Solid tumors require new blood vessels to grow beyond a few cubic millimeters. Tumor blood vessels are complex and dysfunctional and multiple cell types may coalesce to form the tumor vasculature. In a striking example, some tumor cells may directly integrate within vascular structures or form tumor cell-lined conduits that carry blood and fluid (termed vascular mimicry, VM). We have recently isolated and characterized a novel subpopulation of vascular-like tumor cells identified by expression of the vascular cell adhesion molecule, CD31. These CD31+ tumor cells do not express VEGF receptors, they down-regulate the neural crest transcription factor/CD31 repressor AP-2alpha, and they form tumor blood vessels when engrafted in mice. Furthermore, CD31+ tumor cells do not respond to VEGF inhibition and are enriched in tumors challenged with VEGF neutralizing antibodies.
In aim 1 we will use clonal populations of CD31- and CD31+ tumor cells we have derived from human and mouse cell lines and a spontaneous mouse melanoma model to determine the functional role of CD31 in forming perfused vascular structures in tumors.
Aim 2 is to use cell ablation strategies and cutting-edge tumor perfusion studies to determine how CD31+ tumor cells mediate escape from anti-angiogenic therapy.
In aim 3 we will define how loss of the neural crest specifer AP-2alpha controls CD31 expression and generates VM-competent tumor cells. For this aim, we will use genetic deletion and over- expression studies and intravital microscopy to visualize VM-competent tumor cells implanted in the mouse ear. Upon completion of our study aims, we will clarify how CD31+ tumor cells form functional connections with the host vasculature, the molecular mechanisms that generate and maintain this unique subpopulation, and how these vascular like tumor cells mediate escape from anti-angiogenic therapy.

Public Health Relevance

We have identified a novel subpopulation of CD31+ tumor cells that autonomously form vascular-like channels. These tumor cell-lined channels are refractory to anti-angiogenic therapy and may mediate tumor escape from angiogenesis inhibition. We will explore the mechanisms that generate and maintain this CD31+ subpopulation and we will determine how these vascular-like tumor cells integrate with host-derived vascular structures.

National Institute of Health (NIH)
Research Project (R01)
Project #
Application #
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Snyderwine, Elizabeth G
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
Zip Code
Dunleavey, James M; Xiao, Lin; Thompson, Joshua et al. (2014) Vascular channels formed by subpopulations of PECAM1+ melanoma cells. Nat Commun 5:5200