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 1

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Lack of collagen VI leads to a reduction in tumor growth. (A) Whole-moun...
Lack of collagen VI leads to a reduction in tumor growth. (A) Whole-mount analysis of early hyperplasia in 6-week-old collagen VI+/+ or collagen VI–/– MMTV-PyMT transgenic mice. Bottom panel: whole mount from a WT mouse. (B) Collagen VI reduction in hyperplastic foci size. Quantitation of hyperplastic areas at 3 and 6 weeks. n = 5 mice per group. *P < 0.05 vs. WT. (C) Number of hyperplastic foci does not significantly depend on collagen VI presence or absence in the MMTV-PyMT mouse. Quantitation of the number of foci formed in the mammary glands of 3-week-old MMTV-PyMT mice. n = 5 mice per group. (D) A representative H&E stain of a mammary section taken from PyMT+ColVI–/– and PyMT+ColVI+/+ mice at 6 weeks of age. (E) Quantitation of tumor sizes of female and male PyMT+ mice at different ages. n = 10 for each group. The 3 largest lesions were measured in each mouse. (F) Adipocytes (adip), but not breast cancer cells, express collagen VI, whereas breast cancer cells, but not adipocytes, express the collagen VI receptor NG2/CSPG. RT-PCR was performed to determine expression levels of NG2 and collagen VI. Lane 1, human adipocytes; lane 2, Marker (Mr; DNA ladder); lanes 3 and 4, MCF-7 cells; lanes 5 and 6, MCF-7 cells with adipocyte-conditioned medium; lanes 7 and 8, 3T3-L1 adipocytes; lane 9, MCF-7 cells; lane 10, MCF-7 cells with adipocyte-conditioned medium. (G) Expression of collagen VI in mammary adipocytes and early- and late-stage tumors. Quantitative real-time PCR was conducted. GAPDH was used as an internal control. Values for early-stage tumor samples were arbitrarily set to 1.