New models of hematogenous ovarian cancer metastasis demonstrate preferential spread to the ovary and a requirement for the ovary for abdominal dissemination

Abstract

Emerging evidence suggest that many high grade serous ‘ovarian’ cancers (HGSOC) start in the fallopian tube. Cancer cells are then recruited to the ovary and then spread diffusely through the abdomen. The mechanism of ovarian cancer spread was 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. Here we present three metastatic models of ovarian cancer which confirm the ability of ovarian cancer to hematogenously spread. Strikingly, we observe a high rate of metastasis to the ovary with the development of ascites in these models. Interestingly, oophorectomy resulted in a complete loss of peritoneal metastases and ascites. Taken together our data indicates that hematogenously disseminated HGSOC cells have a unique tropism for the ovary and that hematogenous spread in ovarian cancer may be more common than appreciated. Furthermore our studies support a critical role for the ovary in promoting HGSOC 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.

Activin A stimulates migration of the fallopian tube epithelium, an origin of high-grade serous ovarian cancer, through non-canonical signaling

“…However, the mechanism(s) by which ovulation increases the risk of ovarian cancer is less clear. This is important because recent evidence indicates that colonization of the ovary by FTE-derived tumors may be an important step in the progression of HGSOC [10,13] and suggests that this step may represent a therapeutic target in women at high risk of developing HGSOC [10]. The ovary produces a large number of hormones and growth factors that may stimulate migration of tumorigenic FTE cells to the ovaries.…”

“…For example, Coffman et al found that when injected intravenously, HGSOC cells, but not breast cancer or lung adenocarcinoma cells, colonized the ovary [13]. The lifetime number of ovulations is positively associated with the risk of developing ovarian cancer [14].…”

Heterogeneous Cadherin Expression and Multicellular Aggregate Dynamics in Ovarian Cancer Dissemination

“…Hematogenous metastasis has also been described [7], [8]. Free-floating EOC aggregates are abundant in the peritoneal cavity; however, the number, size, and integrity of aggregates vary considerably [9], [10].…”

Tumor Microenvironment and Models of Ovarian Cancer

“…Lan Coffman, MD, PhD, revealed vascular spread of ovarian cancers with 3 different metastatic models. 35 They used (1) mouse tail vein injection of ovarian cancer cells, (2) subcutaneous mouse ovarian tumor, and (3) human xenograft ovarian tumor with humanized microenvironment model to demonstrate formation of distant metastases by vascular spread. They observed high rate of metastasis to the ovary in all 3 models, with intra-abdominal metastatic disease and ascites.…”