7月4日,，美國研究人員在《自然》（Nature）雜志網(wǎng)站上發(fā)表報告說,，他們發(fā)現(xiàn)，對癌癥腫瘤用藥往往達不到預期效果的一個重要原因很可能是存在于腫瘤微環(huán)境中的健康細胞給癌細胞提供了相應的條件,，使它能抵抗藥物并存活下來,。
腫瘤微環(huán)境是指腫瘤局部浸潤的免疫細胞、間質(zhì)細胞及所分泌的活性介質(zhì)等與癌細胞共同構成的局部內(nèi)環(huán)境，這其中包括許多健康的細胞,。
美國布羅德研究所等機構的研究人員在報告中說,，他們觀察了癌癥腫瘤對藥物的反應后發(fā)現(xiàn)，有些藥物明明能殺死在試管中單獨培養(yǎng)的癌細胞,，但實際治療時效果卻總是不佳,。
研究人員說，他們在試管中模擬腫瘤微環(huán)境,，同時培養(yǎng)癌細胞和健康細胞,，然后再使用相關藥物，結果顯示,，那些對孤立的癌細胞有效的藥物在這種情況下效果就會大打折扣,，這說明癌細胞會利用周圍環(huán)境中的健康細胞來抵抗藥物。
研究人員因此建議,，在對癌癥腫瘤進行治療時,，不僅需要對腫瘤組織本身用藥，還要注意采取措施削弱癌細胞與健康細胞之間的聯(lián)系,。（生物谷Bioon.com）
doi:10.1038/nature11183
PMC:
PMID:
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.
