CD105 Is Expressed in Ovarian Cancer Precursor Lesions and Is Required for Metastasis to the Ovary.

Bai Bai,Drapkin Drapkin,Elishaev Elishaev,Buckanovich Buckanovich,Zhu Zhu,Schwartz Schwartz,Vlad Vlad,Coffman Coffman

doi:10.3390/cancers11111710

Abstract

Most high-grade serous ovarian cancers (HGSCs) initiate from the fallopian tube epithelium and then metastasize to the ovary and throughout the abdomen. Genomic analyses suggest that most HGSCs seed the ovary prior to abdominal dissemination. Similarly, animal models support a critical role for the ovary in driving abdominal dissemination. Thus, HGSC cell recruitment to the ovary appears to be a critical component of HGSC cell metastasis. We sought to identify factors driving HGSC recruitment to the ovary. We identified CD105 (endoglin, or ENG, a TGF-β receptor family member) as a mediator of HGSC cell ovarian recruitment. We found that CD105 was expressed on both serous tubal intraepithelial carcinoma (STIC) cells (STICs-HGSC precursors in the fallopian tube epithelium) and HGSC cells. Using data from The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE), we showed that high CD105 expression by HGSC cells correlated with a metastatic signature. Furthermore, intravenous injection of CD105(+) HGSC tumor cells, but not CD105(−), resulted in ovarian-specific metastasis and abdominal dissemination of disease. CD105 knockdown or blockade with a clinically relevant CD105-neutralizing mAb (TRC105), inhibited HGSC metastasis, reduced ascites, and impeded growth of abdominal tumor nodules, thereby improving overall survival in animal models of ovarian cancer. CD105 knockdown was associated with a reduction in TGF-β signaling. Together, our data support CD105 as a critical mediator of ovarian cancer spread to the ovary and implicate it as a potential therapeutic target.

Highlights

80% of ovarian cancer patients present with late-stage disease, metastatic beyond the ovary
CD105 is a TGF-β co-receptor that has been linked with metastasis and cancer stem cells [23,24,36,37]
We hypothesized that CD105 could play a role in the metastasis of high-grade serous ovarian cancers (HGSCs) cells from the fallopian tube epithelium to the ovary

Summary

Introduction

80% of ovarian cancer patients present with late-stage disease, metastatic beyond the ovary. The majority of deaths caused by ovarian cancer relate to metastatic disease, to diffuse abdominal spread resulting in tumor ileus and bowel obstruction. While it was initially presumed that ovarian cancer metastasis was due to direct shedding from the ovary into the abdominal cavity, increasing evidence suggests that ovarian cancer can metastasize via the vasculature. Ovarian tumor cells can survive and develop secondary metastases when introduced into the blood through peritoneovenous shunting [1]. Circulating tumor cells can be identified in the bloodstream of many patients with ovarian cancer [2,3,4,5], and lymphovascular spread and metastasis is well established [6,7,8,9]. Clinical studies indicate hematogenous metastasis can occur independently of peritoneal spread and is associated with poorer survival outcome [10]

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Discussion

Conclusion