除了眾所周知的抽煙這個(gè)風(fēng)險(xiǎn)因素之外,，慢性阻塞性肺疾病(chronic obstructive pulmonary disease, COPD)也會(huì)增加患上肺癌的風(fēng)險(xiǎn)。如今,，來(lái)自美國(guó)科羅拉多大學(xué)癌癥中心的一項(xiàng)最新研究詳細(xì)描述了該風(fēng)險(xiǎn)的一種新的機(jī)制：長(zhǎng)期性缺氧(long-term oxygen depletion)激活促進(jìn)腫瘤生長(zhǎng)的信號(hào),。此外,，這項(xiàng)在動(dòng)物模型上完成的研究證實(shí)這些由COPD誘導(dǎo)的信號(hào)引起的腫瘤可能特別敏感于關(guān)閉這些信號(hào)的用于預(yù)防或者甚至治療的藥物(也就是VEGFR-2和EGFR抑制劑)。相關(guān)研究結(jié)果于2012年6月14日在線發(fā)表在Cancer Prevention Research期刊上,。
論文通信作者York Miller博士說(shuō),，至少在動(dòng)物模型中，來(lái)自肺部缺氧區(qū)域的肺腫瘤中被激活的一種重要的途徑,，并不在來(lái)自其他肺癌中以幾乎相同的程度被激活,。不過(guò)其他機(jī)制也可能促進(jìn)COPD模式動(dòng)物體內(nèi)產(chǎn)生肺癌，比如炎癥,，不過(guò)這項(xiàng)研究表明這種低氧感知途徑在這些COPD肺癌模式動(dòng)物中特異性地被激活,，而且這種感知途徑在很大程度上促進(jìn)腫瘤生長(zhǎng)。
特別地是,，他的研究利用經(jīng)培養(yǎng)患上癌癥的模式動(dòng)物開(kāi)展研究,，并將它們放置在高海拔的房間中以便模仿因患上COPD而在肺部部分區(qū)域觀察到的長(zhǎng)期缺氧。在低氧環(huán)境下的小鼠要比處于正常氧氣水平下的小鼠產(chǎn)生更大的腫瘤,。不過(guò),，按照Miler的說(shuō)法，最令人關(guān)注的是腫瘤生長(zhǎng)的原因,。
研究人員發(fā)現(xiàn)模擬COPD癥狀(包括慢性支氣管炎和肺氣腫)的低氧環(huán)境下的腫瘤生長(zhǎng)是由于HIF-2a信號(hào)引起的,。HIF-2a接著激活促進(jìn)癌癥生長(zhǎng)的包括VEGF,、EGFR配體(即TGFa)在內(nèi)的機(jī)制,。
類似地，正如來(lái)自低氧條件下的腫瘤確實(shí)通過(guò)激活導(dǎo)致VEGF和TGFa過(guò)量產(chǎn)生的途徑來(lái)進(jìn)行生長(zhǎng)的,，因此這些腫瘤對(duì)阻斷這些生長(zhǎng)因子的抗癌治療特別敏感,。毫無(wú)疑問(wèn)，服用藥物凡德他尼(vandetanib)---一種同時(shí)抑制VEGFR和EGFR的試劑---的模式動(dòng)物在低氧條件下不容易患上肺癌,。(生物谷：Bioon.com)
本文編譯自How chronic obstructive pulmonary disease increases risk of lung cancer
doi: 10.1158/1940-6207.CAPR-12-0069-T
PMC:
PMID:
Alveolar Hypoxia Promotes Murine Lung Tumor Growth through a VEGFR-2/EGFR-Dependent Mechanism
Vijaya Karoor1,3, Mysan Le4, Daniel Merrick2,3,4, Karen A. Fagan5, Edward C. Dempsey1,3,4, and York E. Miller
Patients with chronic obstructive pulmonary disease (COPD) are at an increased risk for the development of lung cancer, the mechanisms for which are incompletely understood. We hypothesized that the hypoxic pulmonary microenvironment present in COPD would augment lung carcinogenesis. Mice were subjected to chemical carcinogenesis protocols and placed in either hypoxia or normoxia. Mice exposed to chronic hypoxia developed tumors with increased volume compared with normoxic controls. Both lungs and tumors from hypoxic mice showed a preferential stabilization of HIF-2α and increased expression of VEGF-A, FGF2, and their receptors as well as other survival, proliferation, and angiogenic signaling pathways regulated by HIF-2α. We showed that tumors arising in hypoxic animals have increased sensitivity to VEGFR-2/EGFR inhibition, as chemoprevention with vandetanib showed markedly increased activity in hypoxic mice. These studies showed that lung tumors arising in a hypoxic microenvironment express increased growth, angiogenic, and survival signaling that could contribute to the increased lung cancer risk in COPD. Furthermore, the differential sensitivity of tumors arising in hypoxia to VEGFR-2/EGFR inhibition suggests that the altered signaling present in tumors arising in hypoxic lung might be therapeutically exploited in patients with underlying COPD.
