Inhibition of Ovarian Tumor Growth by Targeting the HU177 Cryptic Collagen Epitope

Abstract

Evidence suggests that stromal cells play critical roles in tumor growth. Uncovering new mechanisms that control stromal cell behavior and their accumulation within tumors may lead to development of more effective treatments. We provide evidence that the HU177 cryptic collagen epitope is selectively generated within human ovarian carcinomas and this collagen epitope plays a role in SKOV-3 ovarian tumor growth in vivo. The ability of the HU177 epitope to regulate SKOV-3 tumor growth depends in part on its ability to modulate stromal cell behavior because targeting this epitope inhibited angiogenesis and, surprisingly, the accumulation of a-smooth muscle actineexpressing stromal cells. Integrin a10b1 can serve as a receptor for the HU177 epitope in a-smooth muscle actineexpressing stromal cells and subsequently regulates Erkdependent migration. These findings are consistent with a mechanism by which the generation of the HU177 collagen epitope provides a previously unrecognized a 10 b 1 ligand that selectively governs angiogenesis and the accumulation of stromal cells, which in turn secrete protumorigenic factors that contribute to ovarian tumor growth. Our findings provide a new mechanistic understanding into the roles by which the HU177 epitope regulates ovarian tumor growth and provide new insight into the clinical results from a phase 1 human clinical study of the monoclonal antibody D93/TRC093 in patients with advanced malignant tumors. (Am J Pathol 2016 http://dx

Cancer-Associated Fibroblasts Build and Secure the Tumor Microenvironment

“…Halofuginone is an inhibitor of collagen I and was shown having anti-tumor activities in mouse models of prostate cancer (Gavish et al, 2002), pancreatic cancer (Spector et al, 2010) and lung cancer (Taras et al, 2006). D93/TRC093 is a humanized monoclonal antibody that specifically binds the HU177 cryptic collagen epitope within the tumor ECM with potential antiangiogenic and antitumor activities (Cretu et al, 2007; Caron et al, 2016). In the study conducted by Caron et al (2016) D93/TRC093 was found to restrict the accumulation of α-SMA+ fibroblasts, which could be explained by the inhibition of integrin α 10 β 1 -mediated fibroblast adhesion and migration on denatured collagen.…”

“…D93/TRC093 is a humanized monoclonal antibody that specifically binds the HU177 cryptic collagen epitope within the tumor ECM with potential antiangiogenic and antitumor activities (Cretu et al, 2007; Caron et al, 2016). In the study conducted by Caron et al (2016) D93/TRC093 was found to restrict the accumulation of α-SMA+ fibroblasts, which could be explained by the inhibition of integrin α 10 β 1 -mediated fibroblast adhesion and migration on denatured collagen. In a phase I clinical study, TRC093 was shown to be well-tolerated and had tumor-inhibitory effects as monotherapy and in combination with bevacizumab in 19 patients carrying different types of solid tumors (Robert et al, 2010).…”

Spontaneous mutation of Dock7 results in lower trabecular bone mass and impaired periosteal expansion in aged female Misty mice

“…Transwell cell migration assays were performed similarly to previously established protocols [28, 29]. Transwell inserts, 6.5 mm with 8 μm pore size, (29442-120, Corning, Corning, NY) were coated with 10 μg/mL collagen I (354236, Corning, Corning, NY) diluted in PBS overnight at 4°C.…”

“…Cell adhesion assays were performed similarly to previously established protocols [28, 29]. Flat bottom 48 well non-tissue culture treated plates (CC7672-7548, USA Scientific, Ocala, FL) were coated with collage I and blocked with BSA according to the protocol described for the transwell cell migration assay.…”

Cryptic collagen elements as signaling hubs in the regulation of tumor growth and metastasis

“…Although this human clinical study Erk phosphorylation (Caron et al, 2016). Surprisingly, Mab D93 also inhibited infiltration of CAF-like cells into SKOV-3 ovarian tumors growing in mice by nearly 70% (Caron et al, 2016). These data in conjunction with previous studies indicate that in addition to inhibiting angiogenesis, direct targeting the HU177 cryptic collagen element may also selectively limit migration and infiltration of CAF-like cells, which are thought to help provide tumors with many protumorigenic growth factors and cytokines as well as facilitating immune suppression.…”