Hypoxia-induced tumor cell autophagy mediates resistance to anti-angiogenic therapy.
While anti-angiogenic therapy was initially greeted enthusiastically by the cancer community, initial successes with this therapeutic modality were tempered by the failure of angiogenesis inhibitors to produce sustained clinical responses in most patients, with resistance to the inhibitors frequently developing. We recently reported that hypoxia increases after the devascularization caused by anti-angiogenic therapy, consistent with the goals of these therapies, but that some tumor cells become resistant and survive the hypoxic insult elicited by anti-angiogenic therapy through autophagy by activating both AMPK and HIF1A pathways. These findings suggest that modulating the autophagy pathway may someday allow anti-angiogenic therapy to fulfill its therapeutic potential. However, further work will clearly be needed to develop more potent and specific autophagy inhibitors and to better understand the regulators of autophagy in malignant cells.
Department of Neurosurgery, Diller Cancer Research Building, University of California at San Francisco (UCSF), San Francisco, CA, USA.
Yu-Long
YL
Hu
Arman
A
Jahangiri
Michael
M
De Lay
Manish K
MK
Aghi
D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D002986:Clinical Trials as Topic; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008954:Models, Biological; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000473:pathology; D059016:Tumor Microenvironment / Q000187:drug effects
D020533:Angiogenesis Inhibitors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit