Affiliation:
1. Department of Nutrition and Natural Products, Migal–Galilee Research Institute, Kiryat Shmona 11016, Israel
2. Shraga Segal Department of Microbiology, Immunology, and Genetics, Ben-Gurion University of the Negev, Beer Sheva 8400101, Israel
3. Department of Oncology, Soroka University Medical Center, Beer Sheva 8400101, Israel
4. Department of Biotechnology, Tel Hai College, Kiryat Shmona 1220800, Israel
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.
Subject
Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis
Reference73 articles.
1. Ovarian cancer development and metastasis;Lengyel;Am. J. Pathol.,2010
2. Cellular pharmacology of cisplatin: Perspectives on mechanisms of acquired resistance;Andrews;Cancer Cells,1990
3. Primary and acquired platinum-resistance among women with high grade serous ovarian cancer;Slaughter;Gynecol. Oncol.,2016
4. Molecular mechanisms of drug resistance in ovarian cancer;Sarookhani;J. Cell. Physiol.,2018
5. Cisplatin: From DNA damage to cancer chemotherapy;Cohen;Prog. Nucleic. Acid. Res. Mol. Biol.,2001