Secreted soluble factors from tumor-activated mesenchymal stromal cells confer platinum chemoresistance to ovarian cancer cells

Abstract

Ovarian cancer (OC) ranks as the second most common type of gynecological malignancy, has poor survival rates, and is frequently diagnosed at an advanced stage. Platinum-based chemotherapy, such as carboplatin, represents the standard-of-care for OC. However, toxicity and acquired resistance to therapy have proven challenging in the treatment of patients, most of who will experience relapse, mainly due to chemoresistance. Chemoresistance, a principal obstacle to durable response in OC patients, is attributed to alterations within the cancer cells, and can also be mediated by the tumor microenvironment (TME). In this study, we report that conditioned medium (CM) derived from murine and human stromal cells, MS-5 and HS-5 respectively, and tumor-activated HS-5, was active in conferring platinum chemoresistance to OC cells. Moreover, CM derived from differentiated murine pre-adipocyte (3T3-L1), but not undifferentiated pre-adipocyte cells, confers platinum chemoresistance to OC cells. Interestingly, CM derived from tumor-activated HS-5 was more effective in conferring chemoresistance than was CM derived from HS-5 cells. Various OC cells exhibit variable sensitivity to CM activity. Moreover, exposure of OC to CM affected ERK1/2 phosphorylation in a non-consistent pattern and in a cell-specific manner, and does not correlate with platinum chemoresistance. Exploring CM content revealed the enrichment of a number of soluble factors in the tumor-activated HS-5, such as soluble uPAR (SuPAR), IL-6, and hepatocyte growth factor (HGF). FDA-approved JAK inhibitors were mildly effective in restoring platinum sensitivity in two of the three OC cell lines in the presence of CM. Exposure to increasing concentrations of HGF resulted in increased proliferation and reduced platinum sensitivity. Crizotinib, an ALK and c-MET inhibitor, in combination with platinum, blocked HGFs ability to promote platinum resistance and restore platinum sensitivity to OC cells. Finally, exposure to 2-hydroxyestardiol (2HE2) was effective in restoring platinum sensitivity to OC cells exposed to CM. Our results showed the significance of soluble factors found in TME in promoting platinum chemoresistance and the potential of combination therapy to restore chemosensitivity to OC cells.