Neoplasia：肿瘤微环境或可影响不同癌症亚型的发展

  近日，来自冷泉港实验室(Cold Spring Harbor Laboratory)的研究人员通过研究发现，两种不同的乳腺癌小鼠模型会因为机体肿瘤微环境的不同特性而表现出疾病进展的不同，
  肿瘤微环境包括可以支持肿瘤生长的细胞和胞外分子，研究者通过观察分析因不同突变而引发的两种类型的乳腺癌，发现了这两种乳腺癌存在不同的肿瘤微环境；其中一种常见因子是以细胞外蛋白基质金属蛋白酶9的形式存在（MMP9），其在所有乳腺癌小鼠模型中的表达水平都比较类似。此前研究发现MMP9和多种类型癌症的进展直接相关，当研究人员将该基因剔除后他们发现MMP9的缺失仅会在一种小鼠模型中延迟肿瘤的发展，但对其它小鼠模型并无影响。
  随后研究者发现，不论MMP9是否促进癌症的发展，其都依赖于肿瘤的微环境，尤其是当MMP9作用的另外一种名为IGFBP-1分子存在时，该分子是一种胰岛素样的生长因子结合蛋白1。MMP9依赖于IGFBPs分子是否表达对乳腺癌的进展会表现出多种不同的效应。如果IGFBP-1分子不存在，那么MMP9就不会表现出效应，反之亦然；IGFBP-1会结合胰岛素样的生长因子(IGFs)，后者在促进癌症发展上扮演着重要的角色，IGFBP-1会使得生长因子被隔离以便其不能促进癌细胞增殖生长。但当MMP9存在时其就会降解IGFBPs并且释放生长因子，被释放的IGFs随后就会加速癌症的进展。
  研究者对人类癌症的数据库进行了分析寻找来确定是否MMP9和IGFBPs的相互作用可以帮助预测人类的乳腺癌预后，结果发现IGF结合蛋白和患者较好的预后直接相关，但一旦MMP9存在时其就不再和患者的较好生存相关了。本文研究对于开发靶向作用MMP9的新型抗癌药物提供了新的研究思路，相关研究或可帮助解释临床上利用MMP9抑制剂为何会出现治疗失败的情况。
  下一步研究者将对不同类型癌症微环境的差异进行研究，肿瘤微环境在不同的肿瘤中是不相同的，而且引发癌症的驱动突变和癌症微环境之间的关系错综复杂，这都需要后期研究者进行深入的研究探讨才能够阐明。（转化医学网360zhyx.com）
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Presence of Insulin-Like Growth Factor Binding Proteins Correlates With Tumor-Promoting Effects of Matrix Metalloproteinase 9 in Breast Cancer12
Neoplasia     doi:10.1016/j.neo.2015.04.003
Jae-Hyun Park34, Morten Grønbech Rasch35, Jing Qiu, Ida Katrine Lund, Mikala Egebladcorrespondenceemail
The stroma of breast cancer can promote the disease’s progression, but whether its composition and functions are shared among different subtypes is poorly explored. We compared stromal components of a luminal [mouse mammary tumor virus (MMTV)–Neu] and a triple-negative/basal-like [C3(1)–Simian virus 40 large T antigen (Tag)] genetically engineered breast cancer mouse model. The types of cytokines and their expression levels were very different in the two models, as was the extent of innate immune cell infiltration; however, both models showed infiltration of innate immune cells that expressed matrix metalloproteinase 9 (MMP9), an extracellular protease linked to the progression of many types of cancer. By intercrossing with Mmp9 null mice, we found that the absence of MMP9 delayed tumor onset in the C3(1)-Tag model but had no effect on tumor onset in the MMTV-Neu model. We discovered that protein levels of insulin-like growth factor binding protein-1 (IGFBP-1), an MMP9 substrate, were increased in C3(1)-Tag;Mmp9−/− compared to C3(1)-Tag;Mmp9+/+ tumors. In contrast, IGFBP-1 protein expression was low in MMTV-Neu tumors regardless of Mmp9 status. IGFBP-1 binds and antagonizes IGFs, preventing them from activating their receptors to promote cell proliferation and survival. Tumors from C3(1)-Tag;Mmp9−/− mice had reduced IGF-1 receptor phosphorylation, consistent with slower tumor onset. Finally, gene expression analysis of human breast tumors showed that high expression of IGFBP mRNA was strongly correlated with good prognosis but not when MMP9 mRNA was also highly expressed. In conclusion, MMP9 has different effects on breast cancer progression depending on whether IGFBPs are expressed.