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 for the treatment of patients. Chemoresistance, a principal obstacle to durable response in OC patients, is attributed to alterations within the cancer cells, and it 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. 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. Moreover, Crizotinib, an ALK and c-MET inhibitor, in combination with platinum, blocked HGF’s ability to promote platinum resistance and to 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.

Ascites in malignant ovarian cancer confer ovarian cancer cells chemoresistance to platinum. Combination treatment with crizotinib and 2-hydroxyestradiol restores platinum sensitivity

“…As previously reported, cellular and soluble TME compartments play a role in conferring platinum chemoresistance to OC cells (21) (22) (23). Those findings showed that direct co-culture of OC with MSC resulted in conferring chemoresistance to therapeutic drugs such as paclitaxel, colchicine, and platinum compounds, alongside blocking of ERK1/2 activation (21).…”

“…This study is a follow-up to our earlier research that showed how a TME component promotes OC chemoresistance (23). Here, we carried out ex vivo assays to track the capacity of malignant ascites derived from OC patients to promote chemoresistance in OC cells.…”

“…Previously we showed that Crizotinib (HGF/c-Met inhibitor) was shown to overcome platinum chemoresistance mediated by tumor activated HS-5 (TA HS-5) conditioned medium (CM) (23). The current study shows that HGF was also enriched in malignant ascites and thus its involvement in promoting platinum chemoresistance was examined.…”

“…Furthermore, 2-hydroxyestardiol (2HE2), an estradiol metabolite that serves as a prodrug converting to 2-methoxyestradil (2ME2), was effective in restoring platinum sensitivity to OC cells growing in direct interaction with MSC (24). Moreover, we reported that conditioned media (CM) derived from human stromal cells (HS-5) and tumor-activated HS-5 (TA-HS-5) were effective in conferring platinum chemoresistance to OC cells (23). The soluble factors IL-6, and hepatocyte growth factor (HGF) were implicated in mediating platinum chemoresistance that could be partially or completely overcome by pharmaceutical inhibitors targeting the JAK/STAT and c-MET signaling pathway, respectively (23).…”

“…Moreover, we reported that conditioned media (CM) derived from human stromal cells (HS-5) and tumor-activated HS-5 (TA-HS-5) were effective in conferring platinum chemoresistance to OC cells (23). The soluble factors IL-6, and hepatocyte growth factor (HGF) were implicated in mediating platinum chemoresistance that could be partially or completely overcome by pharmaceutical inhibitors targeting the JAK/STAT and c-MET signaling pathway, respectively (23).…”