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.
View: Text | PDF
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

×

Figure 8

ETP reconstitution into Col6a1–/–-cancer cells rescues tumor growth.

Options: View larger image (or click on image) Download as PowerPoint
ETP reconstitution into Col6a1–/–-cancer cells rescues tumor growth. C...
Cancer cells isolated from PyMT, PyMT/Col6a1–/–, and PyMT/Col6a1–/–/ETP mice were mixed with the same volume of Matrigel (50 μl) and implanted into WT mice (0.5 × 106 cells/mouse). (A) Tumor growth (mean ± SEM; n = 5–8 per group), determined by caliper measurements. *P = 0.024 vs. Col6a1–/–, unpaired t test. (B) Representative image 35 days after implantation. (C) Tumor weight (mean ± SEM; n = 5–8 per group). *P = 0.023 vs. Col6a1–/–, unpaired t test. (D–H) Tissue fibrosis was determined by Masson’s Trichrome C stain (D), and EMT was determined by immunostaining for E-cadherin (E), vimentin (F), α-SMA (G), and FSP-1 (H). Cytokeratin (epithelial cells) and DAPI (nucleus) were costained in G and H. Positive staining areas were quantified and represented as fold increase over Ctrl-tumors (multiple images, n = 5 per group). *P < 0.05, ***P < 0.001 vs. Col6a1–/–, unpaired t test. Scale bars: 50 μm (E and F); 100 μm (D, G, and H).