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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 10

10B6 blocks ETP-mediated stromal expansion in vivo.

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10B6 blocks ETP-mediated stromal expansion in vivo.
(A) 10B6 (200 μg/mou...
(A) 10B6 (200 μg/mouse) was i.p. injected twice weekly into PyMT mice from 9 to 13 weeks of age. Tumor growth (mean ± SEM; n = 4–6 per group) was determined by weekly caliper measurements. *P < 0.05, **P < 0.01, ***P < 0.001 vs. IgG control, 2-way ANOVA. (B) Primary mammary epithelial cancer cells were isolated from 12-week-old FP635/PyMT and FP635/PyMT/ETP mice and implanted into WT recipients with the same volume of Matrigel. For the 10B6 group, 10B6 was added in a Matrigel plug (10 μg/plug) admixed with ETP+-cancer cells (i.e., ETP+/10B6). A representative whole-body image was acquired 25 days after implantation using IVIS fluorescence scanner. Artificial color indicates fluorescence signal intensity accounts for tumor volume (AU). Quantitative results are represented as mean ± SEM (n = 3 per group). *P < 0.05, unpaired t test. (C–I) 6 weeks after implantation, tumor tissues were excised from Ctrl-, ETP+-, and ETP+/10B6-cancer cells allografted mice and stained for H&E (C), Masson’s Trichrome C (D), α-SMA (E), FSP-1 (F), CD31 (G), F4/80 (H), and Ki67 (I). Quantified results in D–I are mean ± SEM (multiple images, n = 3 per group). *P < 0.05, **P < 0.01, unpaired t test. Scale bars: 50 μm. (J) Working model for ETP in mammary tumor progression.

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