CD44 variant 6 is correlated with peritoneal dissemination and poor prognosis in patients with advanced epithelial ovarian cancer

Abstract

Cancer stem cells (CSCs) drive tumor initiation and metastasis in several types of human cancer. However, the contribution of ovarian CSCs to peritoneal metastasis remains unresolved. The cell adhesion molecule CD44 has been identified as a major marker for CSCs in solid tumors, including epithelial ovarian cancer. CD44 exists as a standard form (CD44s) and also as numerous variant isoforms (CD44v) generated by alternative mRNA splicing. Here we show that disseminated ovarian tumors in the pelvic peritoneum contain highly enriched CD44v6-positive cancer cells, which drive tumor metastasis and are responsible for tumor resistance to chemotherapy. Clinically, an increased number of CD44v6-positive cancer cells in primary tumors was associated with a shortened overall survival in stage III–IV ovarian cancer patients. Furthermore, a subpopulation of CD44v6-positive cancer cells manifested the ability to initiate tumor metastasis in the pelvic peritoneum in an in vivo mouse model, suggesting that CD44v6-positive cells show the potential to serve as metastasis-initiating cells. Thus, the peritoneal disseminated metastasis of epithelial ovarian cancer is initiated by the CD44v6-positive subpopulation, and CD44v6 expression is a biomarker for the clinical outcome of advanced ovarian cancer patients. Given that a distinct subpopulation of CD44v6-positive cancer cells plays a critical role in peritoneal metastasis, definitive treatment should target this subpopulation of CD44v6-positive cells in epithelial ovarian cancer.

Dynamic changes of tumor gene expression during repeated Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) in women with peritoneal cancer

“…Loss of cell adhesion via deregulation of CD44, CLDN4, and CLDN6, followed by increased migration and invasive capabilities through upregulation of MMP2 describes a pattern consistent with localized ovarian cancer cells transforming into metastasizing PC cells, and expands previous data showing that deregulation of proliferation and cell adhesion is a feature of malignant transformation in ovarian and peritoneal cancer [10-13, 19, 28]. Tjhay et al, for instance, have shown that disseminated ovarian tumors in the peritoneum contain highly enriched CD44v6-positive cancer cells and an increased number of CD44v6-positive cancer cells in primary tumors was associated with a shortened overall survival in stage III-IV ovarian cancer [29]. In a xenograft model, Haria et al found that DLX4, a transcription factor encoded by a homeobox gene, induced expression of CD44 in ovarian tumor cells, and inhibition of CD44 abrogated the ability of DLX4 to stimulate tumormesothelial cell interactions [30].…”

CD44 Variant 6 as a Predictive Biomarker for Distant Metastasis in Patients With Epithelial Ovarian Cancer

“…In addition, no significant differences were observed in the number of cycles of chemotherapy and surgical debulking status between CD44v6-high and -low groups. Pathologically, there were 87 (46.8%) serous, 33 A total of 50 distant metastatic sites were identified in 37 of 186 (19.9%) patients. Twenty-five patients had distant metastatic disease at the time of diagnosis, consistent with M1 status, whereas 12 patients had distant metastases during relapse of progressive disease.…”

“…In this study, 186 patients who were surgically treated with or without chemotherapy were included; 48 patients had been included in our previous study investigating peritoneal dissemination of ovarian cancer. 33 Patients with multiple primary cancers or nonepithelial tumors were excluded. Eligible patients were followed up until December 2014.…”

“…33 CD44 variant 6 was stained with the mouse monoclonal antibody CD44 variant 6. Based on the results of a previous study, 33 primary ovarian tumors that contained at least 10% CD44 variant 6-positive ovarian cancer cells were categorized as CD44v6-high, and the tumors that contained less than 10% CD44 variant 6-positive cells were categorized as CD44v6-low. The percentage of CD44 variant 6-positive cells in primary tumors was assessed by counting cells in at least three microscopic fields per slide.…”

“…29,31,32 Additionally, we recently demonstrated that CD44 variant 6-positive ovarian cancer cells play a crucial role in the formation of disseminated tumors in the pelvic peritoneum and possess the potential to serve as metastasis-initiating cells in an ovarian cancer mouse model. 33 Taken together, these findings raise the possibility that CD44 variant 6-positive cancer cells play a key role in the formation of distant metastases in patients with ovarian cancer.…”