近日，皇后大學(xué)的研究者在腫瘤領(lǐng)域權(quán)威雜志Cancer Res上發(fā)表文章"Hypoxia induces escape from innate immunity in cancer cells via increased expression of ADAM10: role of nitric oxide"稱他們發(fā)現(xiàn)一種新的機(jī)制能有力的解釋為什么人體免疫系統(tǒng)經(jīng)常清除不掉癌癥。
這項(xiàng)新的發(fā)現(xiàn)闡述了癌癥細(xì)胞免疫抵抗的可能原因,，同時(shí)也證實(shí)硝酸甘油——一個(gè)應(yīng)用一個(gè)多世紀(jì)的用于治療心絞痛的相對(duì)安全,、低成本藥物,，也許可以有效的控制某些癌癥,。
“這一發(fā)現(xiàn)將出現(xiàn)新的治療某些特定癌癥的方法”，皇后大學(xué)生物醫(yī)學(xué)與分子科學(xué)系教授查爾斯-格雷姆說,，他與金斯敦總醫(yī)院泌尿外科羅伯特-西門子領(lǐng)導(dǎo)了研究團(tuán)隊(duì),。研究者注意到組織氧缺乏或者低氧狀態(tài)在某些癌細(xì)胞逃脫免疫系統(tǒng)監(jiān)視和清除方面起著一定作用。
他們發(fā)現(xiàn)癌癥細(xì)胞氧不足導(dǎo)致一關(guān)鍵酶的產(chǎn)生增多——ADAM10,它使細(xì)胞可抵抗免疫細(xì)胞的攻擊,。但是用一氧化碳模擬劑比如硝酸甘油,，將會(huì)解決缺氧條件癌癥細(xì)胞失去免疫系統(tǒng)攻擊的抵抗。結(jié)果說明硝酸甘油可用于提高對(duì)癌癥的天然免疫反應(yīng),。
本研究的基金來(lái)自加拿大衛(wèi)生研究院以及特里?？怂够饡?huì)跨學(xué)科癌癥研究培訓(xùn)項(xiàng)目,。
該發(fā)現(xiàn)基于皇后大學(xué)研究團(tuán)隊(duì)2009年關(guān)于一氧化碳在抑制前列腺腫瘤生長(zhǎng)方面的研究結(jié)果,。研究者進(jìn)行了首次臨床試驗(yàn)使用低劑量硝酸甘油治療前列腺癌,。
皇后大學(xué)的這一研究包含多于10名患者接受了硝酸甘油和類似物治療癌癥?；屎蟠髮W(xué)技術(shù)轉(zhuǎn)讓辦公室——PARTEQ創(chuàng)新（機(jī)構(gòu)）,，已經(jīng)許可一部分知識(shí)產(chǎn)權(quán)給該大學(xué)所屬的公司，根據(jù)本研究以及其他相關(guān)研究來(lái)開發(fā)產(chǎn)品和治療,。（生物谷Bioon.com）
doi:10.1158/0008-5472.CAN-11-2104
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Hypoxia induces escape from innate immunity in cancer cells via increased expression of ADAM10: role of nitric oxide
Ivraym B Barsoum1, Thomas K Hamilton1, Xin Li1, Tiziana Cotechini1, Ellen A Miles1, D. Robert Siemens2, and Charles H Graham3,*
One key to malignant progression is the acquired ability of tumor cells to escape immune-mediated lysis. Whereas tumor hypoxia is known to play a causal role in cancer metastasis and resistance to therapy, the link between hypoxia and immune escape in cancer remains poorly understood. Here, we show that hypoxia induces tumor cell resistance to lysis that is mediated by immune effectors through a HIF-1-dependent pathway linked to increased expression of the metalloproteinase ADAM10. This enzyme is required for the hypoxia-induced shedding of MHC Class I Chain Related molecule A (MICA), a ligand that triggers the cytolytic action of immune effectors, from the surface of tumor cells. Indeed, our findings demonstrate a mechanistic link between hypoxia-induced accumulation of the α subunit of HIF-1 (HIF-1α), increased expression of ADAM10, and decreased surface MICA levels leading to tumor cell resistance to lysis mediated by innate immune effectors. Nitric oxide mimetic agents interfered with the hypoxia-induced accumulation of HIF-1α, and with the hypoxia-induced up-regulation of ADAM10 expression required for decreased surface MICA expression and resistance to lysis. Furthermore, treatment of tumor-bearing mice with nitroglycerin, a nitric oxide mimetic, attenuated tumor growth by a mechanism that relied upon innate immune effector cells. Together, these findings reveal a novel mechanism by which the hypoxic tumor microenvironment contributes to immune escape in cancer, lending support to potential immunotherapeutic strategies involving the use of nitric oxide mimetics.
