Journal
GENES & DEVELOPMENT
Volume 30, Issue 2, Pages 220-232Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.270439.115
Keywords
invasion; macrophage; tumor microenvironment
Categories
Funding
- National Institutes of Health/National Cancer Institute Cancer Center [P30 CA008748]
- American Cancer Society Research Scholar Grant [RSG-12-076-01-LIB]
- Gerardo Rosenkranz Neuroendocrine Research Fund
- American Brain Tumor Association
- Geoffrey Beene Cancer Center
- Howard Hughes Medical Institute
- National Cancer Institute [5F31CA167863-04]
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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.
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