Scientists have identified a new mechanism by which breakaway tumor cells can escape the vasculature and settle in new locations to establish metastases. In vitro and in vivo studies by researchers at the University Hospital Zurich, and Technische Universität München/Helmholtz Zentrum have shown that the chemokine CCL2 released by metastatic colon cancer cells binds to the CCR2 receptor on vascular endothelial cells and triggers increased vascular permeability via a pathway dependent on downstream JAK2-Stat5 and p38MAPK signaling. This increased permeability allows the cancer cells to squeeze out and settle in the surrounding tissue.

Moreover, the research states, this mechanism appears distinct from the activity of tumor-derived CCL2 on the metastasis-promoting recruitment of monocytes/macrophages. Mathias Heikenwalder, M.D., et al say their results identify inhibition of CCR2 and its downstream targets as a potential therapeutic strategy for preventing CCL2-mediated metastasis. Their findings are reported in Cancer Cell in a paper titled “Endothelial CCR2 Signaling Induced by Colon Carcinoma Cells Enables Extravasation via the JAK2-Stat5 and p38MAPK Pathway.”

The team’s initial studies showed that animals lacking CCR2 (CCr2-/-) developed far fewer lung tumors following injection colon cancer cells than wild-type C57BL/6 animals, even though both cohorts exhibited the same numbers of colon cancer cells in their lungs and equivalent numbers of  CD4+ and CD8+ T cells, CD19+ B cells, NK1.1+ and F4/80+ cells. Instead, confocal microscopy indicated that the lung vasculature of CCr2-/- animals was far less permeable than that of the wild-type animals, preventing the cancer cells from penetrating through the endothelium and into the lung parenchyma.

Although their studies confirmed that the recruitment of CCR2-expressing myeloid cells played a role in contributing to metastasis of the colon cancer cells, the team’s studies confirmed that CCR2 expression on vascular endothelial cells was a critical factor in determining lung permeability and controlled tumor extravasation through the JAK2-Stat5 and p38MAPK pathways. Inhibiting JAK2, Stat5, and p38MAPK prevented the increase in vascular permeability induced by the colon cancer cells in C57BL/6 mice.

In fact, they write, while Ly6Chi monocytes appeared to be necessary for effective metastasis, their presence wasn’t enough to enable the growth of lung tumors. In contrast, endothelial expression of CCR2 was sufficient to allow metastasis.

Interestingly, when they compared normal human colon tissue with human primary nonmetastasized colon tumors (UICC stages I-II), colon tumors that had metastasized to the lymph nodes (UICC stage III), and those that had metastasized to distant organs (UICC stage IV), they found that while CCL2 transcripts were more abundant in stage I-III tumors, CCL2 expression was particularly high in stage I tumors.

“We hypothesize that CCR2 on endothelial cells may resemble a ‘lock-and-key’ signal for opening the vasculature and enabling extravasation of CCL2+ tumor cells,” the authors conclude. “This ‘lock-and-key’ relationship was dependent on CCL2 expression solely from the tumor cells….We suggest that an intimate interaction of CCL2+ colon carcinoma cells with the CCR2+ endothelium is required.

The authors finally propose a model for the role of CCR2 signaling in metastasis. “Upon vascular arrest,” they write, “CCL2+ tumor cells induce a local chemokine gradient, recruiting CCR2+ monocytes. Concomitantly or subsequently direct activation of CCR2 on the endothelium is triggered by tumor cells, which is critical for metastasis. CCL2 activates JAK2 and p38MAPK signaling, leading to enhanced vascular permeability that along with monocyte recruitment enables efficient tumor cell extravasation….Our data identify a yet undescribed role for tumor cell-derived chemokines in metastasis that goes beyond the attraction of inflammatory cells.”

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