Adipocyte-derived collagen VI affects early mammary tumor progression in vivo, demonstrating a critical interaction in the tumor/stroma microenvironment.
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.
Iyengar
Puneeth
P
Department of Cell Biology, Albert Einstein Cancer Center, Albert Einstein College of Medicine, New York, New York 10461, USA.
Espina
Virginia
V
Williams
Terence W
TW
Lin
Ying
Y
Berry
David
D
Jelicks
Linda A
LA
Lee
Hyangkyu
H
Temple
Karla
K
Graves
Reed
R
Pollard
Jeffrey
J
Chopra
Neeru
N
Russell
Robert G
RG
Sasisekharan
Ram
R
Trock
Bruce J
BJ
Lippman
Marc
M
Calvert
Valerie S
VS
Petricoin
Emanuel F
EF
Liotta
Lance
L
Dadachova
Ekaterina
E
Pestell
Richard G
RG
Lisanti
Michael P
MP
Bonaldo
Paolo
P
Scherer
Philipp E
PE
D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D024142:Collagen Type VI / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019938:Cyclin D1 / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism; D005260:Female; D007150:Immunohistochemistry; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D011120:Polyomavirus / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D051176:beta Catenin
C495267:CTNNB1 protein, mouse; D024142:Collagen Type VI; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051176:beta Catenin; D019938:Cyclin D1