Matrix metalloproteinases in stem cell regulation and cancer

Abstract

Since Gross and Lapiere firstly discovered matrix metalloproteinases (MMPs) as important collagenolytic enzymes during amphibian tadpole morphogenesis in 1962, this intriguing family of extracellular proteinases has been implicated in various processes of developmental biology. However, the pathogenic roles of MMPs in human diseases such as cancer have also garnered widespread attention. The most straightforward explanation for their role in cancer is that MMPs, through extracellular matrix degradation, pave the way for tumor cell invasion and metastasis. While this notion may be true for many circumstances, we now know that, depending on the context, MMPs may employ additional modes of functionality. Here, we will give an update on the function of MMPs in development and cancer, which may directly regulate signaling pathways that control tissue homeostasis and may even work in a non-proteolytic manner. These novel findings about the functionality of MMPs have important implications for MMP inhibitor design and may allow us to revisit MMPs as drug targets in the context of cancer and other diseases.

Keywords: Cancer; Cell differentiation; Hemopexin domain; Invasion; Stem cell niche.

Fig. 1

The role of MMP3 in the mammary stem cell niche. (A–C) MMP3 promotes hyperplastic growth in orthotopic transplants of lentivirally transduced mammary epithelial cells. Compared to control transplants (A), overexpression of proteolytically active full-length MMP3 (B) and MMP3-hemopexin domain (C) both promote a hyperplastic growth phenotype. (D.) This can be explained by the specific interaction of MMP3 with the non-canonical Wnt ligand Wnt5b, an inhibitor canonical Wnt signaling. Thereby, overexpression of MMP3 tips the balance towards canonical Wnt signaling, which promotes stem cell expansion and may disrupt epithelial homeostasis and lead to breast tumor formation. (E) Computational structural model of the complex formed by binding of MMP3 (blue) to Wnt5b (green) shown with minimal binding domain (pink). Modified from Kessenbrock et al., 2013.

Fig. 2

The hemopexin (HPX) domain as a non-proteolytic functional unit of MMPs. MMPs typically consist of various domains including the Pre/Pro-domains, which need to be cleaved off to convert the zymogen into an active protease. Proteolytic activity is mediated through catalytic domain (CD). The C-terminal hemopexin (HPX) domain is present at the C-terminus of most members of the MMP family except for MMP7, -23 and -26, and is believed to mainly mediate substrate specificity via protein–protein interactions. Mounting evidence suggests that MMPs may function in a non-proteolytic manner, which is often exhibited through the HPX domain. These functions may be crucially implicated in MMP-mediated promotion of tumor progression. This has important implications for drug design and may explain why clinical trials using small compound inhibitors designed to target the CD of MMPs (MMPi) have yielded disappointing results. Future research should determine whether MMPs may be revisited as anti-cancer drug targets by specifically interfering with the non-proteolytic HPX-mediated function.