近日，皇后大学的研究者在肿瘤领域权威杂志Cancer Res上发表文章"Hypoxia induces escape from innate immunity in cancer cells via increased expression of ADAM10: role of nitric oxide"称他们发现一种新的机制能有力的解释为什么人体免疫系统经常清除不掉癌症。
这项新的发现阐述了癌症细胞免疫抵抗的可能原因，同时也证实硝酸甘油——一个应用一个多世纪的用于治疗心绞痛的相对安全、低成本药物，也许可以有效的控制某些癌症。
“这一发现将出现新的治疗某些特定癌症的方法”，皇后大学生物医学与分子科学系教授查尔斯-格雷姆说，他与金斯敦总医院泌尿外科罗伯特-西门子领导了研究团队。研究者注意到组织氧缺乏或者低氧状态在某些癌细胞逃脱免疫系统监视和清除方面起着一定作用。
他们发现癌症细胞氧不足导致一关键酶的产生增多——ADAM10,它使细胞可抵抗免疫细胞的攻击。但是用一氧化碳模拟剂比如硝酸甘油，将会解决缺氧条件癌症细胞失去免疫系统攻击的抵抗。结果说明硝酸甘油可用于提高对癌症的天然免疫反应。
本研究的基金来自加拿大卫生研究院以及特里福克斯基金会跨学科癌症研究培训项目。
该发现基于皇后大学研究团队2009年关于一氧化碳在抑制前列腺肿瘤生长方面的研究结果。研究者进行了首次临床试验使用低剂量硝酸甘油治疗前列腺癌。
皇后大学的这一研究包含多于10名患者接受了硝酸甘油和类似物治疗癌症。皇后大学技术转让办公室——PARTEQ创新（机构），已经许可一部分知识产权给该大学所属的公司，根据本研究以及其他相关研究来开发产品和治疗。（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.
