Abstract 3934: Tumor-associated endothelial cells promote tumor metastasis by chaperoning circulating tumor cells and protecting them from anoikis.
Authors: Yadav Arti , Kumar Bhavna , Yu Jun-Ge , Old Matthew , Teknos Theodoros N. , Kumar Pawan 
Published: August 2014

Head and neck squamous cell carcinoma (HNSCC) is the sixth most frequent cancer worldwide and five-year survival rates (&lt;50%) are among the lowest of the major cancers. The high mortality associated with advanced HNSCC is in large part due to the metastatic spread to vital organs. Although our understanding of the molecular and biological events that contribute to tumor progression has increased considerably over the last decade, we still know very little about the role of tumor- accessory cells in promoting tumor metastasis. It is estimated that from a 1 cm primary tumor as many as 2 million tumor cells can be shed each day into the circulation, though very few of these tumor cells ever form metastases. Most of the cancer cells, particularly squamous cancer cells, have very low survival rates in circulation and undergo rapid anoikis. In addition to circulating tumor cells, increased levels of circulating endothelial cells are also observed in cancer patients with progressive disease. Interestingly, in this study we have observed a marked increase in Bcl-2 positive circulating endothelial cells in the blood samples of head and neck cancer patients. These results raise an intriguing question about the biological significance of these circulating endothelial cells. In this study, we performed a series of experiments to examine if tumor-associated endothelial cells could promote tumor cell metastasis by binding to circulating tumor cells and chaperoning these tumor cells to distal sites. Our results demonstrate that endothelial cells overexpressing Bcl-2 (EC-Bcl-2) show significantly higher E-selectin expression and exhibit enhanced tumor cell binding. In addition, tumor cells showed a significant decrease in anoikis when co-cultured with EC-Bcl-2. EC-Bcl-2-tumor cell binding and anoikis resistance was mediated by the E-selectin adhesion molecule and Src-FAK survival signaling. We further examined the role of Bcl-2 in tumor cell metastasis using two SCID mice models. In the first model, tumor cells were co-implanted with EC-Bcl-2 or EC-VC (GFP labeled) in the flanks of SCID mice. Tumor cells co-implanted with EC-Bcl-2 showed significantly higher lung metastasis as compared to EC-VC group. Interestingly, blood and lung samples from these animals showed the presence of EC-Bcl-2 cells (GFP-labeled, primary tumor origin) thereby demonstrating that tumor-associated endothelial are released from the primary tumors. In the second in vivo model, we examined the chaperone function of EC-Bcl-2. Animals co-injected with tumor cells and EC-Bcl-2 via the tail vein showed significantly higher lung metastasis as compared to tumor cell and EC-VC or tumor cell alone group. Taken together, these results suggest a novel role for tumor-associated endothelial cells in binding to tumor cells, protecting them from anoikis and chaperoning them to distal sites.

Citation Format: Arti Yadav, Bhavna Kumar, Jun-Ge Yu, Matthew Old, Theodoros N. Teknos, Pawan Kumar. Tumor-associated endothelial cells promote tumor metastasis by chaperoning circulating tumor cells and protecting them from anoikis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3934. doi:10.1158/1538-7445.AM2013-3934