Cancer associated fibroblasts promote tumor growth and metastasis by modulating the tumor immune microenvironment in a 4T1 murine breast cancer model.
Cancer associated fibroblasts promote tumor growth and metastasis by modulating the tumor immune microenvironment in a 4T1 murine breast cancer model.
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DOI：
10.1371/journal.pone.0007965
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发表时间：
2009-11-23
期刊：
影响因子：
3.7
通讯作者：
Reisfeld RA
中科院分区：
文献类型：
--
作者：
Liao D;Luo Y;Markowitz D;Xiang R;Reisfeld RA
与实体瘤相关的局部炎症通常由肿瘤细胞和肿瘤间质释放的因子引起，并促进肿瘤进展。癌症相关的成纤维细胞包括在肿瘤基质中发现的大多数细胞，并且是癌症治疗的吸引人的靶标。在这里，我们的目的是确定靶向癌症相关成纤维细胞治疗转移性乳腺癌的疗效。我们证明，癌症相关的成纤维细胞是转移性乳腺癌的4 T1小鼠模型的肿瘤微环境中的免疫极化的关键调节剂。通过靶向成纤维细胞活化蛋白的DNA疫苗在体内消除癌症相关的成纤维细胞导致免疫微环境从Th 2极化转变为Th 1极化。这种转变的特征在于IL-2和IL-7的蛋白表达增加，肿瘤相关巨噬细胞、髓源性抑制细胞、T调节细胞的募集受到抑制，以及肿瘤血管生成和淋巴管生成减少。此外，该疫苗改善了阿霉素化疗的抗转移作用，并增强了对IL-6和IL-4蛋白表达的抑制，同时增加了树突状细胞和CD 8 + T细胞的募集。联合治疗还降低了肿瘤相关的VEGF、Pdgfc和GM-CSF mRNA和蛋白质表达。我们的研究结果表明，癌症相关的成纤维细胞通过其作为肿瘤微环境中免疫极化的关键调节剂的作用促进肿瘤生长和转移，并且是转移性乳腺癌治疗的有效靶点。
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. 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. 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.
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影响因子：
11.2
作者：
Anderberg C;Li H;Fredriksson L;Andrae J;Betsholtz C;Li X;Eriksson U;Pietras K
通讯作者：
Pietras K
DOI：
10.1084/jem.20050915
发表时间：
2005-12-19
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Casares N;Pequignot MO;Tesniere A;Ghiringhelli F;Roux S;Chaput N;Schmitt E;Hamai A;Hervas-Stubbs S;Obeid M;Coutant F;Métivier D;Pichard E;Aucouturier P;Pierron G;Garrido C;Zitvogel L;Kroemer G
通讯作者：
Kroemer G
影响因子：
11.2
作者：
Liao, Debbie;Corle, Courtney;Johnson, Randall S.
通讯作者：
Johnson, Randall S.
影响因子：
15.9
作者：
Melchionda, F;Fry, TJ;Mackall, CL
通讯作者：
Mackall, CL
影响因子：
50.3
作者：
Crawford, Yongping;Kasman, Ian;Ferrara, Napoleone
通讯作者：
Ferrara, Napoleone