腫瘤領(lǐng)域科學家一直在探尋腫瘤休眠的機制,，但一直沒有得到很好的研究發(fā)現(xiàn),。
近日,，發(fā)表在PNAS雜志上的研究中,，研究人員介紹了一種實驗?zāi)Ｐ?，該模型有助于研究人類腫瘤休眠與血管生成之間的相互作用,，該研究證實局部血管內(nèi)皮生長因子-A和堿性成纖維細胞生長因子的增加加速了血管生成開關(guān)的開啟。
在乳腺癌異種移植模型（MDA-MB-436細胞）中,，差異表達基因分析發(fā)現(xiàn)與不具有血管生成作用的細胞相比,，熱休克蛋白27（HSP27）在促血管生成的腫瘤細胞中顯著上調(diào)。研究人員進一步評估HSP27表達下調(diào)在細胞株,、小鼠模型上的影響,，并進一步分析了人類乳腺癌和黑色素瘤患者臨床數(shù)據(jù)集，明確其作用,。結(jié)果發(fā)現(xiàn)體內(nèi)腫瘤休眠后血管生成腫瘤細胞HSP27穩(wěn)定下調(diào),。引人注目的是只有30個HSP27中的4個被敲除后，異種移植腫瘤70后天才開始快速增長,，這與HSP27蛋白表達的恢復(fù)相關(guān),。值得注意的是，不表達HSP27的腫瘤都逃避不了休眠期,。
HSP27的下調(diào)降低血管內(nèi)皮細胞增殖,， VEGF-A，VEGF-C和堿性成纖維細胞生長因子的分泌也減少。相反,，在不具備血管生成作用的細胞中HSP27的過表達導致體內(nèi)的腫瘤快速生長,。經(jīng)臨床驗證，HSP27蛋白表達與侵略性的腫瘤標志物和乳腺癌,、黑色素瘤患者生存降低。研究結(jié)果揭示了HSP27在平衡腫瘤休眠和腫瘤進展,，介導腫瘤血管生成中的關(guān)鍵作用,，針對HSP27可能是癌癥治療新的有用的策略之一。（生物谷：Bioon.com）
doi:10.1073/pnas.1017909109
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PMID:
Suppression of heat shock protein 27 induces long-term dormancy in human breast cancer
Oddbjrn Straume, Takeshi Shimamurad, Michael J. G. Lampaa,b, Julian Carreterod, Anne M. yanh, Di Jia, et al.
The mechanisms underlying tumor dormancy have been elusive and not well characterized. We recently published an experimental model for the study of human tumor dormancy and the role of angiogenesis, and reported that the angiogenic switch was preceded by a local increase in VEGF-A and basic fibroblast growth factor. In this breast cancer xenograft model (MDA-MB-436 cells), analysis of differentially expressed genes revealed that heat shock protein 27 (HSP27) was significantly up-regulated in angiogenic cells compared with nonangiogenic cells. The effect of HSP27 down-regulation was further evaluated in cell lines, mouse models, and clinical datasets of human patients with breast cancer and melanoma. Stable down-regulation of HSP27 in angiogenic tumor cells was followed by long-term tumor dormancy in vivo. Strikingly, only 4 of 30 HSP27 knockdown xenograft tumors initiated rapid growth after day 70, in correlation with a regain of HSP27 protein expression. Significantly, no tumors escaped from dormancy without HSP27 expression. Down-regulation of HSP27 was associated with reduced endothelial cell proliferation and decreased secretion of VEGF-A, VEGF-C, and basic fibroblast growth factor. Conversely, overexpression of HSP27 in nonangiogenic cells resulted in expansive tumor growth in vivo. By clinical validation, strong HSP27 protein expression was associated with markers of aggressive tumors and decreased survival in patients with breast cancer and melanoma. An HSP27-associated gene expression signature was related to molecular subgroups and survival in breast cancer. Our findings suggest a role for HSP27 in the balance between tumor dormancy and tumor progression, mediated by tumor–vascular interactions. Targeting HSP27 might offer a useful strategy in cancer treatment.
