Faculty Collaboration Database

Context dependent role of the CD36--thrombospondin--histidine-rich glycoprotein axis in tumor angiogenesis and growth. PLoS One 2012;7(7):e40033

Date

07/19/2012

Pubmed ID

22808089

Pubmed Central ID

PMC3393734

DOI

10.1371/journal.pone.0040033

Scopus ID

2-s2.0-84863711486 (requires institutional sign-in at Scopus site)   24 Citations

Abstract

The angiogenic switch is a promising therapeutic target in cancer. Work by our laboratory and others has described an important endogenous anti-angiogenic pathway mediated by interactions of CD36, a receptor on microvascular endothelial cells, with proteins containing thrombospondin (TSP) type I repeat domains (TSR). Recent studies revealed that circulating Histidine Rich Glycoprotein (HRG) inhibits the anti-angiogenic potential of the CD36-TSR pathway by functioning as a decoy receptor that binds and sequesters TSR proteins. As tumors of different origin display variable expression profiles of numerous targets, we hypothesized that the TSP-CD36-HRG axis regulates vascularization and growth in the tumor microenvironment in a context, or tumor type, dependent manner. Growth of Lewis Lung Carcinoma (LL2) and B16F1 Melanoma tumor cell implants in syngeneic wild type (WT), hrg, or cd36 null mice were used as a model to interrogate this signaling axis. LL2 tumor volumes were greater in cd36 null mice and smaller in hrg null mice compared to WT. Immunofluorescent staining showed increased vascularity in cd36 null vs. WT and WT vs. hrg null mice. No differences in tumor growth or vascularity were observed with B16F1 implants, consistent with lack of expression of TSP-1 in B16F1 cells. When TSR expression was induced in B16F1 cells by cDNA transfection, tumor growth and vascularity were similar to that seen with LL2 cells. These data show a role for CD36-mediated anti-angiogenic activity in the tumor microenvironment when TSR proteins are available and demonstrate that HRG modulates this activity. Further, they suggest a mechanism by which tumor microenvironments may regulate sensitivity to TSR containing proteins.

Author List

Hale JS, Li M, Sinyuk M, Jahnen-Dechent W, Lathia JD, Silverstein RL

Author

Roy L. Silverstein MD Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
CD36 Antigens
Carcinoma, Lewis Lung
Cell Line, Tumor
Endothelial Cells
Gene Expression Regulation, Neoplastic
Male
Melanoma, Experimental
Mice
Mice, Knockout
Neovascularization, Pathologic
Organ Specificity
Protein Binding
Proteins
RNA, Small Interfering
Signal Transduction
Skin Neoplasms
Thrombospondin 1
Tumor Burden
Tumor Microenvironment