Abstract 3585: Metastasis of 4T1 murine breast cancer cells to the lung is dependent on the chemokine CCL2/MCP-1 produced by stromal cells in the primary tumor

Abstract

Abstract The chemokine CCL2, also known as MCP-1, plays an important role in the initiation and progression of cancer. Since tumor cells produce CCL2, they are considered to be the main source of this chemokine. Here, we examined the capacity of CCL2 produced by non-tumor cells to affect the growth and lung metastasis of 4T1 mouse breast cancer cells. Primary tumors formed in the mammary pad of WT or CCL2-/- mice grew at a similar rate; however, lung metastases were markedly reduced in CCL2-/- mice, with significantly longer mouse survival. High levels of CCL2 mRNA were detected in tumors growing in WT, but not CCL2-/- mice. Serum CCL2 levels were increased in tumor-bearing WT, but not CCL2-/- mice. Transplantation of CCL2-/- bone marrow cells into WT mice did not alter the incidence of lung metastasis, but transplantation of WT bone marrow cells into CCL2-/- mice increased lung metastasis. The primary tumors of CCL2-/- mice consistently developed necrosis earlier than those of WT mice and showed decreased infiltration by macrophages and reduced angiogenesis. Interestingly, 4T1 cells that metastasized to the lung constitutively expressed elevated levels of CCL2. Intravenous injection of 4T1 cells producing a high level of CCL2 resulted in increased tumor foci in the lung of CCL2-/- mice. Finally, the culture supernatants of 4T1 cells markedly induced CCL2 production in mouse macrophages. Thus, CCL2 produced by tumor cell-activated stromal cells in the primary tumors promotes lung metastasis of 4T1 cells, while tumor cell-derived CCL2 also contributes to the metastasis once tumor cells enter the circulation. A greater understanding of the source and role of CCL2 during tumor progression and the mechanisms by which stromal cells produce this chemokine may lead to novel strategies for cancer treatment. Citation Format: Teizo Yoshimura, O.M. Zack Howard, Toshihiro Ito, Masaki Kuwabara, Akihiro Matsukawa, Keqiang Chen, Ying Liu, Mingyong Liu, Ji Ming Wang. Metastasis of 4T1 murine breast cancer cells to the lung is dependent on the chemokine CCL2/MCP-1 produced by stromal cells in the primary tumor. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3585. doi:10.1158/1538-7445.AM2014-3585