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Inhibiting Autophagy in Renal Cell Cancer and the Associated Tumor Endothelium

Russell, Kira L., BS*†; Gorgulho, Carolina Mendonça, BS*†; Allen, Abigail, BS; Vakaki, Marianna, BS§; Wang, Yue, MD*†; Facciabene, Andrea, PhD; Lee, Daniel, MD, PhD; Roy, Partha, PhD; Buchser, William J., PhD§; Appleman, Leonard J., MD, PhD; Maranchie, Jodi, MD#; Storkus, Walter J., PhD**; Lotze, Michael T., MD*†‡

doi: 10.1097/PPO.0000000000000374
Original Article

The clear cell subtype of kidney cancer encompasses most renal cell carcinoma cases and is associated with the loss of von Hippel-Lindau gene function or expression. Subsequent loss or mutation of the other allele influences cellular stress responses involving nutrient and hypoxia sensing. Autophagy is an important regulatory process promoting the disposal of unnecessary or degraded cellular components, tightly linked to almost all cellular processes. Organelles and proteins that become damaged or that are no longer needed in the cell are sequestered and digested in autophagosomes upon fusing with lysosomes, or alternatively, released via vesicular exocytosis. Tumor development tends to disrupt the regulation of the balance between this process and apoptosis, permitting prolonged cell survival and increased replication. Completed trials of autophagic inhibitors using hydroxychloroquine in combination with other anticancer agents including rapalogues and high-dose interleukin 2 have now been reported. The complex nature of autophagy and the unique biology of clear cell renal cell carcinoma warrant further understanding to better develop the next generation of relevant anticancer agents.

From the Departments of *Surgery,


Bioengineering, University of Pittsburgh, Pittsburgh, PA;

§Department of Genetics, Washington University, St Louis, MO;

Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA; and

Departments of Medicine,


**Dermatology, University of Pittsburgh, Pittsburgh, PA.

The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.

Reprints: Kira L. Russell, BS, PMC Hillman Cancer Center, Rm G.27A 5117, Centre Ave, Pittsburgh, PA 15213. E-mail:

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