Alexander Drilon
Hallmarks of Cancer
• CAs share a set of common distinctive & complementary capabilities that enable tumor growth & met dissemination (Cell 2011;5:646)
Figure 4-1
Cancer Stem Cells
• Characterized by self-renewal & ability to differentiate; found in a variety of CAs including AML, CML, gliomas, breast CA (NEJM 2006;355:1253)
• Two pathways involved in regulation of pattern formation during ontogeny
Wnt pathway: (1) WNT ligands bind to FZD (Frizzled) receptor, (2) disrupts assembly of a complex (AXIN, APC, CK1, GSK3) that tags CTNBB1 (β-catenin) for degradation, (3) CTNBB1 moves to nucleus → binds TCF/LEF freeing it from TLE (Groucho), (4) CTNBB1 & TCF/LEF activate target genes (eg, CCND1, MYC); FAP develops 2° to germline inactivating Mt of APC(Nat Rev Cancer 2013;13:11)
Figure 4-2
Hedgehog pathway: (1) HH ligands SHH (Sonic), DHH (Desert), & IHH (Indian) bind to PTCH1 (Patched) releasing inhibitory effect on SMO (Smoothened), (2) causes dissociation of protein complex including SUFU, PKA, & GLI, (3) GLI translocates to nucleus to (4) activate target genes; BCCs w/activating SMO Mt or inactivating PTCH1 Mt, Gorlin syndrome (BCCs, medulloblastomas, rhabdomyosarcomas) w/germline PTCH1 Mt (Nat Rev Cancer2008;8:743)
Figure 4-3