RESUMEN
Disseminating epithelial ovarian cancer cells often become assembled into spheroids prior to their arrival at metastatic sites within the peritoneal cavity. Although epithelial ovarian carcinoma (EOC) is the deadliest gynecologic malignancy, the mechanisms regulating formation and metastatic potential of spheroids are poorly understood. We show that expression of a cell surface glycoprotein CD44 is an important contributing factor for spheroid formation and spheroid adhesion to mesothelial cells, and its loss impairs mesenteric metastasis. In contrast, loss of CD44 resulted in significant increase of tumor burden at several locoregional sites, including liver, and unleashed distant metastases to the thoracic cavity. Altogether our studies suggest that CD44 regulates metastatic progression of EOC in an organ-specific manner. IMPLICATIONS: Expression of CD44 promotes spheroid formation, mesothelial adhesion, and formation of mesenteric metastasis, but it suppresses development of metastasis to several peritoneal sites, including liver, and the thoracic cavity.
Asunto(s)
Carcinoma Epitelial de Ovario/patología , Receptores de Hialuranos/metabolismo , Trasplante de Neoplasias/patología , Esferoides Celulares/trasplante , Animales , Carcinoma Epitelial de Ovario/inmunología , Adhesión Celular , Línea Celular Tumoral , Movimiento Celular , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones , Metástasis de la Neoplasia , Trasplante de Neoplasias/inmunología , Especificidad de Órganos , Neoplasias Ováricas , Esferoides Celulares/citología , Esferoides Celulares/inmunología , Regulación hacia ArribaRESUMEN
Failure of currently used cytotoxic chemotherapy is one of the main reasons behind high mortality from metastatic high grade serous ovarian carcinoma. We found that high expression of a receptor for fractalkine (CX3CR1) significantly correlated with shorter survival of patients with serous ovarian carcinoma treated with cytotoxic DNA damage chemotherapies, and reduction of CX3CR1 expression resulted in sensitization to several DNA damaging modalities, including x-ray radiation and cisplatin. Here, we show that CX3CR1 plays a role in double-strand DNA break response and repair by regulating expression of RAD50 by a MYC-dependent mechanism. We demonstrate that downregulation of CX3CR1 alone and in a combination with irradiation affects peritoneal metastasis in an organ-specific manner; we show that CX3CR1 regulates lipid uptake which could control omental metastasis. This study identifies CX3CR1 as a novel potential target for sensitization of ovarian carcinoma to DNA damage therapies and reduction of peritoneal carcinomatosis.
