Adipocyte-derived collagen VI affects early mammary tumor progression in vivo, demonstrating a critical interaction in the tumor/stroma microenvironment
Puneeth Iyengar, … , Paolo Bonaldo, Philipp E. Scherer
Puneeth Iyengar, … , Paolo Bonaldo, Philipp E. Scherer
Published May 2, 2005
Citation Information: J Clin Invest. 2005;115(5):1163-1176. https://doi.org/10.1172/JCI23424.
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Article Oncology

Adipocyte-derived collagen VI affects early mammary tumor progression in vivo, demonstrating a critical interaction in the tumor/stroma microenvironment

Abstract

The interactions of transformed cells with the surrounding stromal cells are of importance for tumor progression and metastasis. The relevance of adipocyte-derived factors to breast cancer cell survival and growth is well established. However, it remains unknown which specific adipocyte-derived factors are most critical in this process. Collagen VI is abundantly expressed in adipocytes. Collagen–/– mice in the background of the mouse mammary tumor virus/polyoma virus middle T oncogene (MMTV-PyMT) mammary cancer model demonstrate dramatically reduced rates of early hyperplasia and primary tumor growth. Collagen VI promotes its growth-stimulatory and pro-survival effects in part by signaling through the NG2/chondroitin sulfate proteoglycan receptor expressed on the surface of malignant ductal epithelial cells to sequentially activate Akt and β-catenin and stabilize cyclin D1. Levels of the carboxyterminal domain of collagen VIα3, a proteolytic product of the full-length molecule, are dramatically upregulated in murine and human breast cancer lesions. The same fragment exerts potent growth-stimulatory effects on MCF-7 cells in vitro. Therefore, adipocytes play a vital role in defining the ECM environment for normal and tumor-derived ductal epithelial cells and contribute significantly to tumor growth at early stages through secretion and processing of collagen VI.

Authors

Puneeth Iyengar, Virginia Espina, Terence W. Williams, Ying Lin, David Berry, Linda A. Jelicks, Hyangkyu Lee, Karla Temple, Reed Graves, Jeffrey Pollard, Neeru Chopra, Robert G. Russell, Ram Sasisekharan, Bruce J. Trock, Marc Lippman, Valerie S. Calvert, Emanuel F. Petricoin III, Lance Liotta, Ekaterina Dadachova, Richard G. Pestell, Michael P. Lisanti, Paolo Bonaldo, Philipp E. Scherer

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Collagen VI stabilizes β-catenin and cyclin D1. (A) Dose response to inc...
Collagen VI stabilizes β-catenin and cyclin D1. (A) Dose response to increasing concentrations of collagen VI protein. A Tcf/Lef luciferase reporter construct was transfected into MCF-7 cells. Collagen VI treatment was for 3 hours. (B) Collagen VI–mediated Tcf/Lef induction. Luciferase activity was analyzed after treatment with vehicle, collagen VI (30 μg/ml), or collagen I (30 μg/ml) for 3 hours. (C) Time course of induction of Tcf/Lef activity. Luciferase activity was analyzed at different time points after treatment with 30 μg/ml collagen VI. (D) β-Catenin stability after collagen exposure. MCF-7 cells were metabolically labeled and then chased in the presence of cycloheximide for 30 minutes, 1 hour, and 2 hours. The chase medium contained vehicle, collagen VI (30 μg/ml), or collagen I (30 μg/ml). β-Catenin and GDI-3 were immunoprecipitated and quantitated. The ratio of β-catenin at 2 hours compared to 30 minutes was plotted as an indicator of β-catenin stability (3 independent experiments). No txt, no treatment. (E) Cyclin D1 stability after collagen exposure. MCF-7 cells were exposed for 3 hours to vehicle, human collagen VI (30 μg/ml), or collagen I (30 μg/ml). Cells were then lysed and analyzed for cyclin D1 by Western blot analysis. (F) Collagen VI acts in part through NG2 in MCF-7 cells to stabilize cyclin D1. In the presence of increasing amounts of NG2 neutralizing antibody in the medium (+, 0.15 μg/ml; ++, 0.45 μg/ml; +++, 0.75 μg/ml; ++++, 1 μg/ml), cyclin D1 levels decrease in a dose-dependent manner. Results are shown as mean ± SEM. *P < 0.05.