Abstract TMEM-019: NEW OVARIAN CANCER METASTASIS MODELS DEMONSTRATE PREFERENTIAL HEMATOGENOUS SPREAD OF OVARIAN CANCER CELLS TO THE OVARY AND A REQUIREMENT FOR THE OVARY FOR ABDOMINAL DISSEMINATION
Authors: Coffman Lan G , Burgos-Ojeda Daniela , Wu Rong , Cho Kathleen , Bai Shoumei , Buckanovich Ronald J 
Published: June 2017

BACKGROUND: Mounting evidence suggests that many high grade serous ‘ovarian’ cancers (HGSOC) start in the fallopian tube. Cancer cells are then recruited to the ovary and subsequently spread diffusely through the abdomen. The mechanism of ovarian cancer spread has long been thought to be largely due to direct shedding of tumor cells into the peritoneal cavity with vascular spread being of limited importance. Recent work challenges this dogma, suggesting hematogenous spread of ovarian cancer may play a larger role in ovarian cancer cell metastasis than previously thought. One reason the role of vascular spread of ovarian cancer has not been fully elucidated is the lack of easily accessible models of vascular ovarian cancer metastasis.

METHODS: We developed three metastatic models of ovarian cancer which confirm the ability of ovarian cancer to hematogenously spread. A murine tail vein injection model using human ovarian cancer cell lines was used to observe the general pattern of hematogenous spread when cells are directly introduced into the vasculature. A subcutaneous murine ovarian tumor model was developed to investigate patterns of metastasis in the setting of a fully murine tumor microenvironment. Finally, a human subcutaneous xenograft model using primary patient derived ovarian cancer cells, human carcinoma-associated mesenchymal stem cells and human endothelial cells was developed to investigate patterns of metastasis in the setting of a humanized microenvironment.

RESULTS: In all three models, we demonstrate the formation of distant metastasis via vascular spread. Strikingly, we observe a high rate of metastasis to the ovary (40-100%) in all three models representing a disproportionately large fraction of total metastatic burden. Mice which developed ovarian metastatic disease also developed further intra-abdominal metastatic disease and ascites. Interestingly, in the tail vein injection model, oophorectomy prior to ovarian cancer cell injection resulted in a complete loss of peritoneal metastases, ascites and decreased burden of liver metastasis. This ovary tropism appears to be unique to ovarian cancer cells as intravenous tail vein injection of breast cancer and lung cancer cell lines, while resulting in typical sites of disease in the lung and bone, did not result in ovary involvement.

CONCLUSIONS: Taken together our data indicates that hematogenously disseminated high grade serous ovarian cancer cells have a unique tropism for the ovary and that hematogenous spread in ovarian cancer may be more common than previously appreciated. Furthermore our studies support a critical role for the ovary in promoting high grade serous ovarian cancer cell metastasis to the abdomen. The models developed here represent important new tools to evaluate both the mechanism of cancer cell recruitment to the ovary and to understand and target key steps in ovarian cancer metastasis.

Citation Format: Lan G Coffman, Daniela Burgos-Ojeda, Rong Wu, Kathleen Cho, Shoumei Bai, and Ronald J Buckanovich. NEW OVARIAN CANCER METASTASIS MODELS DEMONSTRATE PREFERENTIAL HEMATOGENOUS SPREAD OF OVARIAN CANCER CELLS TO THE OVARY AND A REQUIREMENT FOR THE OVARY FOR ABDOMINAL DISSEMINATION [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr TMEM-019.