用病毒打垮“癌中之王”
由于胰腺位置隐蔽，早期胰腺癌很难被发现，多数患者在确诊时已是晚期，5年生存率一般不到5%。这种生长快速而且转移率高的癌症，也被称为“癌中之王”。好消息是，科学家们发现胰腺癌与肿瘤微环境的交流，会削弱它们抵御溶瘤病毒的能力。NatureMedicine杂志四月二十日发表的一项研究指出，胰腺癌与其支持细胞的互作，会使它们在溶瘤病毒面前更加脆弱。而溶瘤病毒有望成为治疗胰腺癌的新希望。
肿瘤周围有着复杂的细胞体系，这种微环境在肿瘤生长、浸润和转移中起到了不容忽视的作用。CAF（癌相关成纤维细胞）是肿瘤微环境中的一种重要细胞，它们在遗传学上是正常的，却被癌症利用为肿瘤发展提供代谢物支持。
研究人员发现，与正常细胞相比CAF更容易被溶瘤病毒感染。而CAF分泌的蛋白FGF2，会让肿瘤在溶瘤病毒面前更加脆弱。溶瘤病毒天生就具有靶向肿瘤的能力，不仅能够直接杀死肿瘤细胞，还能训练免疫系统对癌症发起有效攻击。这种病毒在癌症治疗中有着巨大的潜力，之前中山大学颜光美课题组就曾发现过一种能够“精确制导”的天然溶瘤病毒（M1），引起了人们的广泛关注。
溶瘤病毒的主要优势在于，它的毒性比标准化疗低很多，可以在不伤害健康细胞的情况下杀死癌细胞。在临床试验中，溶瘤病毒的副作用一般是轻度发烧或者类似流感的症状，而且这些症状只持续一两天。
已知CAF会提高肿瘤对标准癌症疗法的抗性，而胰腺癌周围的CAF非常多。不过我们不需要过度悲观，研究人员通过研究小鼠模型和人类胰腺癌细胞发现，CAF越多FGF2水平越高，肿瘤对对溶瘤病毒也越敏感。
“我们的研究有重要的临床意义，”文章的资深作者，渥太华大学教授Dr.JohnBell说。“可以帮助人们预测哪些癌症患者能够更好的应答溶瘤病毒。此外，人们也可以在此基础上想办法提高溶瘤病毒的治疗效果。我们希望将这一发现尽快应用到临床测试中去。”
来源：生物通
Reciprocal cellular cross-talk within the tumor microenvironment promotes oncolytic virus activity
Carolina S Ilkow, Monique Marguerie, Cory Batenchuk, Justin Mayer, Daniela Ben Neriah, Sophie Cousineau, Theresa Falls, Victoria A Jennings, Meaghan Boileau, David Bellamy, Donald Bastin, Christiano Tanese de Souza, Almohanad Alkayyal, Jiqing Zhang, Fabrice Le Boeuf, Rozanne Arulanandam, Lawton Stubbert, Padma Sampath, Steve H Thorne, Piriya Paramanthan, Avijit Chatterjee, Robert M Strieter, Marie Burdick, Christina L Addison, David F Stojdl et al.
Tumors are complex ecosystems composed of networks of interacting 'normal' and malignant cells. It is well recognized that cytokine-mediated cross-talk between normal stromal cells, including cancer-associated fibroblasts (CAFs), vascular endothelial cells, immune cells, and cancer cells, influences all aspects of tumor biology1. Here we demonstrate that the cross-talk between CAFs and cancer cells leads to enhanced growth of oncolytic virus (OV)-based therapeutics. Transforming growth factor-β (TGF-β) produced by tumor cells reprogrammed CAFs, dampened their steady-state level of antiviral transcripts and rendered them sensitive to virus infection. In turn, CAFs produced high levels of fibroblast growth factor 2 (FGF2), initiating a signaling cascade in cancer cells that reduced retinoic acid-inducible gene I (RIG-I) expression and impeded the ability of malignant cells to detect and respond to virus. In xenografts derived from individuals with pancreatic cancer, the expression of FGF2 correlated with the susceptibility of the cancer cells to OV infection, and local application of FGF2 to resistant tumor samples sensitized them to virotherapy both in vitro and in vivo. An OV engineered to express FGF2 was safe in tumor-bearing mice, showed improved therapeutic efficacy compared to parental virus and merits consideration for clinical testing.
http://www.nature.com/nm/journal/vaop/ncurrent/full/nm.3848.html
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