图片来源：medicalxpress.com
近日，一项刊登在国际杂志Nature上的研究论文中，来自德克萨斯大学MD癌症研究中心的科学家们通过研究表示，一种名为PTEN的肿瘤抑制基因会受到其所在机体器官的微环境的影响，而且PTEN还可以被不同器官进行调节，对于脑癌转移患者而言，这并不是什么好事儿，因为PTEN的功能在大脑细胞中是处于关闭状态的，让科学家们更惊讶的是，一旦细胞迁移到了其他器官PTEN就会恢复。
本文研究对于开发新型抵御恶性脑癌转移的新型疗法提供了新的思路。研究者Dihua Yu博士指出，癌症转移的发生需要肿瘤细胞适应并且随着转移位点的不同而不断进化演变；目前我们并不清楚肿瘤细胞何时及以何种方式来获取其进行成功转移的外源器官的微环境特性，而本文研究发现，当原发性肿瘤细胞达到大脑时，携带正常PTEN表达的肿瘤细胞或许就会失去PTEN的表达。
经历PTEN缺失的转移性脑癌细胞当其离开大脑后PTEN的水平就会逐渐恢复，PTEN水平缺失的逆转可以通过位于大脑和脊髓中的星形细胞的miRNAs来诱导完成，而星形细胞就是所谓的星状细胞，其可以分泌包含靶向作用PTEN的miRNAs的外核体，并且通过外核体来将PTEN靶向的miRNAs从细胞间转移到肿瘤细胞中。
研究小组还发现，大脑肿瘤细胞中PTEN的缺失会引发细胞因子CCL2分泌的增加，CCL2可以将小胶质细胞恢复至转移性肿瘤中去，从而就可以增强肿瘤细胞的生长，并且保护肿瘤细胞免于死亡。
最后研究者Yu说道，本文研究阐明了转移性肿瘤细胞中PTEN应对不同器官环境反应的可塑性，同时也揭示了PTEN在肿瘤细胞和微环境之间共同进化演变的重要角色；文章中研究者阐明了肿瘤细胞和转移性微环境之间的动态及互交的交联剂之，或为后期开发治疗抗癌症转移性的新型疗法提供希望。
doi:10.1038/nature15376
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Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth
Lin Zhang, Siyuan Zhang, Jun Yao, Frank J. Lowery, Qingling Zhang, Wen-Chien Huang, Ping Li, Min Li, Xiao Wang, Chenyu Zhang, Hai Wang, Kenneth Ellis, Mujeeburahiman Cheerathodi, Joseph H. McCarty, Diane Palmieri, Jodi Saunus, Sunil Lakhani, Suyun Huang, Aysegul A. Sahin, Kenneth D. Aldape, Patricia S. Steeg & Dihua Yu
The development of life-threatening cancer metastases at distant organs requires disseminated tumour cells’ adaptation to, and co-evolution with, the drastically different microenvironments of metastatic sites1. Cancer cells of common origin manifest distinct gene expression patterns after metastasizing to different organs2. Clearly, the dynamic interaction between metastatic tumour cells and extrinsic signals at individual metastatic organ sites critically effects the subsequent metastatic outgrowth3, 4. Yet, it is unclear when and how disseminated tumour cells acquire the essential traits from the microenvironment of metastatic organs that prime their subsequent outgrowth. Here we show that both human and mouse tumour cells with normal expression of PTEN, an important tumour suppressor, lose PTEN expression after dissemination to the brain, but not to other organs. The PTEN level in PTEN-loss brain metastatic tumour cells is restored after leaving the brain microenvironment. This brain microenvironment-dependent, reversible PTEN messenger RNA and protein downregulation is epigenetically regulated by microRNAs from brain astrocytes. Mechanistically, astrocyte-derived exosomes mediate an intercellular transfer of PTEN-targeting microRNAs to metastatic tumour cells, while astrocyte-specific depletion of PTEN-targeting microRNAs or blockade of astrocyte exosome secretion rescues the PTEN loss and suppresses brain metastasis in vivo. Furthermore, this adaptive PTEN loss in brain metastatic tumour cells leads to an increased secretion of the chemokine CCL2, which recruits IBA1-expressing myeloid cells that reciprocally enhance the outgrowth of brain metastatic tumour cells via enhanced proliferation and reduced apoptosis. Our findings demonstrate a remarkable plasticity of PTEN expression in metastatic tumour cells in response to different organ microenvironments, underpinning an essential role of co-evolution between the metastatic cells and their microenvironment during the adaptive metastatic outgrowth. Our findings signify the dynamic and reciprocal cross-talk between tumour cells and the metastatic niche; importantly, they provide new opportunities for effective anti-metastasis therapies, especially of consequence for brain metastasis patients.