makes a cell go rogue? Cells normally only grow when told to  Gas pedal Cells normally stop when they need to  Brakes DNA mutations make incorrect proteins  Gas pedal gets stuck  Brakes don’t work  The Hallmarks of Cancer Hanahan, D. and Weinberg, R. The Hallmarks of Cancer, Cell (2000) 100, p. 57-70 Hanahan, D. and Weinberg, R. Hallmarks of Cancer: The Next Generation, Cell (2011) 144, p. 646-674 Hallmark #1: Self-Sufficiency in Growth Signals Cell growth is normally tightly regulated, requiring a pro-growth signal. Cancer cells bypass this requirement in a number of ways George Weller [CC BY-SA 3.0 (https://creativecommons.org/licenses/by-sa/3.0)], from Wikimedia Commons An Introduction to Cell Signaling Pro-growth molecule (ligand) binds to extracellular domain Intracellular domain becomes active Signaling cascade proceeds Pro-growth proteins are transcribed Mechanisms to Become Self Sufficient Abnormal ligand production, autocrine (self) signaling Induced paracrine (external) signaling Upregulated receptor levels Mutation-induced constitutive signaling Yuji Miyamoto, Koichi Suyama and Hideo Baba [CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)], via Wikimedia Commons Ras Signaling Yuji Miyamoto, Koichi Suyama and Hideo Baba [CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)], via Wikimedia Commons Mutations in Ras Mutations in Ras are found in 20-30% of all cancers Point mutations in Ras are the most common abnormality in proto-oncogenes G12V mutation blocks GAP binding, locking Ras in it’s active state Q61K mutation raises the activation energy of GTP hydrolysis, blocking it Hallmark #2: Insensitivity to Anti- Growth Signals Normal cells need to overcome anti- growth signals in order to divide Anti-growth signals can be both normal and/or induced Anti-growth signals can originate either internally or externally The Tumor Suppressor p53 Transcription Mechanisms of p53 Inactivation >50% of tumors contain a mutation or deletion of p53 R72P mutation blocks DNA binding The Tumor Suppressor Rb George Weller [CC BY-SA 3.0 (https://creativecommons.org/licenses/by-sa/3.0)], from Wikimedia Commons The Tumor Suppressor Rb CNX OpenStax [CC BY 4.0 (https://creativecommons.org/licenses/by/4.0)], via Wikimedia Commons Mechanisms for Disregulation of Rb Mutant Rb  Protein is present, but unable to bind E2F Downregulated Rb  Protein is underexpressed, leaving unbound E2F Overactive Cdks  Wild-type protein is normally expressed, but is constitutively hyperphosphorylated, inactivating it Contact Inhibition Takai et al., Nature Reviews Molecular Cell Biology. 9.8 (Aug. 2008):