Dissecting the Autocrine and Paracrine Roles of the CCR2-CCL2 Axis in Tumor Survival and Angiogenesis

Abstract

The CCL2 CCR2 axis is likely to contributes to the development and progression of cancer diseases by two major mechanisms; autocrine effect of CCL2 as a survival/growth factor for CCR2+ cancer cells and, the attraction of CCR2+ CX3CR1+tumor associated macrophages that in the absence of CCR2 hardly migrate. Thus far no in vivo system has been set up to differentiate the selective contribution of each of these features to cancer development. Here we employed a chimera animal model in which all non-malignant cells are CCR2−/−, but all cancer cells are CCR2+, combined with an adoptive transfer system of bone marrow (BM) CX3CR1+ cells from CCR2+ mice harboring a targeted replacement of the CX3CR1gene by an enhanced green fluorescent protein (EGFP) reporter gene (cx3cr1 gfp), together with the CD45.1 congene. Using this system we dissected the selective contribution of CX3CR1+CCR2+ cells, which comprise only about 7% of CD11b+ BM cells, to tumor development and angiogenesis. Showing that aside for their direct pro-angiogenic effect they are essential for the recruitment of other CD11b+ cells to the tumor site. We further show that the administration of CCR2-Ig, that selectively and specifically neutralize CCL2, to mice in which CCR2 is expressed only on tumor cells, further suppressed tumor development, implicating for the key role of this chemokine supporting tumor survival in an autocrine manner. This further emphasizes the important role of CCL2 as a target for therapy of cancer diseases.

Mesenchymal Stem/Stromal Cells Protect against Autoimmunity via CCL2-Dependent Recruitment of Myeloid-Derived Suppressor Cells

“…Moreover, tumor cell-derived CCL2 has been shown to stimulate metastasis and angiogenesis (48,59), whereas CCL2-or CCR2-blocking agents improve therapeutic responses to immunotherapeutic regimens (47,60). We found in the present study that CCL2 produced by MSCs mobilizes immunosuppressive MDSCs into dLNs of EAU-immunized mice and modulates Th1/Th17 autoimmune responses, subsequently preventing EAU.…”

CCL2/CCR2-Dependent Recruitment of Functional Antigen-Presenting Cells into Tumors upon Chemotherapy

“…In addition, available evidence suggests that neoplastic lesions contain all the cellular and humoral elements that are required to mount a local anticancer immune response even in the absence of DLNs, hence constituting a sort The CCL2/CCR2 system has been previously implicated in the accumulation of tumor-associated macrophages and myeloid-derived suppressor cells within neoplastic lesions, hence supporting tumor growth via proinflammatory and immunosuppressive mechanisms (19). In addition, an autocrine CCL2-dependent signaling pathway has been suggested to promote the survival and mobility of cancer cells (20), whereas tumor cell-derived CCL2 has been shown to stimulate metastasis (21) and angiogenesis (22). In line with these observations, CCL2-or CCR2-targeting agents have been shown to improve the antineoplastic activity of distinct immunotherapeutic regimens (23,24) as well as the efficacy of gemcitabine-and cisplatin-based chemotherapy (25,26).…”

Targeting monocyte chemotactic protein-1 synthesis with bindarit induces tumor regression in prostate and breast cancer animal models

“…These cells accumulate at the tumor site, to initially support tumor development and angiogenesis, resulting in enhanced levels of various inflammatory cytokines, growth factors and chemokines, which further contribute to tumor development and progression. Moreover, as a paracrine factor, MCP-1 induces the differentiation of bone-marrow-derived monocytic cells into TAMs, and shows pro-angiogenic effects on endothelia that also expresses CCR2 [45]. Moreover, in PC-3M-Luc2 cells, MCP-1 can protect the cells from autophagic death via the [28,29,46].…”