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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Carcinogenesis / genetics
  • Carcinoma, Neuroendocrine / enzymology*
  • Carcinoma, Neuroendocrine / genetics
  • Carcinoma, Neuroendocrine / physiopathology
  • Cathepsins / genetics*
  • Cathepsins / metabolism*
  • Disease Models, Animal
  • Gene Deletion*
  • Gene Expression Regulation, Neoplastic
  • Gene Knockout Techniques
  • Macrophages / enzymology
  • Mice
  • Mice, Inbred C57BL
  • Neoplasm Invasiveness / genetics
  • Neovascularization, Pathologic / enzymology
  • Neovascularization, Pathologic / genetics
  • Pancreatic Neoplasms / enzymology*
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / physiopathology

Substances

  • Cathepsins