癌細胞本身所分泌的與發(fā)炎反應(yīng)有關(guān)的細胞素如IL-6, TNF- 具有活化巨噬細胞的能力?；罨蟮木奘杉毎麜M一步地分泌其他物質(zhì)影響癌細胞的轉(zhuǎn)移(metastases),。他們發(fā)現(xiàn)，從一種肺癌細胞株（lung carcinoma cell line, LLC）所分離得到的一種多醣體 Versican 能夠經(jīng)過活化TLR2后,，幫助巨噬細胞產(chǎn)生更多與發(fā)炎反應(yīng)有關(guān)的細胞素并且使LLC轉(zhuǎn)移至肺臟,。例如,，將LLC細胞打入TLR2 剔除鼠后，該鼠幾乎不產(chǎn)生肺癌,；或是將Versican從LLC細胞內(nèi)剔除后再打入一般正常鼠也減少了肺癌的發(fā)生率,。實驗結(jié)果顯示，Versican在引起巨噬細胞活化進而促進癌細胞的轉(zhuǎn)移的作用上,，有某種的相關(guān),。提供了未來阻斷癌細胞轉(zhuǎn)移的可能的方法,。
加州大學(xué)圣地亞哥分校醫(yī)學(xué)院,，臺灣大學(xué)的研究人員識別出了一種由癌變的肺上皮細胞產(chǎn)生的蛋白,，這種蛋白可以通過刺激炎癥細胞的活性增加腫瘤轉(zhuǎn)移，這解釋了癌細胞如何通過搶奪宿主天然免疫系統(tǒng)中的元件來創(chuàng)造一個炎癥微環(huán)境,，幫助肺癌的擴散,，這項發(fā)現(xiàn)也許能幫助發(fā)展出限制這種最致命的癌癥擴散的治療方法。這一研究成果即將公布在1月1日的Nature雜志上,。
領(lǐng)導(dǎo)這一研究的是加州大學(xué)圣地亞哥分校藥理學(xué)與病理學(xué)教授Michael Karin ，另外臺灣大學(xué)參與人員有林婉婉教授,。Karin教授一直致力于研究炎癥對于癌癥發(fā)生和擴散的影響。
在這項研究中,，Karin等人利用一種直接的生化方法識別出了轉(zhuǎn)移癌細胞產(chǎn)生的蛋白,，這些癌細胞產(chǎn)生了一種炎癥的微環(huán)境,，有利于癌癥擴散,。研究人員聚焦于巨噬細胞,、白細胞,，這種細胞在癌癥生長和擴散過程同樣扮演著應(yīng)答外界入侵的重要角色,，篩選了小鼠中轉(zhuǎn)移癌細胞中，能刺激這種炎癥細胞類型（白細胞）的因素,。
結(jié)果研究人員發(fā)現(xiàn)了一種稱為lewis肺癌（lewis lung carcinoma,LLC)的高轉(zhuǎn)移細胞系具有潛在的激活巨噬細胞的能力,，而且LLC細胞分泌的一種蛋白參與了巨噬細胞活性改變，對這種蛋白進行生化方法純化,，從而發(fā)現(xiàn)了這種稱為versican的細胞外基質(zhì)蛋白是主要的巨噬細胞激活因子， 以及轉(zhuǎn)移增強因子,。并且研究人員也發(fā)現(xiàn)versican的作用原理：通過刺激能引發(fā)細胞因子——控免疫系統(tǒng)的信號蛋白一一產(chǎn)生的受體極大的增強LLC轉(zhuǎn)移生長。其中受體TLR2,， 以及細胞因子TNF都是LLC轉(zhuǎn)移的關(guān)鍵因素,。但是TLR2和TNFα的正常功能是用于宿主天然免疫性,，對抗微生物感染的,，Karin認為,，這些研究結(jié)果不僅適用于小鼠模型,，而且在人類肺癌中也存在同樣的機理。
通過搶奪宿主免疫系統(tǒng)中的這些元素,，versican建立了一個炎癥環(huán)境,，幫助癌癥轉(zhuǎn)移擴散,。如果能阻止verscican的表達,，或者將其綁定在TLR2上，那么就能限制肺癌的擴散了,。（生物谷Bioon.com）
生物谷推薦原始出處：
Nature 457, 102-106 (1 January 2009) | doi:10.1038/nature07623
Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis
Sunhwa Kim1, Hiroyuki Takahashi1, Wan-Wan Lin1,2, Pascal Descargues1, Sergei Grivennikov1, Youngjun Kim1,3, Jun-Li Luo1,3 & Michael Karin1
1 Department of Pharmacology and Cancer Center, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0723, USA
2 Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, China
3 Present addresses: Department of Applied Biochemistry, Konkuk University, 322 Danwol-dong, Chungju-City, Chungbuk 380-701, Korea (Y.K.); Department of Cancer Biology, The Scripps Research Institute, 5353 Parkside Drive, Jupiter, Florida 33458, USA (J.-L.L.).
Metastatic progression depends on genetic alterations intrinsic to cancer cells as well as the inflammatory microenvironment of advanced tumours1, 2. To understand how cancer cells affect the inflammatory microenvironment, we conducted a biochemical screen for macrophage-activating factors secreted by metastatic carcinomas. Here we show that, among the cell lines screened, Lewis lung carcinoma (LLC)3 were the most potent macrophage activators leading to production of interleukin-6 (IL-6) and tumour-necrosis factor- (TNF-) through activation of the Toll-like receptor (TLR) family members4 TLR2 and TLR6. Both TNF- and TLR2 were found to be required for LLC metastasis. Biochemical purification of LLC-conditioned medium (LCM) led to identification of the extracellular matrix proteoglycan versican, which is upregulated in many human tumours including lung cancer5, 6, as a macrophage activator that acts through TLR2 and its co-receptors TLR6 and CD14. By activating TLR2:TLR6 complexes and inducing TNF- secretion by myeloid cells, versican strongly enhances LLC metastatic growth. These results explain how advanced cancer cells usurp components of the host innate immune system, including bone-marrow-derived myeloid progenitors7, to generate an inflammatory microenvironment hospitable for metastatic growth.
