Combined deletion of cathepsin protease family members reveals compensatory mechanisms in cancer.

Autor:	Akkari L; Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA; Department of Oncology, University of Lausanne, CH-1066, Lausanne, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, CH-1066, Lausanne, Switzerland., Gocheva V; Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;, Quick ML; Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;, Kester JC; Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;, Spencer AK; Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;, Garfall AL; Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;, Bowman RL; Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;, Joyce JA; Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA; Department of Oncology, University of Lausanne, CH-1066, Lausanne, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, CH-1066, Lausanne, Switzerland.
Jazyk:	angličtina
Zdroj:	Genes & development [Genes Dev] 2016 Jan 15; Vol. 30 (2), pp. 220-32.
DOI:	10.1101/gad.270439.115
Abstrakt:	Proteases are important for regulating multiple tumorigenic processes, including angiogenesis, tumor growth, and invasion. Elevated protease expression is associated with poor patient prognosis across numerous tumor types. Several multigene protease families have been implicated in cancer, including cysteine cathepsins. However, whether individual family members have unique roles or are functionally redundant remains poorly understood. Here we demonstrate stage-dependent effects of simultaneously deleting cathepsin B (CtsB) and CtsS in a murine pancreatic neuroendocrine tumor model. Early in tumorigenesis, the double knockout results in an additive reduction in angiogenic switching, whereas at late stages, several tumorigenic phenotypes are unexpectedly restored to wild-type levels. We identified CtsZ, which is predominantly supplied by tumor-associated macrophages, as the compensatory protease that regulates the acquired tumor-promoting functions of lesions deficient in both CtsB and CtsS. Thus, deletion of multiple cathepsins can lead to stage-dependent, compensatory mechanisms in the tumor microenvironment, which has potential implications for the clinical consideration of selective versus pan-family cathepsin inhibitors in cancer. (© 2016 Akkari et al.; Published by Cold Spring Harbor Laboratory Press.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu