Nature：美研究揭示癌症肿瘤难治之谜

7月4日，美国研究人员在《自然》（Nature）杂志网站上发表报告说，他们发现，对癌症肿瘤用药往往达不到预期效果的一个重要原因很可能是存在于肿瘤微环境中的健康细胞给癌细胞提供了相应的条件，使它能抵抗药物并存活下来。
 
肿瘤微环境是指肿瘤局部浸润的免疫细胞、间质细胞及所分泌的活性介质等与癌细胞共同构成的局部内环境，这其中包括许多健康的细胞。
 
美国布罗德研究所等机构的研究人员在报告中说，他们观察了癌症肿瘤对药物的反应后发现，有些药物明明能杀死在试管中单独培养的癌细胞，但实际治疗时效果却总是不佳。
 
研究人员说，他们在试管中模拟肿瘤微环境，同时培养癌细胞和健康细胞，然后再使用相关药物，结果显示，那些对孤立的癌细胞有效的药物在这种情况下效果就会大打折扣，这说明癌细胞会利用周围环境中的健康细胞来抵抗药物。
 
研究人员因此建议，在对癌症肿瘤进行治疗时，不仅需要对肿瘤组织本身用药，还要注意采取措施削弱癌细胞与健康细胞之间的联系。

doi:10.1038/nature11183
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Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion

Ravid Straussman,1 Teppei Morikawa,2 Kevin Shee,1 Michal Barzily-Rokni,1 Zhi Rong Qian,2 Jinyan Du,1 Ashli Davis,1 Margaret M. Mongare,1 Joshua Gould,1 Dennie T. Frederick,3 Zachary A. Cooper,3 Paul B. Chapman,4 David B. Solit,4, 5 Antoni Ribas,6, 7 Roger S. Lo,7, 8 Keith T. Flaherty,3 Shuji Ogino,2, 9 Jennifer A. Wargo3 & Todd R. Golub

Drug resistance presents a challenge to the treatment of cancer patients. Many studies have focused on cell-autonomous mechanisms of drug resistance. By contrast, we proposed that the tumour micro-environment confers innate resistance to therapy. Here we developed a co-culture system to systematically assay the ability of 23 stromal cell types to influence the innate resistance of 45 cancer cell lines to 35 anticancer drugs. We found that stroma-mediated resistance is common, particularly to targeted agents. We characterized further the stroma-mediated resistance of BRAF-mutant melanoma to RAF inhibitors because most patients with this type of cancer show some degree of innate resistance1, 2, 3, 4. Proteomic analysis showed that stromal cell secretion of hepatocyte growth factor (HGF) resulted in activation of the HGF receptor MET, reactivation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-OH kinase (PI(3)K)–AKT signalling pathways, and immediate resistance to RAF inhibition. Immunohistochemistry experiments confirmed stromal cell expression of HGF in patients with BRAF-mutant melanoma and showed a significant correlation between HGF expression by stromal cells and innate resistance to RAF inhibitor treatment. Dual inhibition of RAF and either HGF or MET resulted in reversal of drug resistance, suggesting RAF plus HGF or MET inhibitory combination therapy as a potential therapeutic strategy for BRAF-mutant melanoma. A similar resistance mechanism was uncovered in a subset of BRAF-mutant colorectal and glioblastoma cell lines. More generally, this study indicates that the systematic dissection of interactions between tumours and their micro-environment can uncover important mechanisms underlying drug resistance.