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 2

Expression profiles of ETP.

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Expression profiles of ETP. (A) COL6 is composed of COL6α1, -α2, and -α3...
(A) COL6 is composed of COL6α1, -α2, and -α3 chains. The C5 domain of the α3 chain, cleaved off the COL6 microfilament, is highlighted in red. Shown are amino acid sequences compared between the human and mouse COL6α3-C5 domain. Conserved sequences are highlighted in yellow. (B) Western blots showing abundant secretion of ETP from adipocytes. Conditioned media from 3T3-L1 preadipocytes and fully differentiated adipocytes were subjected to Western blotting using α-mETP and α-COL6. Arrows indicate the secreted form of ETP. (C) ETP immunostaining of mammary gland tissues from obese animals, ob/ob and db/db mice, compared with lean controls (n = 5 per group). Arrows indicate crown structure. Scale bars: 50 μm. (D and E) holo-COL6 and ETP immunostaining of tumor tissues from 9-week-old PyMT mice with α-COL6 (D) and α-mETP antibody (E), respectively. Lung tissues from 13-week-old PyMT mice were used for metastasized tumor lesions (F). Scale bars: 50 μm. (G) α-COL6– and α-ETP–positive staining area in tumor or stroma for the primary tumors. Data are mean ± SEM of multiple fields in n = 5 per group. ***P < 0.001 vs. tumor, unpaired t test.