Endothelial cells expressing Bcl-2 promotes tumor metastasis by enhancing tumor angiogenesis, blood vessel leakiness and tumor invasion

Lab Invest. 2008 Jul;88(7):740-9. doi: 10.1038/labinvest.2008.46. Epub 2008 May 19.


Metastatic spread of tumor cells to vital organs is the major cause of mortality in cancer patients. Bcl-2, a key antiapoptotic protein, is expressed at high levels in a number of human tumors. We have recently shown that Bcl-2 is also overexpressed in tumor-associated blood vessels in head-and-neck cancer patients. Interestingly, enhanced Bcl-2 expression in tumor blood vessels is directly correlated with metastatic status of these cancer patients. In addition, endothelial cells (ECs) expressing Bcl-2 showed increased production of interleukin-8 (IL-8) resulting in significantly enhanced tumor cell proliferation and tumor cell invasion. Therefore, we hypothesized that Bcl-2 expression in tumor-associated ECs may promote tumor metastasis by enhancing tumor cell invasiveness and release in the circulation. To test our hypothesis, we coimplanted tumor cells along with ECs expressing Bcl-2 (EC-Bcl-2) in the flanks of SCID mice. Our results demonstrate that incorporation of EC-Bcl-2 in primary tumors significantly enhanced tumor cell metastasis to lungs and this EC-Bcl-2-mediated tumor metastasis was independent of primary tumor size. In addition, Bcl-2-mediated tumor metastasis directly correlated with increased tumor angiogenesis. Bcl-2 expression in ECs also promoted transendothelial cell permeability, blood vessel leakiness and tumor cell invasion. EC-Bcl-2-mediated tumor cell proliferation and tumor cell invasion were significantly mediated by IL-8. These results suggest that Bcl-2, when expressed at higher levels in tumor-associated ECs, may promote tumor metastasis by enhancing tumor angiogenesis, blood vessel leakiness and tumor cell invasiveness.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Vessels / pathology
  • Capillary Permeability
  • Cell Proliferation
  • Endothelial Cells / metabolism*
  • Endothelial Cells / pathology
  • Endothelium, Vascular / metabolism
  • Endothelium, Vascular / pathology
  • Interleukin-8 / biosynthesis
  • Mice
  • Mice, SCID
  • Microcirculation / pathology
  • Models, Biological*
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Neoplasm Transplantation
  • Neoplasms, Experimental / blood supply*
  • Neoplasms, Experimental / metabolism
  • Neoplasms, Experimental / pathology*
  • Neovascularization, Pathologic / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / biosynthesis*
  • Transplantation, Heterologous


  • Interleukin-8
  • Proto-Oncogene Proteins c-bcl-2