Distinct functions of macrophage-derived and cancer cell-derived cathepsin Z combine to promote tumor malignancy via interactions with the extracellular matrix
01.10.2014
Akkari L, Gocheva V, Kester JC, Hunter KE, Quick ML, Sevenich L, Wang HW, Peters C, Tang LH, Klimstra DS, Reinheckel T, Joyce JA.
Genes Dev. 2014;28(19):2134-50.
During the process of tumor progression, cancer cells can produce the requisite growth- and invasion-promoting factors, or instead rely on non-cancerous cells in the tumor microenvironment as an alternative, cell-extrinsic source. However, whether the cellular source influences the function of such tumor-promoting factors remains an open question. Here, we examined the roles of the cathepsin Z (CtsZ) protease, which is provided by tumor cells and macrophages in pancreatic neuroendocrine cancers in humans and mice. We found that tumor proliferation was exclusively regulated by cancer cell-intrinsic functions of CtsZ, whereas tumor invasion required contributions from both macrophages and cancer cells. Interestingly, several of the tumor-promoting functions of CtsZ were proteolysis-independent, and instead mediated via the RGD-binding motif in the enzyme prodomain, which regulated interactions with the extracellular matrix. Together, these results underscore the complexity of interactions within the tumor microenvironment, and indicate that cellular source can indeed impact molecular function.
