Adipocyte-derived endotrophin promotes malignant tumor progression
Jiyoung Park, Philipp E. Scherer
Jiyoung Park, Philipp E. Scherer
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Research Article Oncology

Adipocyte-derived endotrophin promotes malignant tumor progression

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 6

Histological analysis for tumor tissues of PyMT/ETP versus PyMT mice.

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Histological analysis for tumor tissues of PyMT/ETP versus PyMT mice. (A...
(A) Proliferation indices were determined by immunostaining with Ki67. Quantified results represent mean ± SEM (n = 5 per group). P = NS vs. PyMT, unpaired t test. (B) Fibrosis indices were determined by Masson’s Trichrome C stain. Percent fibrotic area over the tumor lesions was quantified. Data represent mean ± SEM (n = 5 per group). **P = 0.01 vs. PyMT, unpaired t test. Arrows indicate collagen fibrils. (C) Functional blood vessel areas were determined by lectin perfusion. Podoplanin (lymphangiogenesis marker) and DAPI (nucleus) were costained. Quantified results represent mean ± SEM (n = 5 per group). **P = 0.003 vs. PyMT, unpaired t test. (D) Hypoxia was determined by pimonidazole-HCl injection. Hypoxic lesions were stained in dark brown. Quantified results represent mean ± SEM (n = 5 per group). ***P = 0.0007 vs. PyMT, unpaired t test. (E–H) Total RNA was prepared from the tumor tissues from PyMT/ETP and PyMT mice. mRNA levels for the genes responsible for fibrosis and EMT (E and F), angiogenesis and lymphangiogenesis (G), and inflammation (H) were determined by qRT-PCR. mRNA levels were normalized with β-actin and represented as mean ± SEM (n = 8 per group). Relative values of each gene are represented as fold change relative to PyMT. *P < 0.05, ***P < 0.001 vs. PyMT, 2-way ANOVA. Scale bars: 50 μm (A–C); 100 μm (D). Insets in A are enlarged ×5.