Chemokine CCL2/MCP-1 negatively regulates metastasis in a highly bone marrow-metastatic mouse breast cancer model.
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.
Takahashi
Munehisa
M
Neuroscience Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1, Higashi, Tsukuba, Ibaraki, 305-8566, Japan.
Miyazaki
Hiroshi
H
Furihata
Mutsuo
M
Sakai
Hirofumi
H
Konakahara
Takeo
T
Watanabe
Morihiro
M
Okada
Tomoko
T
D000818:Animals; D001483:Base Sequence; D019046:Bone Marrow Neoplasms / Q000556:secondary*; D001943:Breast Neoplasms / Q000473:pathology*; D002448:Cell Adhesion; D002455:Cell Division; D018932:Chemokine CCL2 / Q000502:physiology*; D017931:DNA Primers; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis / Q000503:physiopathology*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction
D018932:Chemokine CCL2; D017931:DNA Primers