Tumor-associated MΦ play a central role in lung cancer growth and metastasis, with bidirectional cross-talk between MΦ and cancer cells via CCR2 and CX3CR1 signaling as a central underlying mechanism. These findings suggest that the therapeutic strategy of blocking CCR2 and CX3CR1 may prove beneficial for halting lung cancer progression.

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Lung Cancer is the leading cause of cancer deaths worldwide. It is increasingly appreciated that the tumor stroma, consistent of a heterogeneous population of non-neoplastic host cells, is an essential part of cancer initiation, growth and progression. Tumor-associated macrophages (TAMs) can influence cancer progression and metastasis, but the responsible mechanisms remain unclear. Here, we focus on the involvement of bone-marrow derived macrophages (BM- MM) and two of their major chemotactic pathways (CX3CR1-CX3CL1 and CCR2-CCL2 axis) in cancer proliferation and migration. We demonstrate that conditioned medium (CM) derived from co-cultures of lewis lung carcinoma (LLC1) cells with BM- MM (purity >99%) enhances proliferation of LLC1-cells significantly from 1.79±0.1717 to 2.43±0.2067 in an absorbance based BrdU-Assay and a higher colony-number was found in a colony-formation-assay compared to control. In addition LLC1-migration in presence of CM was 5 fold increased compared to controls (172.9±2.18 versus 33.93±2.29). Further, analysis of the cytokine profile of co-culture-derived CM showed regulation of pro-inflammatory cytokines (Interleukin-6 and Interleukin-1α), anti-inflammatory cytokines (Interleukin-10 and Interleukin-1RA) and several chemokines (CCL5 and CCL2). Importantly, evaluation of tumor growth in chemokine receptor knockout mice, CX3CR1-KO and CCR2-KO demonstrated reduced tumor size compared to wild type mice. CX3CR1-KO and CCR2-KO tumor showed reduced in vivo proliferation as assessed by PCNA immunostaining (12.46%±3.188 versus 46.45%±2.922). Further analysis of the tumor microenvironment in CX3CR1-KO and CCR2-KO demonstrated a significant decrease in monocyte/ macrophage accumulation compared to control tumors as assessed by FACS. Compared to the percentage of macrophages in control tumor (7.518±0.78%), a significant decrease was observed in CCR2-KO (2.96± 0.233%) and CX3CR1-KO (3.975±0.6019%) tumors. Based on these findings, we conclude that macrophage plays a crucial role in lung cancer progression and the knowledge of tumor-host interactions can provide novel therapeutic approaches for lung cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1484. doi:1538-7445.AM2012-1484