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Tumor-associated fibroblasts predominantly come from local and not circulating precursors.

ABSTRACT: Fibroblasts are common cell types in cancer stroma and lay down collagen required for survival and growth of cancer cells. Although some cancer therapy strategies target tumor fibroblasts, their origin remains controversial. Multiple publications suggest circulating mesenchymal precursors as a source of tumor-associated fibroblasts. However, we show by three independent approaches that tumor fibroblasts derive primarily from local, sessile precursors. First, transplantable tumors developing in a mouse expressing green fluorescent reporter protein (EGFP) under control of the type I collagen (Col-I) promoter (COL-EGFP) had green stroma, whereas we could not find COL-EGFP(+) cells in tumors developing in the parabiotic partner lacking the fluorescent reporter. Lack of incorporation of COL-EGFP(+) cells from the circulation into tumors was confirmed in parabiotic pairs of COL-EGFP mice and transgenic mice developing autochthonous intestinal adenomas. Second, transplantable tumors developing in chimeric mice reconstituted with bone marrow cells from COL-EGFP mice very rarely showed stromal fibroblasts expressing EGFP. Finally, cancer cells injected under full-thickness COL-EGFP skin grafts transplanted in nonreporter mice developed into tumors containing green stromal cells. Using multicolor in vivo confocal microscopy, we found that Col-I-expressing fibroblasts constituted approximately one-third of the stromal mass and formed a continuous sheet wrapping the tumor vessels. In summary, tumors form their fibroblastic stroma predominantly from precursors present in the local tumor microenvironment, whereas the contribution of bone marrow-derived circulating precursors is rare.

SUBMITTER: Arina A

PROVIDER: S-EPMC4941507 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Tumor-associated fibroblasts predominantly come from local and not circulating precursors.

Arina Ainhoa A Idel Christian C Hyjek Elizabeth M EM Alegre Maria-Luisa ML Wang Ying Y Bindokas Vytautas P VP Weichselbaum Ralph R RR Schreiber Hans H

Proceedings of the National Academy of Sciences of the United States of America 20160617 27

Fibroblasts are common cell types in cancer stroma and lay down collagen required for survival and growth of cancer cells. Although some cancer therapy strategies target tumor fibroblasts, their origin remains controversial. Multiple publications suggest circulating mesenchymal precursors as a source of tumor-associated fibroblasts. However, we show by three independent approaches that tumor fibroblasts derive primarily from local, sessile precursors. First, transplantable tumors developing in a ...[more]

PMID: 27317748

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Project description:Simple Summary Tumor dormancy is a state in which some cancer cells are dormant by less cell proliferation, and are resistant to treatments, thus leading to late recurrence. As nuclear receptor subfamily 2 group F member 1 (NR2F1) is a biomarker of dormancy shown in experimental settings, we studied its clinical relevance by analyzing comprehensive gene expression profiles of approximately 7000 breast cancer patients using computational biological approaches. NR2F1 gene expression of bulk tumors correlated with the suppression of cell proliferation and metastasis-related pathways, but not with metastasis or survival. Using single-cell sequence cohorts, we found that NR2F1 was predominantly expressed in cancer-associated fibroblasts, particularly in inflammatory type, rather than in cancer cells. Further, NR2F1 expression in breast cancer cells did not consistently correlate with stem cell-like traits. Our findings suggest that the NR2F1 gene expression signal from a patient’s bulk tumor is not from the cancer cells. Abstract Background: Tumor dormancy is a crucial mechanism responsible for the late recurrence of breast cancer. Thus, we investigated the clinical relevance of the expression of NR2F1, a known dormancy biomarker. Methods: A total of 6758 transcriptomes of bulk tumors from multiple breast cancer patient cohorts and two single-cell sequence cohorts were analyzed. Results: Breast cancer (BC) with high NR2F1 expression enriched TGFβ signaling, multiple metastases, and stem cell-related pathways. Cell proliferation-related gene sets were suppressed, and MKi67 expression was lower in high NR2F1 BC. In tumors with high Nottingham grade, NR2F1 expression was found to be lower. There was no consistent relationship between NR2F1 expression and metastasis or survival. Cancer mutation rates, immune responses, and immune cell infiltrations were lower in high NR2F1 tumors, whereas the infiltration of stromal cells including cancer-associated fibroblasts (CAFs) was higher. NR2F1 was predominantly expressed in CAFs, particularly inflammatory CAFs, rather than in cancer cells, consistently in the two single-cell sequence cohorts. Conclusions: NR2F1 expression in breast cancer is associated with tumor dormancy traits, and it is predominantly expressed in CAFs in the tumor microenvironment.

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Tumor-associated fibroblasts predominantly come from local and not circulating precursors.

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Tumor-associated fibroblasts predominantly come from local and not circulating precursors.

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