Mediavilla-Varela Melanie, Luddy Kimberly, Noyes David, Khalil Farah K, Neuger Anthony M, Soliman Hatem, Antonia Scott J
Department of Immunology; H. Lee Moffitt Cancer Center; Tampa, FL USA.
Anatomic Pathology Department; H. Lee Moffitt Cancer Center; Tampa, FL USA.
Cancer Biol Ther. 2013 Sep;14(9):860-8. doi: 10.4161/cbt.25643. Epub 2013 Jul 17.
Recently it has become clear that the cost associated with the Warburg effect, which is inefficient production of ATP, is offset by selective advantages that are produced by resultant intracellular metabolic alterations. In fact tumors may be addicted to the Warburg effect. In addition these alterations result in changes in the extracellular tumor microenvironment that can also produce selective advantages for tumor cell growth and survival. One such extracellular alteration is increased adenosine concentrations that have been shown to impair T cell mediated rejection and support angiogenesis. The expression of the A2A receptor in non-small cell cancer (NSCLC) tissues, cell lines and cancer associated fibroblasts (CAF) was determined by performing immunohistrochemistry and immunoblot analysis. The efficacy of the A2A receptor antagonists in vivo was evaluated in a PC9 xenograft model. To determine the mode of cell death induced by A2A receptor antagonists flow cytometry, immunoblot, and cytotoxic analysis were performed. We found that a significant number of lung adenocarcinomas express adenosine A2A receptors. Antagonism of these receptors impaired CAF and tumor cell growth in vitro and inhibited human tumor xenograft growth in mice. These observations add to the rationale for testing adenosine A2A receptor antagonists as anticancer therapeutics. Not only could there be prevention of negative signaling in T cells within the tumor microenvironment and inhibition of angiogenesis, but also an inhibitory effect on tumor-promoting, immunosuppressive CAFs and a direct inhibitory effect on the tumor cells themselves.
最近已经明确，与瓦伯格效应相关的成本（即ATP的低效产生）被细胞内代谢改变所产生的选择性优势所抵消。事实上，肿瘤可能对瓦伯格效应上瘾。此外，这些改变导致细胞外肿瘤微环境发生变化，这也可为肿瘤细胞的生长和存活产生选择性优势。一种这样的细胞外改变是腺苷浓度升高，已证明其会损害T细胞介导的排斥反应并支持血管生成。通过进行免疫组织化学和免疫印迹分析来确定非小细胞癌（NSCLC）组织、细胞系和癌症相关成纤维细胞（CAF）中A2A受体的表达。在PC9异种移植模型中评估A2A受体拮抗剂在体内的疗效。为了确定A2A受体拮抗剂诱导的细胞死亡模式，进行了流式细胞术、免疫印迹和细胞毒性分析。我们发现大量肺腺癌表达腺苷A2A受体。这些受体的拮抗作用在体外损害了CAF和肿瘤细胞的生长，并在小鼠中抑制了人肿瘤异种移植的生长。这些观察结果为测试腺苷A2A受体拮抗剂作为抗癌治疗药物提供了理论依据。这不仅可以预防肿瘤微环境中T细胞的负信号传导并抑制血管生成，还可以对促进肿瘤的免疫抑制性CAF产生抑制作用，并对肿瘤细胞本身产生直接抑制作用。
