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

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 5

ETP augments primary tumor growth and pulmonary metastasis in the background of PyMT mice.

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ETP augments primary tumor growth and pulmonary metastasis in the backgr...
(A) ETP immunostaining, with a high ETP-positive signal in tumor tissues from 12-week-old PyMT and PyMT/ETP mice. Scale bars: 50 μm. Intensity of ETP staining was quantified and represented as mean ± SEM (n = 5 per group). *P = 0.02 vs. PyMT, unpaired t test. (B) Whole-mount staining of mammary gland tissues from 8-week-old PyMT and PyMT/ETP mice, with early neoplastic lesion areas increased by ETP. (C) Tumor volume was determined by weekly caliper measurements from PyMT (n = 35) and PyMT/ETP (n = 38) mice. Results are represented as mean ± SEM. P = NS, 2-way ANOVA. (D and E) ETP augmented pulmonary metastasis. (D) Pulmonary metastatic growth was determined by measuring the tumor incidence in lung tissues (8- to 17-week-old, n = 22–25 per group). H&E-stained preparations for lung tissues were used for analysis. Shown is percent metastasis-free mice over time. *P = 0.025, log-rank test. (E) Representative H&E stain for lung tissues showing the degree of pulmonary metastasis in 15- and 17-week-old PyMT and PyMT/ETP mice. (F) Representative whole-body images for tumor burden. Tumor volume for 13-week-old FP635/PyMT and FP635/PyMT/ETP mice was monitored by IVIS fluorescence scanner. Metastatic burden was determined by fluorescence signals in lung tissues. Quantified results are represented as mean ± SEM (n = 8–9 per group). *P = 0.0117, **P = 0.0011 vs. PyMT, unpaired t test.