Metastasis is a complex multistep process that involves critical interactions between cancer cells and a variety of stromal components in the tumor microenvironment, which profoundly influence the different aspects of the metastatic cascade and organ tropism of disseminating cancer cells. Ovarian cancer is the most lethal gynecological malignancy and is characterized by peritoneal disseminated metastasis. Evidence has demonstrated that ovarian cancer possesses specific metastatic tropism for the adipose-rich omentum, which has a pivotal role in the creation of the metastatic tumor microenvironment in the intraperitoneal cavity. Considering the distinct biology of ovarian cancer metastasis, the elucidation of the cellular and molecular mechanisms underlying the reciprocal interplay between ovarian cancer cells and surrounding stromal cell types in the adipose-rich metastatic microenvironment will provide further insights into the development of novel therapeutic approaches for patients with advanced ovarian cancer. Herein, we review the biological mechanisms that regulate the highly orchestrated crosstalk between ovarian cancer cells and various cancer-associated stromal cells in the metastatic tumor microenvironment with regard to the omentum by illustrating how different stromal cells concertedly contribute to the development of ovarian cancer metastasis and metastatic tropism for the omentum.

The impact of EpCAM expression on response to chemotherapy and clinical outcomes in patients with epithelial ovarian cancer The impact of EpCAM expression on response to chemotherapy and clinical outcomes in patients with epithelial ovarian cancer

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.

Epithelial ovarian cancer is a highly lethal gynecological malignancy that is characterized by the early development of disseminated metastasis. Though ovarian cancer has been generally considered to preferentially metastasize via direct transcoelomic dissemination instead of the hematogenous route, emerging evidence has indicated that the hematogenous spread of cancer cells plays a larger role in ovarian cancer metastasis than previously thought. Considering the distinctive biology of ovarian cancer, an in-depth understanding of the biological and molecular mechanisms that drive metastasis is critical for developing effective therapeutic strategies against this fatal disease. The recent “cancer stem cell theory” postulates that cancer stem cells are principally responsible for tumor initiation, metastasis, and chemotherapy resistance. Even though the hallmarks of ovarian cancer stem cells have not yet been completely elucidated, metastasized ovarian cancer cells, which have a high degree of chemoresistance, seem to manifest cancer stem cell properties and play a key role during relapse at metastatic sites. Herein, we review our current understanding of the cell-biological mechanisms that regulate ovarian cancer metastasis and chemotherapy resistance, with a pivotal focus on ovarian cancer stem cells, and discuss the potential clinical implications of evolving cancer stem cell research and resultant novel therapeutic approaches.

Background: Epithelial ovarian cancer has a clear predilection for the omentum as the site of metastasis; however, its contribution to clinical outcomes remains unresolved. This study aimed to evaluate the prognostic significance and efficacy of chemotherapy in the presence of omental metastasis. Methods: A retrospective cohort study was performed in 56 patients with stage III–IV ovarian cancer who underwent primary debulking surgery between 2004 and 2018 at Kumamoto University Hospital. Results: Thirty-six (64.3%) patients were categorized into the omental metastasis-positive group, whereas 20 (35.7%) patients were in the omental metastasis-negative group. The 5-year overall survival rates were 43.4% in the omental metastasis-positive group and 93.8% in the omental metastasis-negative group. Statistically significant differences were observed in overall survival (p = 0.002) and progression-free survival (p = 0.036) between the omental metastasis-positive and metastasis-negative groups. Notably, multivariate analysis demonstrated that the existence of omental metastasis is an independent risk factor for overall survival in patients with stage III–IV ovarian cancer (hazard ratio 8.90, 95% confidence interval 1.16–69.77; p = 0.038). Furthermore, the omental metastasis-positive group had significantly lower overall response rates to chemotherapy for recurrent disease, compared to the omental metastasis-negative group (31.6% vs. 85.7%, p = 0.026). Conclusion: Our present data demonstrated that omental metastasis is closely associated with an unfavorable prognosis due to increased chemoresistance in patients with stage III–IV ovarian cancer. Elucidating the biological mechanism of omental metastasis will shed light on novel therapeutic approaches for the management of advanced ovarian cancer patients.