Abstract
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.
Highlights
Ovarian carcinoma, the fifth leading cause of death from cancer in women, comprises a number of malignancies of both epithelial and nonepithelial origin [1]
ES2 was isolated from a patient initially diagnosed with Epithelial ovarian carcinoma (EOC) of the clear cell histotype [37], while a more recent study suggested that it closer recapitulates the immune profiles of the endometrioid histotype [38]; a combination of its unique genomic profile and the presence of a mutation in p53 placed this cell line as "possibly HGSOC" [35]
We compared expression of CD44 in these cell lines using Western blot and found that the standard CD44 isoform was predominantly expressed in ES2 and SKOV-3, cell lines with nearly 100% efficiency in spheroid formation, whereas its expression was significantly lower in OVSAHO, the least capable of forming spheroids in vitro (Fig. 1D)
Summary
The fifth leading cause of death from cancer in women, comprises a number of malignancies of both epithelial and nonepithelial origin [1]. Epithelial ovarian carcinoma (EOC) is the most predominant type, which, in turn, encompasses several different histotypes, such as serous [high-grade (HGSOC) and low-grade], endometrioid, clear cell, and mucinous, that arise in epithelial cells of the ovary, fallopian tube, or endometrium [2, 3]. Common elements between these histotypes include presence of spheroids in ascites, involvement of the ovaries with a subsequent locoregional intraperitoneal pattern of metastatic spread, and late presentation. Prevention and treatment of the recurrent disease is of paramount importance for increasing patient survival. Prevention of recolonization of the intraabdominal tissues is one of the possible approaches to block rampant expansion of these metastases
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