Abstract 4954: Hematogenous metastasis of ovarian cancer: Re-thinking mode of spread

Abstract

Abstract Background: Most patients with ovarian cancer have widely metastatic disease within the abdominal cavity at primary diagnosis; historically, this was thought to occur via intraperitoneal “seeding”. Here, we report unexpected findings related to hematogenous ovarian cancer metastasis with a strong tropism for the omentum. Methods: We established a novel parabiosis model where the skin of female mice was fused surgically from the shoulder to the hip joint. Two weeks later, the “host” parabiont mice were injected with tumor cells into ovary. Once the host mice became moribund, the parabionts were separated, and the host mice were euthanized. Tumor development and patterns of metastasis were analyzed in the host mice. A series of additional in vitro and in vivo experiments were carried out to decipher the underlying mechanisms. Results: The parabiosis models demonstrated that tumor cells injected into the ovary of each “host” mouse metastasized to the corresponding “guest” mouse, predominantly to the omentum. Using high-throughput transcriptome analysis and phospho-proteome arrays, we demonstrated that ErbB3, an EGFR family receptor tyrosine kinase (RTK) was highly expressed in the ovarian cancer cells that hematogenously metastasized to the omentum (SKOV3-OM3) compared to parental cells. The ErbB3-NRG1 axis activated Src/PI3K/AKT signaling pathway, which in turn induced loss of polarity and increased invasion of ovarian cancer cells. Depletion of murine NRG1 using target specific siRNAs almost completely abolished omental metastasis. In contrast, overexpression of ErbB3 resulted in enhanced tumor formation and omental metastatic spread, which confirms the role of ErbB3 in hematogenous omental metastasis. Additional studies with a function-blocking antibody specific to ErbB3 led to substantial reduction in hematogenous metastasis of ovarian cancer cells. Conclusions: Collectively, our results provide the first evidence that ovarian cancer cells are capable of hematogenous metastasis, but with strong tropism for the omentum. These findings not only provide a new understanding of ovarian cancer metastasis, but also identify novel therapeutic targets. Citation Format: Sunila Pradeep, Seung Wook Kim, Sherry Wu, Nishimuara Masato, Takahito Miyake, Choi Hyun-Jin, Rajesha Rupaimoole, Jinsong Liu, Isahai Fidler, Gabriel Lopez, Anil Sood. Hematogenous metastasis of ovarian cancer: Re-thinking mode of spread. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4954. doi:10.1158/1538-7445.AM2014-4954