来自德克萨斯大学MD安德森癌症中心的科学家们发现，肿瘤细胞转移到脑后PTEN会被关闭。令人惊讶地是，一旦细胞迁移到其他器官PTEN便会恢复。
这一研究发现对于开发出尤其针对晚期脑癌患者的新型有效的抗转移疗法极为重要。研究结果发表在10月19日的《自然》（Nature）杂志上。
威胁生命的癌症在远处器官转移需要被传播的肿瘤细胞与截然不同的微环境的转移位点相适应和共同进化。相同来源的肿瘤细胞转移到不同的器官后会显示出不同的基因表达谱。显然，转移的肿瘤细胞和外在信号之间在转移器官的动态相互作用影响其转移后的生长。然而，扩散的肿瘤细胞在什么时候并且怎么样获得转移器官的利于转移肿瘤细胞生长微环境的仍然是不清楚的。这篇研究文章揭示了正常表达PTEN（一种重要的肿瘤抑制因子）的人和小鼠的肿瘤细胞在传播到脑部后丢失PTEN的表达，但是传播到其他器官后不会。在转移到脑后丢失PTEN的肿瘤细胞在离开脑部微环境后PTEN的表达水平会得到恢复。这种脑微环境依赖的、可逆的PTEN mRNA和蛋白下调是有脑部星型胶质细胞来源的microRNAs调控的。星型胶质细胞来源的exosome介导了与转移肿瘤细胞之间的靶向PTEN的microRNAs的传递。体内实验证明，星型胶质细胞特异性敲除靶向PTEN的microRNAs或者阻断星型胶质细胞分泌exosome可恢复PTEN并抑制脑部的转移。此外，这种适应性脑转移肿瘤细胞的PTEN丢失导致趋化因子CCL2分泌的增加，招募表达IBA1表达的骨髓来源的细胞，从而通过增加繁殖和抑制凋亡来相互促进脑转移肿瘤细胞的生长。该研究揭示了转移肿瘤细胞的PTEN表达对不同器官微环境的显著可塑性，为转移细胞与其微环境的在适应性转移生长的过程中相互影响的重要作用提供了重要的证据。该研究发现阐明了肿瘤细胞与转移微环境的动态、相互的交流的新机制，更重要的是，为抑制肿瘤转移，尤其是脑转移提供了新的策略。
通讯作者余棣华网页：http://faculty.mdanderson.org/Dihua_Yu/Default.asp?SNID=2010740509
原文来源：Zhang, L., et al. (2015). Microenvironment-inducedPTEN loss by exosomal microRNA primes brain metastasis outgrowth. Nature. 2015, 527,100–104.
Abstract: 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 sites. Cancer cells of common origin manifest distinct gene expression patterns after metastasizing to different organs. Clearly, the dynamic interaction between metastatic tumour cells and extrinsic signals at individual metastatic organ sites critically effects the subsequent metastatic outgrowth. 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 ofPTEN, 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 andprotein downregulation is epigenetically regulated by microRNAs from brainastrocytes. 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 reducedapoptosis. Our findings demonstrate a remarkable plasticity of PTEN expressionin 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 signifythe dynamic and reciprocal cross-talk between tumour cells and the metastaticniche; importantly, they provide new opportunities for effective anti-metastasis therapies, especially of consequence for brain metastasis patients.
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