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

• DOI: 10.1172/jci23424
• Publication Date: 2008-02-18T19:40:58Z
• 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; Lance Liotta; Ekaterina Dadachova; Richard G. Pestell; Michael P. Lisanti; Paolo Bonaldo; Philipp E. Scherer
• Keywords: 0303 health sciences; Adipose tissue; Cancer; Mammary tumor; Tumor progression; Extracellular matrix; Collagen VI; Mammary Neoplasms, Animal; Collagen Type VI; Immunohistochemistry; 3. Good health; Cytoskeletal Proteins; Mice; 03 medical and health sciences; Adipocytes; Trans-Activators; Animals; Cyclin D1; Female; Polyomavirus; beta Catenin

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 beta-catenin and stabilize cyclin D1. Levels of the carboxyterminal domain of collagen VIalpha3, 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.