肿瘤微环境中一种新型促侵袭因子的发现——细胞外ATP功能及机制的研究进

根据世界卫生组织的最新统计数据，全球癌症每年新发病例约1 400多万人，同时约有820万人因癌症死亡，其中90%是因肿瘤的复发转移导致。恶性肿瘤给患者造成的危害关键就在于它能够转移，因此肿瘤转移始终是肿瘤防治的重大课题及研究难点。如果能够精准了解并掌握肿瘤转移的规律和机制，控制转移发生、发展的关键环节，肿瘤问题就能够得到根本的解决。 我们团队在过去近20年的研究工作中发现肿瘤微环境中存在的三磷酸腺苷（adenosine triphosphate，ATP）具有明显促进肿瘤细胞侵袭的作用，针对ATP的促侵袭机制进行了系统深入的研究，并在国际上首次提出肿瘤微环境中的ATP是一种重要的促侵袭因子的观点，为肿瘤侵袭发生的机制及调控提供了新的科学依据。本文将结合我们的工作对这一领域的研究进展给予论述。

Identification of a new pro-invasion factor in tumor microenvironment: progress in function and mechanism of extracellular ATP

Up to 90% of all cancer related morbidity and mortality can be attributed to metastasis. In recent years the study of tumor microenvironment, its cellular and molecular components, and how they can affect neoplastic progression toward metastasis, has become a hot focus in cancer research. Accumulated evidence shows that the formation of metastasis is a multi step sequential process, in which, the tumor cells continuously interact with the host microenvironment. Host derived factors, i-e. growth factors/inhibitors, angiogenic factors, chemokines, etc. together with different types of host cells, play important roles in the tumor progression towards metastasis. The interaction between the tumor cells and host microenvironment determines the fate of metastasis. The reveal of this interaction mechanism provides us an opportunity to find effective mode of interference and develop novel anti-metastasis drugs. In this review, we have summarized our work on a new pro-invasion factor identified in tumor microenvironment and how it affects tumor invasion and metastass. Adenosine triphosphate (ATP), the key intracellular energy currency, accumulates within the tumor microenvironment and is closely involved in cancer cell metabolism and in antitumor immunity. The established role of ATP as a growth modulator and a proinflammatory mediator endues ATP and other purines with potential players in host-tumor interaction. Our study demonstrated that extracellular ATP stimulated human cancer invasion in in vitro tests. Increased migration and invasive ability across Matrigel was observed in some human carcinoma cell lines, including the prostate, breast, colon, melanoma and lung, when stimulated with ATP or its analogues. ATP enhanced the motility of cancer cells via increasing the amount and length of lamellipodia and filopodia, which were necessary for the cell motility. Significant increase in Rac1 and Cdc42 activities was observed. Using cDNA microarray we found that the expression of a panel of invasion/metastasis-related genes was significantly changed, including the increased expression of interleukin（IL）-8 and matrix metalloproteinase-3（MMP-3） after ATP treatment. Changes of some epithelial-mesenchymal transition (EMT)-related factors were also observed, including the increase of snail, decrease of E-cadherin and claudin-1. Multiple P2Y receptors subtypes were expressed on tumor cells, but P2Y2 and P2X7 receptors were found to be mainly responsible for the pro invasive effect of ATP. Down-regulation of either P2Y2 or P2X7 abolished ATP effect on cancer invasion and expression of EMT/invasion-related genes. Further, we found that P2Y2 receptor trans-activated with epidermal growth factor receptor (EGFR) and co-activated extracellular regulated protein kinases (ERK1/2) signaling pathway, which was involved in regulating expression of EMT and other related genes. In nude mice experiment, the pro-invasive effect of ATP was further confirmed. In summary, our results reveal that ATP is a potential pro-invasive factor in tumor microenvironment. P2Y2/P2X7 receptors act as a mediator in the regulation of ATP-induced EMT and invasion of cancer cells. Given that tumor microenvironment is rich in ATP and other purines, we hypo-thesize that ATP might be a potential invasion stimulator in tumor microenvironment. Blocking ATP receptor might be a therapeutic target on cancer.