CCL2-CCR2 Chemokine Signaling Facilitates Tumor Cell Extravasation

Extravasation is a critical step in metastasis that is regulated by interactions between cancer cells and the tumor microenvironment, including endothelial cells and monocytes. Increased expression of inflammatory factors, such as chemokine (C-C motif) ligand 2 (CCL2), by tumor cells promotes the recruitment of monocytes that enhance metastasis. Wolf and colleagues describe an additional role for CCL2 and its receptor chemokine (C-C motif) receptor 2 (CCR2) in tumor cell extravasation via modulation of endothelial cell signaling. In the absence of Ccr2 expression, lung metastasis was significantly decreased and was associated with diminished monocyte recruitment. In addition, Ccr2 deficiency resulted in an impaired ability of tumor cells to extravasate and a corresponding decrease in vascular permeability, suggesting that CCR2-mediated regulation of lung endothelium also facilitates metastasis formation. Metastasis was dependent on stromal CCR2 within the microenvironment, as Ccr2 expression in both endothelial and myeloid cells contributed to efficient extravasation and establishment of lung tumors. Increased levels of the CCR2 ligand CCL2 were detected within the lung, and silencing of Ccl2 expression in tumor cells prevented monocyte recruitment and significantly reduced tumor cell extravasation and metastasis. Induction of vascular permeability and transmigration of tumor cells through lung endothelium required tumor cell–derived CCL2 and endothelial expression of CCR2, supporting an important role for this chemokine axis in tumor cell extravasation. Furthermore, inhibition of JAK2–STAT5 and p38MAPK attenuated extravasation and lung metastasis, implicating these pathways as downstream targets of CCL2-CCR2–mediated signaling in endothelial cells. Importantly, elevated CCL2 expression in human colon cancer samples was correlated with increased metastatic potential. These results delineate a mechanism whereby tumor cell–derived CCL2 activates CCR2⁺ endothelial cells to stimulate vascular permeability and subsequent extravasation and suggest potential therapeutic strategies to suppress metastasis.

Wolf MJ, Hoos A, Bauer J, Boettcher S, Knust M, Weber A, et al. Endothelial CCR2 signaling induced by colon carcinoma cells enables extravasation via the JAK2-Stat5 and p38MAPK pathway. Cancer Cell 2012;22:91–105.