Early vascular deficits are correlated with delayed mammary tumorigenesis in the MMTV-PyMT transgenic mouse following genetic ablation of the NG2 proteoglycan
1 Cancer Center, Tumor Microenvironment Program, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037 USA
2 Center for Comparative Medicine, University of California at Davis, County Road 98 and Hutchison Drive, Davis, CA 95616 USA
3 Department of Pathology, University of California at San Diego, 9500 Gilman Drive, UC303 Room 102, La Jolla, CA 92093-0063 USA
4 Department of Research Evaluation and Scientific Programs, Susan G. Komen for the Cure, 5005 LBJ Freeway Suite 250, Dallas, TX 75244 USA
5 Histology Group, Viacyte Inc., Bldg 2 Room 305, 3550 General Atomics Court, San Diego, CA 92121 USA
6 Medical Direction Department, Biolumina, 75 Varick Street 10th Floor, New York, NY 10013 USA
7 Department of Biochemistry, St. Jude Childrens's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105 USA
Breast Cancer Research 2012, 14:R67 doi:10.1186/bcr3174Published: 24 April 2012
The neuron-glial antigen 2 (NG2) proteoglycan promotes pericyte recruitment and mediates pericyte interaction with endothelial cells. In the absence of NG2, blood vessel development is negatively impacted in several pathological models. Our goal in this study was to determine the effect of NG2 ablation on the early development and function of blood vessels in mammary tumors in the mammary tumor virus-driven polyoma middle T (MMTV-PyMT) transgenic mouse, and to correlate these vascular changes with alterations in mammary tumor growth.
Three different tumor paradigms (spontaneous tumors, transplanted tumors, and orthotopic allografts of tumor cell lines) were used to investigate the effects of NG2 ablation on breast cancer progression in the MMTV-PyMT transgenic mouse. In addition to examining effects of NG2 ablation on mammary tumor growth, we also investigated effects on the structure and function of tumor vasculature.
Ablation of NG2 led to reduced early progression of spontaneous, transplanted, and orthotopic allograft mammary tumors. NG2 was not expressed by the mammary tumor cells themselves, but instead was found on three components of the tumor stroma. Microvascular pericytes, myeloid cells, and adipocytes were NG2-positive in both mouse and human mammary tumor stroma. The effect of NG2 on tumor progression therefore must be stromal in nature. Ablation of NG2 had several negative effects on early development of the mammary tumor vasculature. In the absence of NG2, pericyte ensheathment of endothelial cells was reduced, along with reduced pericyte maturation, reduced sprouting of endothelial cells, reduced assembly of the vascular basal lamina, and reduced tumor vessel diameter. These early deficits in vessel structure are accompanied by increased vessel leakiness, increased tumor hypoxia, and decreased tumor growth. NG2 ablation also diminishes the number of tumor-associated and TEK tyrosine kinase endothelial (Tie2) expressing macrophages in mammary tumors, providing another possible mechanism for reducing tumor vascularization and growth.
These results emphasize the importance of NG2 in mediating pericyte/endothelial cell communication that is required for proper vessel maturation and function. In the absence of normal pericyte/endothelial cell interaction, poor vascular function results in diminished early progression of mammary tumors.