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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Increased levels of the C-terminal domain of collagen VIα3 in tumor cell...
Increased levels of the C-terminal domain of collagen VIα3 in tumor cells in the proximity of adipocytes. (A) High levels of the carboxyterminal domain of collagen VIα3 in a human mammary tumor sample. Top panel: collagen VI staining around human breast carcinoma cells near the vicinity of the adipocytes (arrows). Bottom panel: reduced staining in tumor cells more distant from adipocytes in the same tumor section. (B) Polyclonal-to-monoclonal ratio of collagen VI. Reverse-phase protein arrays determined levels of the C-terminal domain from collagen VIα3 (top) and the full-length collagen VI protein (middle) found in normal and tumor tissue of human cancer specimens. Bottom panel: ratio of relative signals obtained for polyclonal and monoclonal antibodies, indicating a bias toward higher levels of the α3 C-terminal domain. (C) The carboxyterminal fragment of collagen VIα3 accumulates on the surface of tumors. Polyclonal IgGs from immune and nonimmune preparations against the carboxyterminal domain of collagen VIα3 were radiolabeled with 188-rhenium. Preparations were injected either i.p. (top) or i.v. in the tail vein (bottom) into 10-week-old MMTV-PyMT mice. The outline of the mouse is indicated. Mice were imaged on a Siemens LEM+ZLC DIGITRAC gamma camera. (D) Recombinant carboxyterminal C3–C5 domains of collagen VIα3 display potent pro-mitogenic activity. MCF-7 cells were treated with conditioned medium containing recombinant carboxyterminal collagen VIα3 protein or conditioned medium from control transfected cells for 24, 48, or 72 hours. Cell number was normalized to the control cells at the respective time points. *P < 0.05.