Chemokine CCL2/MCP-1 negatively regulates metastasis in a highly bone marrow-metastatic mouse breast cancer model

Abstract

Bone is the most frequent site of breast cancer metastasis, and once such metastasis occurs, complete remission is extremely difficult to achieve. In an effort to define the mechanisms underlying metastatic spread of breast cancer to bone, we previously developed and characterized the highly bone metastatic 4T1E/M3 mouse breast cancer cells. We found that following injection into mice, 4T1E/M3 cells exhibited greater bone metastasis and greater in vitro anchorage-independent growth and cell migration than their parental cells (4T1E). We also found that expression of intracellular adhesion molecule-1 (ICAM-1) is crucially involved in these metastatic activities of 4T1E/M3 cells. In the present study, our analysis of gene and protein expression revealed that production of chemokine CCL2 (MCP-1) is dramatically reduced in 4T1E/M3 cells, and that restoration of CCL2 expression in 4T1E/M3 cells diminishes their metastasis to bone and lung. Overexpression of CCL2 in 4T1E/M3 cells significantly reduced not only in vitro anchorage-independent cell growth and cell migration, but also mRNA and cell surface expression of ICAM-1. Conversely, knocking down CCL2 in 4T1E parental cells augmented their metastatic spread to spine and lung. The expression of ICAM-1 was also upregulated in 4T1E-derived CCL2 knockdown cells. Taken together, these results suggest that CCL2 expression may negatively regulate breast cancer metastasis to bone marrow and lung in our model and that expression of ICAM-1 plays a crucial role in that process.

Role of CD200 expression in regulation of metastasis of EMT6 tumor cells in mice

“…Breast Cancer Res Treat (2011) 130:49-60 57 cancer metastasis, directly and through effects on altered host resistance mechanisms [6,[8][9][10]. Antibody and T cell immune reactivity, and macrophage activation control tumor growth [37,38], are all regulated by CD200:CD200R [31].…”

“…In mouse models, expression of chemokines or chemokine receptors [8][9][10] regulates metastatic spread, possibly by recruiting inflammatory-type cells to the local tumor environment, which produce angiogenic factors and matrix-degrading enzymes [7,11]. Recruitment of cells inhibiting host immunity including Gr-1 ?…”

Inflammatory chemokines and metastasis—tracing the accessory

“…In contrast to the well-documented function of the CCL2-CCR2 axis in promoting metastasis, there are reports describing the opposite effect resulting in inhibition of tumor progression and metastasis (58,59). Host-derived CCL2 and CCL3 recruited CD4 + and CD8 + lymphocytes and NK cells that controlled tumor progression and metastasis (60).…”

“…Overexpression of CCL2 in 4T1 breast cancer cells resulted in reduced metastasis. However, the mechanism remained to be described (58). In an orthotopic breast cancer model using 4T1 cells, CCL2 had a protumorigenic activity at primary sites, while it inhibited metastasis to the lungs (59).…”

In vivo animal models of spinal metastasis

“…Together with their widespread and relatively cheap availability, high sequence homology and similar organ systems to humans, it appears that the mouse offers a suitable in vivo model for studying human metastasis. This is reflected by the popular usage of mouse models of spinal metastasis in recent years [6,7,19,[23][24][25].…”