癌细胞“狡猾”?没事,我们有对策
2017/08/05
当正常的成纤维细胞被被癌细胞“劫持”后,它们会叛变成“癌相关成纤维细胞”(CAFs),帮助肿瘤生长、扩散并躲避药物的攻击。近期,科学家们第一次找到了对于CAFs而言必不可少的关键酶——NOX4,通过靶向这一酶类,我们能够抑制癌相关成纤维细胞,从而控制肿瘤的发生、发展。


肿瘤细胞很“聪明”,它们除了武装自己、无限扩增且多变之外,还会“勾引”周围的正常细胞,包括成纤维细胞(Fibroblasts)、免疫细胞。其中,成纤维细胞是结缔组织中最常见的细胞,负责将不同类型的阻止器官联结在一起。当它们被癌细胞“劫持”后,它们会叛变成“癌相关成纤维细胞”(CAFs),帮助肿瘤生长、扩散并躲避药物的攻击。

那么我们是否可以靶向这些“亲肿瘤”的成纤维细胞呢?遗憾的是,迄今为止,相关研究都没有成功。

8月3日,《Journal of the National Cancer Institute》期刊发表一篇文章,首次揭示了这一思路的可行性:靶向已被癌细胞“劫持”的健康细胞,能够治疗多种不同类型的癌症。

来自于南安普顿大学的研究团队发现,高水平的癌相关成纤维细胞会导致较低的癌症存活率,例如肠癌、头颈癌。癌相关成纤维细胞会让癌症变得更有侵略性,增加治疗的难度。

突破点在于他们首次找到一个关键酶——NOX4能够抑制癌相关成纤维细胞的行为,减少患癌小鼠体内肿瘤大小(50%)。他们证实,NOX4酶对于这些叛变的成纤维细胞协助肿瘤生长必不可少,且在多种癌症中都存在这一相同机制。

可喜的是,借助一种治疗器官纤维化的药物,他们能够阻止NOX4的功能。“这一发现能够为新的抗癌手段提供线索,有助于提高现有抗癌药物的疗效。研究团队将继续验证这一方法改善免疫疗法、放化疗等治疗方法的效果。” 南安普敦大学的实验病理学教授Gareth Thomas解释道。

英国癌症研究中心的高级科学信息官Áine McCarthy博士表示:“有些癌症很难治疗,因为它们会利用身体的健康细胞帮助它们生长、转移。多年来,科学家们抑制试图解开这背后的秘密。现在,这一研究为实现这一目标迈出了重要一步。”

这些发现表明,CAFs可以成为药物的目标,它们的‘亲肿瘤’效应已经在小鼠模型上证实可以被逆转。“这是一个起点,未来我们将针对这一基础性研究开发出更光谱、高效的抗癌方法。”研究人员表示。

参考资料:

Scientists deliver knockout blow to multiple cancers

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  • Targeting the Myofibroblastic Cancer-Associated Fibroblast Phenotype Through Inhibition of NOX4

    Background Cancer-associated fibroblasts (CAFs) are tumor-promoting and correlate with poor survival in many cancers, which has led to their emergence as potential therapeutic targets. However, effective methods to manipulate these cells clinically have yet to be developed. Methods CAF accumulation and prognostic significance in head and neck cancer (oral, n = 260; oropharyngeal, n = 271), and colorectal cancer (n = 56) was analyzed using immunohistochemistry. Mechanisms regulating fibroblast-to-myofibroblast transdifferentiation were investigated in vitro using RNA interference/pharmacological inhibitors followed by polymerase chain reaction (PCR), immunoblotting, immunofluorescence, and functional assays. RNA sequencing/bioinformatics and immunohistochemistry were used to analyze NAD(P)H Oxidase-4 (NOX4) expression in different human tumors. NOX4’s role in CAF-mediated tumor progression was assessed in vitro, using CAFs from multiple tissues in Transwell and organotypic culture assays, and in vivo, using xenograft (n = 9–15 per group) and isograft (n = 6 per group) tumor models. All statistical tests were two-sided. Results Patients with moderate/high levels of myofibroblastic-CAF had a statistically significant decrease in cancer-specific survival rates in each cancer type analyzed (hazard ratios [HRs] = 1.69–7.25, 95% confidence intervals [CIs] = 1.11 to 31.30, log-rank P ≤ .01). Fibroblast-to-myofibroblast transdifferentiation was dependent on a delayed phase of intracellular reactive oxygen species, generated by NOX4, across different anatomical sites and differentiation stimuli. A statistically significant upregulation of NOX4 expression was found in multiple human cancers (P < .001), strongly correlating with myofibroblastic-CAFs (r = 0.65–0.91, adjusted P < .001). Genetic/pharmacological inhibition of NOX4 was found to revert the myofibroblastic-CAF phenotype ex vivo (54.3% decrease in α-smooth muscle actin [α-SMA], 95% CI = 10.6% to 80.9%, P = .009), prevent myofibroblastic-CAF accumulation in vivo (53.2%–79.0% decrease in α-SMA across different models, P ≤ .02) and slow tumor growth (30.6%–64.0% decrease across different models, P ≤ .04). Conclusions These data suggest that pharmacological inhibition of NOX4 may have broad applicability for stromal targeting across cancer types.

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