Cancer associated fibroblasts promote tumor growth and metastasis by modulating the tumor immune microenvironment in a 4T1 murine breast cancer model.
TLDR
It is demonstrated 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.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.
Methodology/Principal Findings
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/Significance
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.read more
Citations
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Immunity, Inflammation, and Cancer
TL;DR: The principal mechanisms that govern the effects of inflammation and immunity on tumor development are outlined and attractive new targets for cancer therapy and prevention are discussed.
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The biology and function of fibroblasts in cancer
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Hallmarks of cancer: interactions with the tumor stroma.
Kristian Pietras,Arne Östman +1 more
TL;DR: The current understanding of tumor cell interactions with the tumor stroma is reviewed with a particular focus on cancer-associated fibroblasts and pericytes.
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Immunological hallmarks of stromal cells in the tumour microenvironment
TL;DR: Evidence thatStromal determinants interact with leukocytes and influence antitumour immunity is discussed, with emphasis on the immunological attributes of stromal cells that may foster their protumorigenic function.
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Fibroblast heterogeneity in the cancer wound
TL;DR: A comprehensive review on the fundamental role of cancer-associated fibroblasts in shaping the tumor microenvironment and promoting tumor initiation and progression is provided.
References
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Journal ArticleDOI
The hallmarks of cancer.
TL;DR: This work has been supported by the Department of the Army and the National Institutes of Health, and the author acknowledges the support and encouragement of the National Cancer Institute.
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Inflammation and cancer
Lisa M. Coussens,Zena Werb +1 more
TL;DR: It is now becoming clear that the tumour microenvironment, which is largely orchestrated by inflammatory cells, is an indispensable participant in the neoplastic process, fostering proliferation, survival and migration.
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Fibroblasts in cancer
TL;DR: Fibroblasts are a key determinant in the malignant progression of cancer and represent an important target for cancer therapies.
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Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing.
TL;DR: Tumors of epithelioma are composed of two discrete but interdependent compartments: the malignant cells themselves and the stroma that they induce and in which they are dispersed.
Journal ArticleDOI
Microenvironmental regulation of metastasis
TL;DR: Experimental data demonstrating the role of the microenvironment in metastasis is described, areas for future research are identified and possible new therapeutic avenues are suggested.