title: Cancer associated fibroblasts promote tumor growth and metastasis by modulating the tumor immune microenvironment in a 4T1 murine breast cancer model.
abstract: BACKGROUND
  Local inflammation associated with solid tumors commonly results from factors released by tumor cells and the tumor stroma, and promotes tumor progression. Cancer associated fibroblasts comprise a majority of the cells found in tumor stroma and are appealing targets for cancer therapy. Here, our aim was to determine the efficacy of targeting cancer associated fibroblasts for the treatment of metastatic breast cancer.
  
  
  RESULTS
  We demonstrate that cancer associated fibroblasts are key modulators of immune polarization in the tumor microenvironment of a 4T1 murine model of metastatic breast cancer. Elimination of cancer associated fibroblasts in vivo by a DNA vaccine targeted to fibroblast activation protein results in a shift of the immune microenvironment from a Th2 to Th1 polarization. This shift is characterized by increased protein expression of IL-2 and IL-7, suppressed recruitment of tumor-associated macrophages, myeloid derived suppressor cells, T regulatory cells, and decreased tumor angiogenesis and lymphangiogenesis. Additionally, the vaccine improved anti-metastatic effects of doxorubicin chemotherapy and enhanced suppression of IL-6 and IL-4 protein expression while increasing recruitment of dendritic cells and CD8(+) T cells. Treatment with the combination therapy also reduced tumor-associated Vegf, Pdgfc, and GM-CSF mRNA and protein expression.
  
  
  CONCLUSIONS
  Our findings demonstrate that cancer associated fibroblasts promote tumor growth and metastasis through their role as key modulators of immune polarization in the tumor microenvironment and are valid targets for therapy of metastatic breast cancer.
authors: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America.
authors: Debbie
authors: D
authors: Liao
authors: Yunping
authors: Y
authors: Luo
authors: Dorothy
authors: D
authors: Markowitz
authors: Rong
authors: R
authors: Xiang
authors: Ralph A
authors: RA
authors: Reisfeld
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D015851:Interleukin-7 / Q000378:metabolism; D008222:Lymphokines / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D018417:Th1 Cells / Q000166:cytology; D018418:Th2 Cells / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D007376:Interleukin-2; D015851:Interleukin-7; D008222:Lymphokines; D010982:Platelet-Derived Growth Factor; D042461:Vascular Endothelial Growth Factor A; C411423:platelet-derived growth factor C; D016178:Granulocyte-Macrophage Colony-Stimulating Factor