Ovarian cancer has been generally considered to preferentially metastasize via transcoelomic rather than hematogenous dissemination [55,56,57]. Transcoelomic metastasis is implicated in the exfoliation of cancer cells from primary ovarian tumors, their survival as multicellular spheroids that float in the ascitic fluid, and their subsequent metastatic colonization in the peritoneal cavity [55,58,59,60] (Figure 1). Previous studies demonstrated that ovarian cancer stem cells play a pivotal role in the formation of multicellular spheroids during the transcoelomic peritoneal dissemination of ovarian cancer [61,62]. Liao et al. showed that spheroids in the malignant ascites are enriched in cancer stem cells that are primarily responsible for ovarian cancer tumorigenesis, progression, and transcoelomic metastasis [41]. The authors also revealed that these sphere-forming cancer cells express stemness-related genes—such as Notch1, Nanog, Cdcp1, and Myc—and upregulate CD117 expression and ALDH activity, thereby promoting the development of peritoneal and omental metastasis in an in vivo ovarian cancer xenograft model [41]. More recently, Roy et al. elucidated the functional role of CD133 expression in the early steps of peritoneal metastasis. Using an ex vivo peritoneal explant adhesion assay, they demonstrated that CD133 expression significantly increased the adhesion and invasion of ovarian cancer cells to the peritoneal mesothelium, suggesting that CD133-positive ovarian cancer cells are involved in communicating with the microenvironmental niche in the peritoneum [46]. In this regard, a previous study identified a key role for peritoneal mesothelial cells in the maintenance of ovarian cancer stemness, thus raising the possibility that the peritoneal microenvironment has the potential to form a cancer stem cell niche for ovarian cancer dissemination [63]. In addition, a recent study by Burgos-Ojeda et al. showed that CD24-positive ovarian cancer cells manifest increased levels of STAT3 phosphorylation compared with CD24-negative cells, an increase which is associated with enhancing disseminated metastasis [47]. More importantly, the blockade of STAT3 phosphorylation with a JAK 2 inhibitor significantly reduced ovarian cancer metastasis in an established genetic mouse model of ovarian cancer [47]. On another front, our study group demonstrated a crucial role for CD44 variant 6 (CD44v6) in the regulation of various biological functions during the transcoelomic metastasis of ovarian cancer [37]. A clinicopathological analysis of CD44v6 expression indicated that peritoneal disseminated tumors are highly enriched in CD44v6-positive ovarian cancer cells compared with corresponding primary tumors, suggesting that CD44v6-positive cancer cells are associated with peritoneal transcoelomic dissemination and that the peritoneum may function as a metastatic microenvironmental niche that contributes to the process of metastatic colonization in the peritoneal cavity. Intriguingly, and consistent with these clinical observations, a subpopulation of CD44v6-positive cancer cells gave rise to extensive disseminated metastatic tumors in the peritoneal cavity, whereas CD44v6-negative cancer cells manifested a lower metastatic ability in an in vivo mouse model. Furthermore, a limiting dilution assay demonstrated that CD44v6-positive cancer cells showed a greater tumor initiating capability than CD44v6-negatice cancer cells, indicating that the subpopulation of CD44v6-positive cancer cells may serve as specialized metastasis-initiating cells within the intraperitoneal milieu [37] (Figure 1 and Table 1).

Generally, although transcoelomic dissemination has been thought to be the major route of ovarian cancer metastasis [60], a recent study by Pradeep et al. revealed novel mechanisms of hematogenous metastasis to the omentum followed by intraperitoneal disseminated metastasis in a parabiosis mouse model that allowed for the sharing of blood circulation [64]. They showed that circulating ovarian cancer cells derived from the host mouse can first metastasize to the omentum of the conjoined guest mouse via a hematogenous route and subsequently spread to the peritoneal cavity, thus shifting the paradigm in mechanisms that regulate the disseminated metastasis of ovarian cancer in the peritoneal cavity. Mechanistically, the ErbB3/Neuregulin-1 signaling axis has been shown to play a functional role in such hematogenous ovarian cancer metastasis with a strong tropism toward the omentum [64]. Additionally, with respect to distant parenchymal metastasis via the hematogenous route in ovarian cancer, our recent study demonstrated that CD44v6-positive ovarian cancer cells represent a central player in the development of distant metastasis in parenchymal organs [38] (Figure 1). Clinicopathological evidence corroborated the fact that ovarian cancers with greater numbers of CD44v6-positive cancer cells were associated with higher rates of distant metastasis at the time of ovarian cancer diagnosis. Furthermore, an immunohistochemical analysis detected a significantly higher percentage of CD44v6-positive cells in distant metastatic tumors than primary ovarian tumors, suggesting that CD44v6-positive cancer cells play a key role in driving distant metastasis via a hematogenous spread. More importantly, a Kaplan–Meier analysis showed that distant metastasis-free survival was significantly different between CD44v6-high and -low groups, indicating that CD44v6 expression is involved in greater distant metastatic relapse in patients with stage I–III ovarian cancer. It should be noted here that a multivariate analysis identified CD44v6 expression as an independent risk factor for distant metastatic relapse, implying that CD44v6 expression may be a crucial predictive biomarker for distant parenchymal metastasis in ovarian cancer patients [38]. A number of studies of late years have indicated that ALDH activity is closely linked to both ovarian cancer stemness and metastasis [65,66]. Bai et al. showed that epidermal growth factor-like domain 6 (EGFL6), which acts as a stem cell regulatory factor, promotes the asymmetric division of ALDH-positive ovarian cancer stem cells and thereby increases cancer cell proliferation in vitro and tumor growth in vivo [43]. Interestingly, the authors also found that vascular EGFL6 expression enhances the distant metastasis of ovarian cancer cells through the hematogenous route, whereas an EGFL6 blockade reduces the hematogenous spread of ovarian cancer cells to distant parenchymal organs [43]. These findings provide a therapeutic rationale for targeting specific molecules in the microenvironmental niche (Figure 1 and Table 1).