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Adipocyte-derived endotrophin promotes malignant tumor progression
Jiyoung Park, Philipp E. Scherer
Jiyoung Park, Philipp E. Scherer
Published October 8, 2012
Citation Information: J Clin Invest. 2012;122(11):4243-4256. https://doi.org/10.1172/JCI63930.
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Research Article Oncology

Adipocyte-derived endotrophin promotes malignant tumor progression

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Abstract

Adipocytes represent a major cell type in the mammary tumor microenvironment and are important for tumor growth. Collagen VI (COL6) is highly expressed in adipose tissue, upregulated in the obese state, and enriched in breast cancer lesions and is a stimulator of mammary tumor growth. Here, we have described a cleavage product of the COL6α3 chain, endotrophin (ETP), which serves as the major mediator of the COL6-mediated tumor effects. ETP augmented fibrosis, angiogenesis, and inflammation through recruitment of macrophages and endothelial cells. Moreover, ETP expression was associated with aggressive mammary tumor growth and high metastatic growth. These effects were partially mediated through enhanced TGF-β signaling, which contributes to tissue fibrosis and epithelial-mesenchymal transition (EMT) of tumor cells. Our results highlight the crucial role of ETP as an obesity-associated factor that promotes tumor growth in the context of adipocyte interactions with tumor and stromal cells.

Authors

Jiyoung Park, Philipp E. Scherer

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Figure 9

ETP acts as a chemokine augmenting tumor growth.

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ETP acts as a chemokine augmenting tumor growth.
(A) Tumor growth signif...
(A) Tumor growth significantly increased in ETP+-tumor tissue allograft into WT mice. Tumor volume was determined 1 month after implantation (representative images). Data represent mean ± SEM (n = 5 per group). ***P < 0.001, unpaired t test. (B) In vivo Matrigel bioassay. Matrigel (50 μl) was mixed with ETP (100 ng/plug) or PBS and implanted into WT mice in the presence of IgG, 1D11, or 10B6 (20 μg/plug). 2 days after implantation, plugs were excised and stained for H&E. Scale bars: 100 μm. (C–L) Cancer cells were plated in the bottom chamber 1 day prior to seeding MS-1 cells (5 × 105 cells/well) and macrophages (1 × 105 cells/well) atop the membrane chamber in Transwell and incubated for 18–24 hours (C). (D–K) Representative images of multiple independent experiments. Scale bars: 100 μm. (L) Quantitation (mean ± SEM; n = 3 per group). ***P < 0.001, **P < 0.05, *P < 0.01, unpaired t test. (M) MS-1 migration assay. MS-1 cells (5 × 105 cells/well) were plated atop the chamber in Transwell and incubated for 24 hours. Chemotaxis was set up by following cell migration from DMEM/serum-free to DMEM/2% FBS/PBS or DMEM/2% FBS/ETP protein (1 μg/well). Images are representative of multiple independent experiments. Data represent mean ± SEM (n = 3 per group). ***P = 0.008, unpaired t test. Scale bars: 100 μm.

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