確診為局部膀胱癌的癌癥患者，有80％的癌癥患者存活期有五年,，但一旦癌細(xì)胞擴(kuò)散,，只有20％的人生存期為三年?！杜R床研究雜志》最近刊登的一則研究不僅揭示了膀胱癌是如何轉(zhuǎn)移至肺部的,，同時(shí)也指出了抑制這種膀胱癌細(xì)胞轉(zhuǎn)移的方法。
具體來(lái)說(shuō)，該項(xiàng)研究表明參與腫瘤細(xì)胞遷移過(guò)程的蛋白質(zhì)——多功能蛋白聚糖（versican）是肺轉(zhuǎn)移的驅(qū)動(dòng)因子,，高聚糖水平與膀胱癌患者的預(yù)后較差相關(guān),。這項(xiàng)研究首次證明當(dāng)腫瘤細(xì)胞產(chǎn)生蛋白R(shí)hoGDI2時(shí)，腫瘤細(xì)胞聚糖的產(chǎn)生是如何減少的,，進(jìn)而降低了癌細(xì)胞在肺部的生長(zhǎng)能力,。
科羅拉多大學(xué)癌癥中心Dan Theodorescu醫(yī)學(xué)博士，也是該論文的主要作者說(shuō)：過(guò)去十年來(lái)我們已經(jīng)知道,，治療膀胱癌的主要挑戰(zhàn)是治療或預(yù)防疾病的轉(zhuǎn)移,，這項(xiàng)研究是對(duì)后者的進(jìn)步即預(yù)防膀胱癌擴(kuò)散到肺部，我們可以提高患者的生存期,。
當(dāng)癌癥從它產(chǎn)生的位置轉(zhuǎn)移到其它部位時(shí),，這并不是細(xì)胞突然變得具有移動(dòng)性，從而能夠通過(guò)血液或淋巴到達(dá)轉(zhuǎn)移灶,。事實(shí)上,，這些癌細(xì)胞可能已經(jīng)在病人的血液中存在了一段時(shí)間，只有當(dāng)腫瘤細(xì)胞最終能在它接觸到的器官如肺等部位生長(zhǎng)時(shí),，轉(zhuǎn)移才會(huì)發(fā)生,。
當(dāng)?shù)谝粋€(gè)癌細(xì)胞接觸到器官也就是肺時(shí)，腫瘤細(xì)胞要想生存下來(lái)會(huì)碰到困境,。癌細(xì)胞能通過(guò)表達(dá)聚糖的形式克服這種困境,。癌細(xì)胞表達(dá)更多聚糖，它們就會(huì)得到巨噬細(xì)胞的更多幫助,。
癌細(xì)胞產(chǎn)生聚糖越多就能募集到更多的巨噬細(xì)胞,，進(jìn)而援助癌細(xì)胞生存，提高發(fā)展成臨床顯著的肺癌的可能性,。
Theodorescu和他的同事們研究發(fā)現(xiàn)蛋白質(zhì)RhoGDI2能減少聚糖的表達(dá),。癌細(xì)胞產(chǎn)生更多的RhoDI2，那聚糖就越少,。因此只需少量的巨噬細(xì)胞就能使這些高RhoGDI2的癌細(xì)胞難于生存,。
果然當(dāng)Theodorescu和他的同事用RhoGDI2處理腫瘤細(xì)胞后，腫瘤細(xì)胞聚糖表達(dá)降低了,，轉(zhuǎn)移也減少了,。
Theodorescu說(shuō)：“我們相信這項(xiàng)研究為抑制腫瘤轉(zhuǎn)移的提出了新的機(jī)制，即通過(guò)改變腫瘤微環(huán)境包括減少巨噬細(xì)胞的存在進(jìn)而抑制腫瘤轉(zhuǎn)移提供了重要的依據(jù)”,。
事實(shí)上,，這篇論文顯也是第一次證實(shí)聚糖誘導(dǎo)巨噬細(xì)胞幫助腫瘤的能力取決于一種稱為CCL2蛋白質(zhì)。抑制CCL2的藥物已經(jīng)在臨床試驗(yàn)中用于研究治療其他疾病,。
如果在人身上能獲得如同實(shí)驗(yàn)室研究階段所得到的效果，即抑制CCL2減少聚糖誘導(dǎo)巨噬細(xì)胞促進(jìn)腫瘤生長(zhǎng)的能力的話,，這些CCL2抑制劑將不久就能在用于治療膀胱癌患者,。CCL2抑制劑或許有可能降低膀胱癌轉(zhuǎn)移的幾率,，從而能顯著改善高風(fēng)險(xiǎn)膀胱癌患者的預(yù)后情況果。（生物谷： Bioon）
doi:10.1172/JCI61392
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RhoGDI2 suppresses lung metastasis in mice by reducing tumor versican expression and macrophage infiltration
Neveen Said, Marta Sanchez-Carbayo, Steven C. Smith, Dan Theodorescu
Half of patients with muscle-invasive bladder cancer develop metastatic disease, and this is responsible for most of the deaths from this cancer. Low expression of RhoGTP dissociation inhibitor 2 (RhoGDI2; also known as ARHGDIB and Ly-GDI) is associated with metastatic disease in patients with muscle-invasive bladder cancer. Moreover, a reduction in metastasis is observed upon reexpression of RhoGDI2 in xenograft models of metastatic cancer. Here, we show that RhoGDI2 suppresses lung metastasis in mouse models by reducing the expression of isoforms V1 and V3 of the proteoglycan versican (VCAN; also known as chondroitin sulfate proteoglycan 2 [CSPG2]). In addition, we found that high versican levels portended poor prognosis in patients with bladder cancer. The functional importance of tumor expression of versican in promoting metastasis was established in in vitro and in vivo studies in mice that implicated a role for the chemokine CCL2 (also known as MCP1) and macrophages. Further analysis indicated that RhoGDI2 suppressed metastasis by altering inflammation in the tumor microenvironment. In summary, we demonstrate what we believe to be a new mechanism of metastasis suppression that works by reducing host responses that promote metastatic colonization of the lung. Therapeutic targeting of these interactions may provide a novel adjuvant strategy for delaying the appearance of clinical metastasis in patients.
