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

Puneeth IyengarDepartments of Cell Biology and Medicine , Albert Einstein Cancer Center , Albert Einstein College of Medicine , New York , New York , USAVirginia EspinaLaboratory of Pathology , National Cancer Institute , Bethesda , Maryland , USATerence W. WilliamsDepartment of Molecular Pharmacology , Albert Einstein Cancer Center , Albert Einstein College of Medicine , New York , New York , USAYing LinDepartments of Cell Biology and Medicine , Albert Einstein Cancer Center , Albert Einstein College of Medicine , New York , New York , USADavid BerryHarvard-Massachusetts Institute of Technology Division of Health Sciences and Technology , Cambridge , Massachusetts , USALinda A. JelicksDepartment of Physiology and Biophysics , Albert Einstein Cancer Center , Albert Einstein College of Medicine , New York , New York , USAHyangkyu LeeDepartment of Molecular Pharmacology , Albert Einstein Cancer Center , Albert Einstein College of Medicine , New York , New York , USAKarla A. TempleCommittee on Human Nutrition and Nutritional Biology , University of Chicago , Chicago , Illinois , USAReed A. GravesDepartment of Biochemistry , State University of New York at Buffalo , School of Medicine and Biomedical Sciences , Buffalo , New York , USAJeffrey W. PollardNeeru ChopraDepartment of Pathology , Albert Einstein Cancer Center , Albert Einstein College of Medicine , New York , New York , USARobert G. RussellLombardi Comprehensive Cancer Center, Georgetown University Medical School, Georgetown, Washington, DC, USARam SasisekharanCenter for Biological Engineering , Massachusetts Institute of Technology , Cambridge , Massachusetts , USABruce J. TrockDepartment of Urology , Johns Hopkins University , Baltimore , Maryland , USAMarc E. LippmanDepartment of Internal Medicine , University of Michigan , Ann Arbor , Michigan , USAValerie CalvertFDA-National Cancer Institute Clinical Proteomics Program , Office of Cellular and Gene Therapy , Center for Biologics Evaluation and Research , FDA , Bethesda , Maryland , USAEmanuel F. PetricoinFDA-National Cancer Institute Clinical Proteomics Program , Office of Cellular and Gene Therapy , Center for Biologics Evaluation and Research , FDA , Bethesda , Maryland , USALance A. LiottaLaboratory of Pathology , National Cancer Institute , Bethesda , Maryland , USAEkaterina DadachovaAlbert Einstein Cancer Center, Albert Einstein College of Medicine, New York, New York, USARichard G. PestellLombardi Comprehensive Cancer Center , Georgetown University Medical School , Georgetown , Washington , DC , USAMichael P. LisantiDepartment of Molecular Pharmacology , Albert Einstein Cancer Center , Albert Einstein College of Medicine , New York , New York , USAPaolo BonaldoAlbert Einstein Cancer Center , Albert Einstein College of Medicine , New York , New York , USAPhilipp E. SchererDepartment of Histology, Microbiology and Medical Biotechnologies , University of Padova , Padova , Italy

2005en

ABI

Annotatsiya

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 growthstimulatory 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 fulllength 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.

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DOI: 10.1172/jci200523424

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