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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Figure 2

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Adipocytes from collagen VI+/– and collagen VI–/– mice are less potent s...
Adipocytes from collagen VI+/– and collagen VI–/– mice are less potent stimulators of tumor growth. Collagen VI also has greater impact on early than on late tumor progression. (A) SUM159-PT cells (1 × 105) were coinjected into 8-week-old nude mice with the same number of isolated primary mammary adipocytes from collagen VI+/+, collagen VI+/–, collagen VI–/– mice, or 3T3-L1 adipocytes. Four weeks after injection, the sizes of the resulting foci were measured. n = 4 mice in each cohort. Results are shown as mean ± SEM. (B) MMTV-PyMT transgenic mice were sacrificed, and large, late tumor sections (from lesions larger than 1,500 mm3) and some small transformed mammary tissue for early tumor samples (lesions smaller than 300 mm3) were isolated. Tumor pieces were transplanted into partially cleared mammary glands of collagen VI+/+ and collagen VI–/– mice (n = 4). After 3 weeks, whole mounts were made. The tumor focus had a dense cellular make-up in the WT background, compared with reduced cellular density in the collagen VI–null host. Tumor areas were quantitated. Note that the absence of collagen VI protein does not affect the growth of late-stage tumor transplants. *P < 0.05. (C) Collagen VI induces proteins whose gene products are upregulated on the DNA microarrays. MCF-7 cells were treated for 6 hours with collagen VI or collagen I (each at 30 μg/ml) and extracts were generated for Western blots. EGR2, ATF4, IL-8, and GDI-3 as a loading control were measured. The levels of induction seen were similar to those seen by DNA microarrays.