近日，研究人员发现在实验室胰腺神经内分泌癌动物模型中，双重阻断血管内皮生长因子（vascular endothelial growth factor，VEGF）和c-Met信号通路能抑制肿瘤的浸润和转移。研究论文发表在美国癌症研究协会的最新杂志Cancer Discovery上。
加州大学旧金山分校综合癌症中心的主要研究员医学博士Donald M. McDonald教授说：“抑制VEGF以及c-Met信号通路对抑制肿瘤生长具有协同效应，联合抑制能降低肿瘤细胞的侵袭转移能力。
早期实验室研究表明：运用药物如贝伐单抗或舒尼替尼来抑制VEGF信号可能会引起一些副作用包括促进肿瘤细胞的侵袭转移。
虽然已有研究证实c-Met的表达会促进肿瘤细胞的侵袭转移，但运用抗VEGF治疗是否会升高c-Met的表达还不甚明了。为了弄清楚这一点，McDonald和他的同事们进行了两个阶段的实验研究。基因突变诱发胰腺神经内分泌肿瘤的小鼠给予拮抗VEGF的抗体，结果肿瘤体积虽然减小了，但肿瘤的侵袭转移能力提高了。抗VEGF治疗方法也加剧了肿瘤缺氧程度以及c-Met的表达和活性。
然而当VEGF和c-Met同时被抑制时，不但肿瘤体积减少了，其侵袭转移也被会抑制。研究人员测试了三个c-MET抑制剂：Crizotinib、PF-04217903和Cabozantinib，前两者靶向c-MET但并不作用于VEGF，Cabozantinib是VEGF和c-Met的双重抑制剂。
麦克唐纳说，他们之所以选择神经内分泌胰腺肿瘤进行研究是因为这一基因改造小鼠肿瘤模型已被广泛使用研究。这项研究的目的是为了探索肿瘤侵袭转移的机制，研究结果并没有证据表明这种机制仅存在于胰腺肿瘤中，可能也适用于其他类型肿瘤。(生物谷 Bioon.com)
doi:10.1158/2159-8290.CD-11-0240
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Suppression of Tumor Invasion and Metastasis by Concurrent Inhibition of c-Met and VEGF Signaling in Pancreatic Neuroendocrine Tumors
Barbara Sennino1, Toshina Ishiguro-Oonuma1, Ying Wei2, Ryan M. Naylor1, Casey W. Williamson1, Vikash Bhagwandin3, Sebastien P. Tabruyn1, Weon-Kyoo You1, Harold A. Chapman2, James G. Christensen4, Dana T. Aftab5 and Donald M. McDonald1
Invasion and metastasis increase after the inhibition of VEGF signaling in some preclinical tumor models. In the present study we asked whether selective VEGF inhibition is sufficient to increase invasion and metastasis and whether selective c-Met inhibition is sufficient to block this effect. Treatment of pancreatic neuroendocrine tumors in RIP-Tag2 mice with a neutralizing anti-VEGF antibody reduced tumor burden but increased tumor hypoxia, hypoxia-inducible factor-1α, and c-Met activation and also increased invasion and metastasis. However, invasion and metastasis were reduced by concurrent inhibition of c-Met by PF-04217903 or PF-02341066 (crizotinib). A similar benefit was found in orthotopic Panc-1 pancreatic carcinomas treated with sunitinib plus PF-04217903 and in RIP-Tag2 tumors treated with XL184 (cabozantinib), which simultaneously blocks VEGF and c-Met signaling. These findings document that invasion and metastasis are promoted by selective inhibition of VEGF signaling and can be reduced by the concurrent inhibition of c-Met.
