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 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.
Original language | English |
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Pages (from-to) | 1163-76 |
Number of pages | 14 |
Journal | Journal of Clinical Investigation |
Volume | 115 |
Issue number | 5 |
DOIs | |
Publication status | Published - May 2005 |
Keywords / Materials (for Non-textual outputs)
- Adipocytes
- Animals
- Collagen Type VI
- Cyclin D1
- Cytoskeletal Proteins
- Female
- Immunohistochemistry
- Mammary Neoplasms, Animal
- Mice
- Polyomavirus
- Trans-Activators
- beta Catenin