title: Stromal MCP-1 in mammary tumors induces tumor-associated macrophage infiltration and contributes to tumor progression.
abstract: There is growing evidence that tumor-associated macrophages (TAMs) promote tumor growth and dissemination. Many individual reports have focused on the protumor function of molecules linked to the recruitment of macrophages, but little is known about which factor has the strongest impact on recruitment of macrophages in breast cancer. To elucidate this question, we performed RT-PCR using species-specific primers and evaluated tumoral and stromal mRNA expression of macrophage chemoattractants separately in human breast tumor xenografts. The correlation between the tumoral or stromal chemoattractant mRNA expression including monocyte chemoattractant protein-1 (MCP-1) (CCL2), MIP-1alpha (CCL3), RANTES (CCL5), colony-stimulating factor 1, tumor necrosis factor alpha, platelet-derived growth factor (PDGF)-BB and macrophage infiltration were compared. There was significant positive correlation between stromal MCP-1 expression and macrophage number (r = 0.63), and negative correlation between tumoral RANTES expression and macrophage number (r = -0.75). However, no significant correlation was found for the other tumoral and stromal factors. The interaction between the tumor cells and macrophages was also investigated. Tumor cell-macrophage interactions augmented macrophage-derived MCP-1 mRNA expression and macrophage chemotactic activity in vitro. Treatment of immunodeficient mice bearing human breast cancer cells with a neutralizing antibody to MCP-1 resulted in significant decrease of macrophage infiltration, angiogenetic activity and tumor growth. Furthermore, immunohistochemical analysis of human breast cancer tissue showed stromal MCP-1 had a significant correlation with relapse free survival (p = 0.029), but tumoral MCP-1 did not (p = 0.105). These findings indicate that stromal MCP-1 produced as a result of tumor-stromal interactions may be important for the progression of human breast cancer and macrophages may play an important role in this tumor-stroma interaction.
authors.affiliation: Pathology Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa-City, Chiba, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fujimoto
authors.forename: Takafumi
authors.initials: T
authors.lastname: Sangai
authors.forename: Genichiro
authors.initials: G
authors.lastname: Ishii
authors.forename: Akashi
authors.initials: A
authors.lastname: Ikehara
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nagashima
authors.forename: Masaru
authors.initials: M
authors.lastname: Miyazaki
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ochiai
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000077214:Becaplermin; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism* / Q000503:physiopathology*; D018932:Chemokine CCL2 / Q000502:physiology*; D054405:Chemokine CCL3 / Q000235:genetics / Q000378:metabolism; D018946:Chemokine CCL5 / Q000235:genetics / Q000378:metabolism; D002633:Chemotaxis; D017077:Culture Media, Conditioned; D018450:Disease Progression; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D017737:Macrophages, Peritoneal / Q000502:physiology*; D051379:Mice; D016513:Mice, SCID; D018613:Microscopy, Confocal; D008875:Middle Aged; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; C111835:CCL2 protein, human; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D054405:Chemokine CCL3; D018946:Chemokine CCL5; D017077:Culture Media, Conditioned; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000077214:Becaplermin