2012年9月11日 訊 /生物谷BIOON/ --當(dāng)腫瘤轉(zhuǎn)移或者在機(jī)體其它區(qū)域進(jìn)行擴(kuò)散時(shí),，最終使得癌癥病人死亡的原因往往不是原發(fā)性的腫瘤。近日,，來自威爾康乃爾醫(yī)學(xué)院的研究者將注意力轉(zhuǎn)移到了結(jié)直腸癌的發(fā)病原因上,，他們重點(diǎn)研究了癌癥細(xì)胞如何通過識(shí)別關(guān)鍵的化學(xué)信號(hào)分子來進(jìn)行腫瘤的轉(zhuǎn)移。同時(shí)研究者也開發(fā)出了低成本,、無需進(jìn)行手術(shù)的遺傳開關(guān)來對(duì)結(jié)直腸癌癌細(xì)胞的行為進(jìn)行開關(guān)控制,。相關(guān)研究成果刊登在了9月4日的國際雜志Journal of Clinical Investigation上。
在這項(xiàng)研究中,，研究者發(fā)現(xiàn)了一種稱為炎癥趨化因子相關(guān)的特殊信號(hào)分子機(jī)制可以誘導(dǎo)結(jié)直腸癌細(xì)胞進(jìn)行轉(zhuǎn)移。炎癥趨化因子是一種可移動(dòng)的因子,，因?yàn)槠淇梢詭椭?xì)胞在集體中進(jìn)行移動(dòng),，其對(duì)于機(jī)體抵御感染的免疫效應(yīng)非常重要。
研究者確定了一種特殊的炎癥趨化因子受體CCR9和炎癥趨化因子配體CCL25之間的聯(lián)系,，這種聯(lián)系和結(jié)直腸癌愛細(xì)胞轉(zhuǎn)移有關(guān),。炎癥趨化因子的正常表達(dá)可以使得癌細(xì)胞處于腸道之中，但是一旦細(xì)胞缺失CCR9的表達(dá),，那么癌細(xì)胞將會(huì)擴(kuò)散,。換句話說，癌細(xì)胞就會(huì)“劫持”信號(hào)分子機(jī)制,。
這些昂研究發(fā)現(xiàn)為抗癌癥轉(zhuǎn)移療法提供了一定的思路,，研究者Chen用工程學(xué)技術(shù)制造出了攜帶有CCL25和CCR9轉(zhuǎn)移開關(guān)的小鼠，當(dāng)小鼠體內(nèi)注射入癌癥細(xì)胞后,，這些開關(guān)就可以進(jìn)行開關(guān),。首先，細(xì)胞表達(dá)CCR9受體,，此時(shí)癌細(xì)胞僅僅處于腸道中,，關(guān)閉開關(guān)后會(huì)使得癌細(xì)胞失去信號(hào)分子機(jī)制，隨后癌癥轉(zhuǎn)移便開始發(fā)生,。
研究者表示,，這種新型技術(shù)（新型開關(guān)）可以消除傳統(tǒng)研究癌癥轉(zhuǎn)移方法的瓶頸,，傳統(tǒng)的治療方法比昂貴，使用新型開關(guān),，我們就可以更深入地研究癌癥的轉(zhuǎn)移以為開發(fā)新型抗癌療法提供更大的幫助,。（生物谷Bioon.com）
編譯自：Metastatic 'switch' could lead to cancer therapies
doi:10.1172/JCI62110
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PMID:
Chemokine 25–induced signaling suppresses colon cancer invasion and metastasis
Huanhuan Joyce Chen1,2, Robert Edwards3, Serena Tucci4,5, Pengcheng Bu2,6, Jeff Milsom7, Sang Lee7, Winfried Edelmann8, Zeynep H. Gümüs4,5, Xiling Shen2,6 and Steven Lipkin1
Chemotactic cytokines (chemokines) can help regulate tumor cell invasion and metastasis. Here, we show that chemokine 25 (CCL25) and its cognate receptor chemokine receptor 9 (CCR9) inhibit colorectal cancer (CRC) invasion and metastasis. We found that CCR9 protein expression levels were highest in colon adenomas and progressively decreased in invasive and metastatic CRCs. CCR9 was expressed in both primary tumor cell cultures and colon-cancer-initiating cell (CCIC) lines derived from early-stage CRCs but not from metastatic CRC. CCL25 stimulated cell proliferation by activating AKT signaling. In vivo, systemically injected CCR9+ early-stage CCICs led to the formation of orthotopic gastrointestinal xenograft tumors. Blocking CCR9 signaling inhibited CRC tumor formation in the native gastrointestinal CCL25+ microenvironment, while increasing extraintestinal tumor incidence. NOTCH signaling, which promotes CRC metastasis, increased extraintestinal tumor frequency by stimulating CCR9 proteasomal degradation. Overall, these data indicate that CCL25 and CCR9 regulate CRC progression and invasion and further demonstrate an appropriate in vivo experimental system to study CRC progression in the native colon microenvironment.
