Type II transmembrane serine proteases as potential targets for cancer therapy

Abstract

Carcinogenesis is accompanied by increased protein and activity levels of extracellular cell-surface proteases that are capable of modifying the tumor microenvironment by directly cleaving the extracellular matrix, as well as activating growth factors and proinflammatory mediators involved in proliferation and invasion of cancer cells, and recruitment of inflammatory cells. These complex processes ultimately potentiate neoplastic progression leading to local tumor cell invasion, entry into the vasculature, and metastasis to distal sites. Several members of the type II transmembrane serine protease (TTSP) family have been shown to play critical roles in cancer progression. In this review the knowledge collected over the past two decades about the molecular mechanisms underlying the pro-cancerous properties of selected TTSPs will be summarized. Furthermore, we will discuss how these insights may facilitate the translation into clinical settings in the future by specifically targeting TTSPs as part of novel cancer treatment regimens.

Figure 1. Simple schematic representation showing two TTSPs, matriptase and hepsin, that are localized on the cell surface of cancer cells

Proteolytic cleavage of stromal cell-secreted pro-HGF to signaling competent HGF elicits the HGF/c-Met pro-oncogenic signaling pathway in cancer. Matriptase activates pro-HGF in squamous cell carcinomas (Szabo et al., 2011) and in breast cancer in vivo (Zoratti et al., 2015). Hepsin has been reported to activate pro-HGF in immortalized mammary epithelial cells (Tervonen et al., 2016) and in prostate cancer cells (Owen et al., 2010). TMPRSS2 (not shown) has been proposed to activate pro-HGF in prostate cancer (Lucas et al., 2014). The development of inhibitors of matriptase, hepsin or TMPRSS2 may represent alternatives to existing receptor tyrosine kinase inhibitors to impair invasion, proliferation and metastasis. Diagnostic imaging of protease activity is also being explored using, e.g. specific antibodies and activity-based probes.