Membrane GRP78: Pathologic and Therapeutic Roles in Ovarian Cancer

Abstract

Ovarian cancer is the fifth leading cause of cancer-related death in the United States and the most lethal gynecologic malignancy. Patients with ovarian cancer are generally diagnosed at stage III or IV, when ascites fluid becomes a common symptom. The volume of ascites positively correlates with the extent of ovarian cancer metastasis and negatively with prognosis; however, the mechanisms explaining their effect are unknown. We hypothesize that ascites enriches for cancer stem-like cells. Our present study demonstrates that mice injected with ID8 cells, a murine epithelial ovarian cancer line, have remarkably shortened survival, when injected together with ascites supernatant derived from tumor-bearing mice. Moreover, compared to their counterparts cultured in regular medium, ID8 cells cultured in ascites fluid, or isolated directly from ascites, show an increased expression of stem cell markers Oct4 and CD133. These cells also exhibit enhanced self-renewing ability in sphere assay, suggesting that ascites enriches for stem-like cells. Furthermore, we demonstrate that ascites enriches for cells expressing cell surface GRP78, a stress-inducible endoplasmic reticulum chaperone which also appears on the plasma membrane (memGRP78) of aggressive cancers. MemGRP78 + cells correlate with stem cell properties of self-renewal and tumor initiation, suggesting GRP78 is a novel stem cell marker. Importantly, antibodies against the COOH terminal domain of GRP78 significantly reduce the self-renewing ability of murine and human ovarian cancer cells pre-incubated with ascites.In conclusion, our study demonstrates that ascites enriches for stem-like cells in ovarian cancer cell lines. Furthermore, the inhibitory effect of antibodies against the COOH terminal domain of GRP78 suggests that memGRP78 is a logical therapeutic target for ovarian cancer.