Abstract
Extracellular matrix (ECM) plays an important role in tumor development and dissemination, but few points of therapeutic intervention targeting ECM of the tumor microenvironment have been exploited to date. Recent observations suggest that the enzymatic introduction of disulfide bond cross-links into the ECM may be modulated to affect cancer progression. Specifically, the disulfide bond-forming activity of the enzyme Quiescin sulfhydryl oxidase 1 (QSOX1) is required by fibroblasts to assemble ECM components for adhesion and migration of cancer cells. Based on this finding and the increased QSOX1 expression in the stroma of aggressive breast carcinomas, we developed monoclonal antibody inhibitors with the aim of preventing QSOX1 from participating in pro-metastatic ECM remodeling. Here we show that QSOX1 inhibitory antibodies decreased tumor growth and metastasis in murine cancer models and had added benefits when provided together with chemotherapy. Mechanistically, the inhibitors dampened stromal participation in tumor development, as the tumors of treated animals showed fewer myofibroblasts and poorer ECM organization. Thus, our findings demonstrate that specifically targeting excess stromal QSOX1 secreted in response to tumor-cell signaling provides a means to modulate the tumor microenvironment and may complement other therapeutic approaches in cancer.
Highlights
Tumor-induced remodelling of genetically normal adjacent tissues offers opportunities for the development of novel anti-cancer strategies
Supplementing primary NF cultures with conditioned medium from H460 human lung cancer cells, which do not secrete detectable levels of Quiescin sulfhydryl oxidase 1 (QSOX1) [5], increased QSOX1 expression to a comparable level as seen in cancer-associated fibroblasts (CAFs) (Figure 1B). These results show that increased QSOX1 secretion is a feature of human CAFs
In this report we demonstrate the efficacy of inhibitory antibodies against the catalyst of disulfide bond formation QSOX1 in attenuating tumor growth and metastasis in cancer models in mice
Summary
Tumor-induced remodelling of genetically normal adjacent tissues offers opportunities for the development of novel anti-cancer strategies. Stiffening of interstitial ECM in the vicinity of breast tumors promotes metastasis [1] One mechanism behind this observation appears to be cross-linking of collagen and elastin fibers by enzymes of the lysyl oxidase (LOX) family in the cancer-associated stroma, which provides an enhanced substrate for focal adhesion formation and pro-migratory signaling in tumor cells [2]. We observed that inhibition of QSOX1 during fibroblast growth prevented formation of the copious pro-migratory ECM deposited by these cells, resulting in a failure of tumor cells to penetrate the fibroblast layer [5] This finding identified a novel point for intervention in stromal support of tumors and established QSOX1 inhibitory antibodies as a means to affect this process. QSOX1 modifies ECM extracellularly [5], so excess QSOX1 produced by cancer-associated stromal fibroblasts in a physiological context is expected to be accessible for blocking by antibodies administered systemically
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
