Interaction of cancer cells with platelets mediated by Necl-5/poliovirus receptor enhances cancer cell metastasis to the lungs

Abstract

Necl-5 is an immunoglobulin (Ig)-like molecule that was originally identified as a poliovirus receptor and is often upregulated in cancer cells. We recently found that it colocalizes with integrin a v b 3 at the leading edges of moving cells and enhances growth factor-induced cell movement and proliferation. Upon cell-cell contact, Necl-5 is removed from the cell surface by its trans-interaction with the cell adhesion molecule nectin-3, resulting in reduced cell movement and proliferation. Here, we investigated the role of Necl-5 in the interaction of cancer cells with platelets. Necl-5 was upregulated in CT26 cells, a colon adenocarcinoma cell line. When CT26 cells were injected into the tail vein of mice, they were arrested in the pulmonary vessels by adhering to platelets and subsequently metastasized to the lungs. Overexpression of Necl-5 in CT26 cells enhanced this metastasis, while inhibition of the trans-interaction of Necl-5 with CD226 by an anti-Necl-5 monoclonal antibody reduced the metastasis. Depletion of platelets by treatment with a rabbit anti-mouse platelet serum reduced the Necl-5-enhanced metastasis in mice. Thus, the trans-interaction of upregulated Necl-5 in cancer cells with its counterreceptor in platelets, probably CD226, is critical for efficient metastasis of cancer cells to the lungs.

Overexpression of Necl‐5 correlates with unfavorable prognosis in patients with lung adenocarcinoma

“…(11,15,19,25) According to these earlier reports and the already-reported biological properties of Necl-5, Necl-5 up-regulation in cancer cells may play a role in tumor invasion. However, an analysis of Necl-5 expression in a large number of surgically resected human cancer tissues has not been reported previously, nor has the clinical significance of Necl-5 been ascertained.…”

“…(25) According to previous reports and the elucidated biological properties of Necl-5, Necl-5 up-regulation in cancer cells may play a role in their invasion and metastasis, and possibly influence prognosis in patients. But an analysis of Necl-5 expression using a large number of surgically resected human cancer tissues has not been reported.…”

“…(24) Furthermore, an experiment in which colon adenocarcinoma cells were injected into the tail vein of mice showed that up-regulated expression of cell surface Necl-5 increased the number of metastatic foci in the lungs. (25) According to previous reports and the elucidated biological properties of Necl-5, Necl-5 up-regulation in cancer cells may play a role in their invasion and metastasis, and possibly influence prognosis in patients. But an analysis of Necl-5 expression using a large number of surgically resected human cancer tissues has not been reported.…”

Platelet-derived thrombospondin-1 is a critical negative regulator and potential biomarker of angiogenesis

“…There is a strong body of evidence indicating a role for platelets in cancer metastasis, and treatments involving platelet-reducing agents have been beneficial in reducing the number of metastatic lesions in several mouse models. 10,11,39,40 Despite platelets being one of the largest single sources of angiogenic regulators, 38 their role in the earliest stages of tumor angiogenesis, regulation, and transport throughout the body has not been extensively studied. A single report described the involvement of platelets, and specifically TSP-1, in the regulation of angiogenesis during the reperfusion of ischemic limbs.…”

Nectin-Like Molecule-5 Regulates Intimal Thickening After Carotid Artery Ligation in Mice

“…1 The results of the present study implicate Necl-5 as a therapeutic target for intimal thickening that contributes to restenosis after coronary intervention. For example, an anti-Necl-5 mAb 42 may have the potential to prevent intimal thickening, although further extensive studies are required to determine the clinical utility of direct Necl-5 inhibition. …”