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Ascites Increases Expression/Function of Multidrug Resistance Proteins in Ovarian Cancer Cells

Significance Statement

 Ascites is a common symptom in stage III/IV ovarian cancer, and it is associated with a poor prognosis. However, the mechanisms by which ascites influences ovarian cancer cell biology are poorly understood. Chemotherapy treatment is the standard of care for late stage ovarian cancer. However, these cancers frequently exhibit chemotherapy resistance, resulting in tumor recurrence and patient mortality. Our studies are important in suggesting that ascites enriches for a multi-drug resistant subpopulation of ovarian cancer cells that express ATP binding cassette proteins (ABC transporters), resulting in: 1) efflux of chemotherapy from the tumor cell, and 2) chemotherapy resistance. To demonstrate relevance of our findings to ovarian cancer patients, we show that efflux function is increased in ascites-derived human ovarian cancer cells compared to that in primary-tumor derived human ovarian cancer cells. These studies are important in suggesting the need to identify logical therapeutic targets on this subset of ascites-associated, drug-resistant ovarian cancer cells. Notably, in parallel work, we have demonstrated that a cell surface expressed form of Glucose-regulated protein 78 (GRP78) is a targetable marker on ascites-associated tumor cells. Antibodies directed to the carboxyl terminal domain of GRP78 eliminate ascites-associated, multidrug resistant ovarian cancer cells (Mo et al., 2015. Molecular Cancer Therapeutics 14(3); 747.). Collectively, our studies provide a strong rationale for testing combination therapy (chemotherapy + GRP78-neutralizing antibodies) for late stage ovarian cancer. 

Figure Legend

 Ovarian cancers are heterogeneous, being composed of chemo-sensitive tumor cells (gray) and chemo-resistant tumor cells (orange). Primary tumors are composed predominantly of chemo-sensitive tumor cells with low MDR expression/efflux function (left side of model). Our previous work indicates that ascites enriches for tumor cells with cancer stem cell-like characteristics (Mo et al., Mol. Cancer Ther., 2015), one of which is the increased expression/function of MDR proteins. Accordingly, tumor cells isolated from the primary ovarian tumor are more sensitive to paclitaxel (a first line chemotherapeutic in ovarian cancer patients) than are ovarian tumor cells isolated from ascites. Chemo-resistant cells in ascites survive chemotherapy treatment, eventually resume proliferation, and account for future tumor relapse (right side of the model). Collectively, our studies support the hypothesis that ascites contributes significantly to chemo-resistance in ovarian cancer patients.

Ascites-Increases-Expression-function-of-Multidrug-Resistance-Proteins-in-Ovarian-. Global Medical Discovery

Journal Reference

PLoS One. 2015 Jul 6;10(7):e0131579.

Mo L1, Pospichalova V2, Huang Z3, Murphy SK4, Payne S1, Wang F1, Kennedy M1, Cianciolo GJ1, Bryja V2, Pizzo SV1, Bachelder RE1.

 

Show Affiliations
  1. Department of Pathology, Duke University Medical Center, Durham, North Carolina, 27710, United States of America.
  2. Faculty of Science, Masaryk University, Kotlarska 2, 61137, Brno, Czech Republic.
  3. Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina, 27710, United States of America.
  4. Department of Pathology, Duke University Medical Center, Durham, North Carolina, 27710, United States of America; Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina, 27710, United States of America.

Abstract

Chemotherapy resistance is the major reason for the failure of ovarian cancer treatment. One mechanism behind chemo-resistance involves the upregulation of multidrug resistance (MDR) genes (ABC transporters) that effectively transport (efflux) drugs out of the tumor cells. As a common symptom in stage III/IV ovarian  cancer patients, ascites is associated with cancer progression. However, whether ascites drives multidrug resistance in ovarian cancer cells awaits elucidation. Here, we demonstrate that when cultured with ascites derived from ovarian cancer-bearing mice, a murine ovarian cancer cell line became less sensitive to paclitaxel, a first line chemotherapeutic agent for  ovarian cancer patients. Moreover, incubation of murine ovarian cancer cells in vitro with ascites drives efflux function in these cells. Functional studies show ascites-driven efflux is suppressible by specific inhibitors of either of two ABC transporters [Multidrug Related Protein (MRP1); Breast Cancer Related Protein (BCRP)]. To demonstrate relevance of our findings to ovarian cancer patients, we studied relative efflux in human ovarian cancer cells obtained from either patient ascites or from primary tumor. Immortalized cell lines developed from human ascites show increased susceptibility to efflux inhibitors (MRP1, BCRP) compared to a cell line derived from a primary ovarian cancer, suggesting an association between ascites and efflux function in human ovarian cancer. Efflux in ascites-derived human ovarian cancer cells is associated with increased expression of ABC transporters compared to that in primary tumor-derived human  ovarian cancer cells. Collectively, our findings identify a novel activity for ascites in promoting ovarian cancer multidrug resistance.

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