A role for CCL2 in both tumor progression and immunosurveillance.

摘要

The chemokine CCL2, which is best known for its chemotactic functions, isexpressed not only by immune cells, but also by several types of malignant andstromal cells. CCL2 has been shown to exert both pro- and anti-tumor effects.However, recent results demonstrate a main role for CCL2 in tumor progression andmetastasis, suggesting that this chemokine may constitute a therapeutic targetfor anticancer drugs. Mammary carcinoma models, including models of implantable, transgenic, and chemically-induced tumors, were employed in the setting of Ccl2or Ccr2 knockout mice or CCL2 neutralization with a monoclonal antibody tofurther investigate the role of the CCL2/CCR2 signaling axis in tumor progressionand metastatic spread. In our implantable tumor models, an anti-CCL2 monoclonalantibody inhibited the growth of primary malignant lesions in a biphasic mannerand reduced the number of metastases. However, in Ccl2(-/-) or Ccr2(-/-) micedeveloping implanted or transgenic tumors, the number of pulmonary metastases wasincreased despite a reduction in the growth rate of primary neoplasms. TransgenicMtag.Ccl2(-/-) or Mtag.Ccr2(-/-) mice also exhibited a significantly earlier ofdisease onset. In a chemical carcinogenesis model, anti-CCL2 monoclonal antibody inhibited the growth of established lesions but was ineffective in the tumorinduction phase. In contrast to previous studies indicating a role for CCL2 inthe establishment of metastases, we have demonstrated that the absence ofCCL2/CCR2-signaling results in increased metastatic disease. Thus, the CCL2/CCR2 signaling axis appears to play a dual role in mediating early tumorimmunosurveillance and sustaining the growth and progression of establishedneoplasms. Our findings support the use of anti-CCL2 therapies for the treatment of established breast carcinoma, although the complete abrogation of the CCL2signaling cascade may also limit immunosurveillance and support metastaticspread.