A role for CCL2 in both tumor progression and immunosurveillance

Abstract

The chemokine CC L2, which is best known for its chemotactic functions, is expressed not only by immune cells, but also by several types of malignant and stromal cells. CC L2 has been shown to exert both pro- and anti-tumor effects. However, recent results demonstrate a main role for CC L2 in tumor progression and metastasis, suggesting that this chemokine may constitute a therapeutic target for anticancer drugs. Mammary carcinoma models, including models of implantable, transgenic, and chemically-induced tumors, were employed in the setting of Ccl2 or Ccr2 knockout mice or CC L2 neutralization with a monoclonal antibody to further investigate the role of the CC L2/CCR 2 signaling axis in tumor progression and metastatic spread. In our implantable tumor models, an anti-CC L2 monoclonal antibody inhibited the growth of primary malignant lesions in a biphasic manner and reduced the number of metastases. However, in Ccl2-/- or Ccr2-/- mice developing implanted or transgenic tumors, the number of pulmonary metastases was increased despite a reduction in the growth rate of primary neoplasms. Transgenic Mtag.Ccl2-/- or Mtag.Ccr2-/- mice also exhibited significantly earlier disease onset. In a chemical carcinogenesis model, anti-CC L2 monoclonal antibody inhibited the growth of established lesions but was ineffective in the tumor induction phase. In contrast to previous studies indicating a role for CC L2 in the establishment of metastases, we have demonstrated that the absence of CC L2/CCR 2-signaling results in increased metastatic disease. Thus, the CC L2/CCR 2 signaling axis appears to play a dual role in mediating early tumor immunosurveillance and sustaining the growth and progression of established neoplasms. Our findings support the use of anti-CC L2 therapies for the treatment of established breast carcinoma, although the complete abrogation of the CC L2 signaling cascade may also limit immunosurveillance and support metastatic spread.