Dysfunctional endothelial cells directly stimulate cancer inflammation and metastasis
Author(s)Franses, Joseph Wang; Drosu, Natalia C.; Gibson, William J.; Chitalia, Vipul C.; Edelman, Elazer R.
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Although the influence of context-dependent endothelial cell (EC) regulation of vascular disease and repair is well-established, the privileged roles ECs play as paracrine regulators of tumor progression has only recently become appreciated. We hypothesized that if the same endothelial physiology governs vascular and cancer biology then EC control in cancer should follow endothelial regulation of vascular health. Healthy ECs promote vascular repair and inhibit tumor invasiveness and metastasis. Dysfunctional ECs have the opposite effects in vascular disease, and we now ask if dysfunctionally activated ECs will promote cancer cell inflammatory signaling and aggressive properties. Indeed, while factors released from quiescent ECs induce balanced inflammatory signaling, correlating with decreased proliferation and invasiveness, factors released from dysfunctional ECs robustly activated NF-κB and STAT3 signaling within cancer cells, correlating with increased in vitro invasiveness and decreased proliferation and survival. Furthermore, matrix-embedded dysfunctional ECs stimulated intratumoral pro-inflammatory signaling and spontaneous metastasis, while simultaneously slowing primary tumor growth, when implanted adjacent to Lewis lung carcinoma tumors. These studies may broaden our appreciation of the roles of endothelial function and dysfunction, increase understanding and control of the tumor microenvironment, and facilitate optimization of anti-angiogenic and vascular-modifying therapies in cancer and other diseases.
DepartmentWhitaker College of Health Sciences and Technology; Institute for Medical Engineering and Science; Harvard University--MIT Division of Health Sciences and Technology
International Journal of Cancer
John Wiley & Sons, Inc/Union for International Cancer Control
Franses, Joseph W., Natalia C. Drosu, William J. Gibson, Vipul C. Chitalia, and Elazer R. Edelman. “Dysfunctional Endothelial Cells Directly Stimulate Cancer Inflammation and Metastasis.” Int. J. Cancer 133, no. 6 (April 8, 2013): 1334–1344.
Author's final manuscript