近日,，研究人員發(fā)現(xiàn)在實驗室胰腺神經(jīng)內(nèi)分泌癌動物模型中,，雙重阻斷血管內(nèi)皮生長因子（vascular endothelial growth factor,，VEGF）和c-Met信號通路能抑制腫瘤的浸潤和轉(zhuǎn)移。研究論文發(fā)表在美國癌癥研究協(xié)會的最新雜志Cancer Discovery上,。
加州大學(xué)舊金山分校綜合癌癥中心的主要研究員醫(yī)學(xué)博士Donald M. McDonald教授說：“抑制VEGF以及c-Met信號通路對抑制腫瘤生長具有協(xié)同效應(yīng),，聯(lián)合抑制能降低腫瘤細(xì)胞的侵襲轉(zhuǎn)移能力。
早期實驗室研究表明：運用藥物如貝伐單抗或舒尼替尼來抑制VEGF信號可能會引起一些副作用包括促進(jìn)腫瘤細(xì)胞的侵襲轉(zhuǎn)移,。
雖然已有研究證實c-Met的表達(dá)會促進(jìn)腫瘤細(xì)胞的侵襲轉(zhuǎn)移,，但運用抗VEGF治療是否會升高c-Met的表達(dá)還不甚明了。為了弄清楚這一點,，McDonald和他的同事們進(jìn)行了兩個階段的實驗研究,。基因突變誘發(fā)胰腺神經(jīng)內(nèi)分泌腫瘤的小鼠給予拮抗VEGF的抗體,，結(jié)果腫瘤體積雖然減小了,，但腫瘤的侵襲轉(zhuǎn)移能力提高了,。抗VEGF治療方法也加劇了腫瘤缺氧程度以及c-Met的表達(dá)和活性,。
然而當(dāng)VEGF和c-Met同時被抑制時,，不但腫瘤體積減少了，其侵襲轉(zhuǎn)移也被會抑制,。研究人員測試了三個c-MET抑制劑：Crizotinib,、PF-04217903和Cabozantinib，前兩者靶向c-MET但并不作用于VEGF,，Cabozantinib是VEGF和c-Met的雙重抑制劑,。
麥克唐納說，他們之所以選擇神經(jīng)內(nèi)分泌胰腺腫瘤進(jìn)行研究是因為這一基因改造小鼠腫瘤模型已被廣泛使用研究,。這項研究的目的是為了探索腫瘤侵襲轉(zhuǎn)移的機制,，研究結(jié)果并沒有證據(jù)表明這種機制僅存在于胰腺腫瘤中，可能也適用于其他類型腫瘤,。(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.
