Kumar Pawan, Ning Yu, Polverini Peter J
Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA.
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.
肿瘤细胞向重要器官的转移扩散是癌症患者死亡的主要原因。Bcl-2是一种关键的抗凋亡蛋白，在许多人类肿瘤中高表达。我们最近发现，Bcl-2在头颈癌患者的肿瘤相关血管中也过度表达。有趣的是，肿瘤血管中Bcl-2表达的增强与这些癌症患者的转移状态直接相关。此外，表达Bcl-2的内皮细胞（ECs）显示白细胞介素-8（IL-8）的产生增加，导致肿瘤细胞增殖和肿瘤细胞侵袭显著增强。因此，我们推测肿瘤相关ECs中Bcl-2的表达可能通过增强肿瘤细胞的侵袭性和在循环中的释放来促进肿瘤转移。为了验证我们的假设，我们将肿瘤细胞与表达Bcl-2的ECs（EC-Bcl-2）共同植入SCID小鼠的侧腹。我们的结果表明，原发性肿瘤中加入EC-Bcl-2显著增强了肿瘤细胞向肺部的转移，并且这种EC-Bcl-2介导的肿瘤转移与原发性肿瘤大小无关。此外，Bcl-2介导的肿瘤转移与肿瘤血管生成增加直接相关。ECs中Bcl-2的表达还促进了跨内皮细胞通透性、血管渗漏和肿瘤细胞侵袭。EC-Bcl-2介导的肿瘤细胞增殖和肿瘤细胞侵袭显著由IL-8介导。这些结果表明，当在肿瘤相关ECs中高水平表达时，Bcl-2可能通过增强肿瘤血管生成、血管渗漏和肿瘤细胞侵袭性来促进肿瘤转移。
