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.
View: Text | PDF
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

×

Figure 4

Options: View larger image (or click on image) Download as PowerPoint
Immunohistochemical analysis of pathologically matched tumors from colla...
Immunohistochemical analysis of pathologically matched tumors from collagen+/+ and collagen–/– mice in the MMTV-PyMT background. (A) Absence of collagen VIα3 signal in collagen–/– mice. Staining for collagen VIα3 (with carboxyterminal polyclonal antibody) on mammary sections from pathologically matched hyperplasias developed in collagen+/+ and collagen–/– mice. Arrows point in the direction of increased levels of staining. Asterisks denote local mammary adipocytes. Magnification, ×25. (B) NG2/CSPG is expressed at the highest levels in malignant regions adjacent to adipocytes in WT mice. Note the positive staining in WT backgrounds on the leading edges of the tumor mass. Magnification, ×25. (C) Cyclin D1 is expressed at the highest levels in malignant regions adjacent to adipocytes. Magnification, ×10. (D) GSK3β is phosphorylated at the highest levels in malignant regions adjacent to adipocytes. Magnification, ×10. (E) Ki67 expression is present in cells proliferating throughout the mammary lesions. Staining for the proliferation marker Ki67 in pathologically matched lesions from WT and collagen VI–null mice demonstrates diffuse expression throughout the tumor masses in both genotypes. Magnification, ×25. (F) Akt is phosphorylated and activated at higher levels in tumors that have developed in the presence of collagen VI signaling. Staining for the ser473-phosphorylated Akt in pathologically matched tumors from collagen VI WT and knockout mice demonstrated significant staining in cells on the tumor periphery in the WT mice but not in collagen VI–null mice. Asterisks denote local mammary adipocytes in close proximity to the malignancies. Arrowheads point to the pAkt-positive cells. Magnification, ×25.