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.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
1R01CA177875-01A1
Application #
8693221
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Snyderwine, Elizabeth G
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Physiology
Type
Schools of Medicine
DUNS #
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Dunleavey, James M; Xiao, Lin; Thompson, Joshua et al. (2014) Vascular channels formed by subpopulations of PECAM1+ melanoma cells. Nat Commun 5:5200