Project description:The goal of controlling ovarian cancer metastasis formation has elicited considerable interest in identifying the tissue microenvironments involved in cancer cell colonization of the omentum. Omental adipose is a site of prodigious metastasis in both ovarian cancer models and clinical disease. This tissue is unusual for its milky spots, comprised of immune cells, stromal cells, and structural elements surrounding glomerulus-like capillary beds. The present study shows the novel finding that milky spots and adipocytes play distinct and complementary roles in omental metastatic colonization. In vivo assays showed that ID8, CaOV3, HeyA8, and SKOV3ip.1 cancer cells preferentially lodge and grow within omental and splenoportal fat, which contain milky spots, rather than in peritoneal fat depots. Similarly, medium conditioned by milky spot-containing adipose tissue caused 75% more cell migration than did medium conditioned by milky spot-deficient adipose. Studies with immunodeficient mice showed that the mouse genetic background does not alter omental milky spot number and size, nor does it affect ovarian cancer colonization. Finally, consistent with the role of lipids as an energy source for cancer cell growth, in vivo time-course studies revealed an inverse relationship between metastatic burden and omental adipocyte content. Our findings support a two-step model in which both milky spots and adipose have specific roles in colonization of the omentum by ovarian cancer cells.
Project description:Emerging evidence indicates that hypoxia plays a critical role in governing the transcoelomic metastasis of ovarian cancer. Hence, targeting hypoxia may be a promising approach to prevent the metastasis of ovarian cancer. Here, we report that BCL2A1, a BCL2 family member, acts as a hypoxia-inducible gene for promoting tumor progression in ovarian cancer peritoneal metastases. We demonstrated that BCL2A1 was induced not only by hypoxia but also other physiological stresses through NF-κB signaling and then was gradually reduced by the ubiquitin-proteasome pathway in ascites-derived ovarian cancer cells. The upregulated BCL2A1 was frequently found in advanced metastatic ovarian cancer cells, suggesting its clinical relevance in ovarian cancer metastatic progression. Functionally, BCL2A1 enhanced the foci formation ability of ovarian cancer cells in a stress-conditioned medium, colony formation in an ex vivo omental tumor model, and tumor dissemination in vivo. Under stress conditions, BCL2A1 accumulated and colocalized with mitochondria to suppress intrinsic cell apoptosis by interacting with the BH3-only subfamily BCL2 members HRK/BAD/BID in ovarian cancer cells. These findings indicate that BCL2A1 is an early response factor that maintains the survival of ovarian cancer cells in the harsh tumor microenvironment.
