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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 Article has an altmetric score of 24

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 7

ETP augments metastasis through enforcing TGF-β–dependent EMT.

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ETP augments metastasis through enforcing TGF-β–dependent EMT.
(A) E-cad...
(A) E-cadherin immunostaining for tumor tissues from PyMT and PyMT/ETP. (B and C) SBE-luciferase reporter assay. See Supplemental Methods for details. Data represent fold increase (3 independent experiments). **P < 0.01, *P < 0.05, 2-way ANOVA. pRA-ctrl, empty; pRA-sETP, secretion form; pRA-ETP, intracellular form. (D–G) Allografts of Met-1 cells in the presence of either ETP (20 ng/plug) or PBS mixed with 1D11 or IgG (10 μg/plug) within a Matrigel plug. 10 days after implantation, additional 1D11 or IgG (100 μg) was i.p. injected once a week during tumor progression. (D) Tumor volumes represent means ± SEM (n = 5 per group). *P < 0.05, 2-way ANOVA. (E) H&E staining. The ratio of stromal area in tumor tissues was quantified. Data represent mean ± SEM (n = 5 per group). *P < 0.05, unpaired t test. T; tumor and S; stroma. (F) Fibrosis was determined by Masson’s Trichrome C stain. Data represent mean ± SEM (n = 5 per group). **P < 0.01, ***P < 0.001, unpaired t test. (G) Western blotting for EMT markers E-cadherin, vimentin, and α-SMA. β-actin, loading control. Data represent fold increase (n = 5 per group). *P < 0.05, **P < 0.01, ***P < 0.001, unpaired t test. (H) Control and ETP+-cancer cells were isolated from FP635/PyMT and FP635/PyMT/ETP mice and conveyed into WT mice by tail vein injection (0.5 × 106 cells/mouse). Either IgG or 1D11 (100 μg) was i.p. injected every 5 days. 20 days post injection, metastasized cancer cells in the lung tissues were determined by fluorescence intensity. Data represent fold increase (n = 3–4 per group). **P < 0.01, *P < 0.05, unpaired t test. Scale bars: 20 μm (A); 50 μm (E); 100 μm (F).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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