技术专题

近日，来自美国德克萨斯MD安德森癌症中心的研究人员发现抑制免疫受体蛋白TLR4可能并不适用于治疗所有癌，TLR4在乳腺癌中既可促进癌细胞生长也可抑制癌细胞生长，而这种看似矛盾的作用则主要取决于TP53发生的突变类型。这项研究结果最近发表在国际学术期刊PNAS上。

TLR4有许多同家族成员，是参与许多免疫学途径的重要受体分子，之前许多研究证明TLR4是一个癌基因，能够促进肿瘤生长，因此一直以来人们都把TLR4看作是基于免疫疗法治疗癌症的重要靶向分子，同时也有很多针对TLR4设计开发的治疗药物正在得到研发。

但在这项研究中，研究人员发现TLR4要发挥促肿瘤生长功能还需要依赖TP53的活性，在一些TP53为野生型的乳腺癌细胞中，TLR4并不能发挥癌基因功能，与之相反，它可以作为生长抑制因子发挥作用，如果在这种情况下抑制TLR4会变得非常危险，这会促进肿瘤细胞的生长。随后，他们又将TLR4与TP53突变联系起来分析乳腺癌病人的生存趋势，发现当存在TP53突变时，TLR4的高水平表达与病人的生存率走低密切相关，而细胞中存在正常TP53时，病人的生存率趋势与TP53突变的情况正相反。

最后，研究人员还指出，这项研究发现的TLR4与TP53之间的关联性并不仅仅存在于乳腺癌，在其他一些存在TP53突变的癌症类型中，如卵巢癌、头颈癌和膀胱癌，TLR4的表达水平也比较高。

总得来说，这项研究发现TLR4在乳腺癌细胞中是否可以发挥癌基因作用还需要依赖TP53的突变情况，建立了TLR4与TP53活性之间的联系，对于进一步了解TLR4的癌基因作用发挥，合理使用靶向药物具有重要指导意义。

doi: 10.1073/pnas.1420811112

TLR4 has a TP53-dependent dual role in regulating breast cancer cell growth

Svasti Haricharan1 and Powel Brown

Breast cancer is a leading cause of cancer-related death, and it is important to understand pathways that drive the disease to devise effective therapeutic strategies. Our results show that Toll-like receptor 4 (TLR4) drives breast cancer cell growth differentially based on the presence of TP53, a tumor suppressor. TP53 is mutationally inactivated in most types of cancer and is mutated in 30-50% of diagnosed breast tumors. We demonstrate that TLR4 activation inhibits growth of TP53 wild-type cells, but promotes growth of TP53mutant breast cancer cells by regulating proliferation. This differential effect is mediated by changes in tumor cell cytokine secretion. Whereas TLR4 activation in TP53 mutant breast cancer cells increases secretion of progrowth cytokines, TLR4 activation in TP53 wild-type breast cancer cells increases type I IFN (IFN-γ) secretion, which is both necessary and sufficient for mediating TLR4-induced growth inhibition. This study identifies a novel dichotomous role for TLR4 as a growth regulator and a modulator of tumor microenvironment in breast tumors. These results have translational relevance, demonstrating that TP53mutant breast tumor growth can be suppressed by pharmacologic TLR4 inhibition, whereas TLR4 inhibitors may in fact promote growth of TP53 wild-type tumors. Furthermore, using data generated by The Cancer Genome Atlas consortium, we demonstrate that the effect of TP53 mutational status on TLR4 activity may extend to ovarian, colon, and lung cancers, among others, suggesting that the viability of TLR4 as a therapeutic target depends on TP53 status in many different tumor types.