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Genes Dev. 2016 Jan 15;30(2):220-32. doi: 10.1101/gad.270439.115.

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

Author information

1
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.
2
Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;

Abstract

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.

KEYWORDS:

invasion; macrophage; tumor microenvironment

PMID:
26773004
PMCID:
PMC4719311
DOI:
10.1101/gad.270439.115
[Indexed for MEDLINE]
Free PMC Article

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