The combinatorial activation of the PI3K and Ras/MAPK pathways is sufficient for aggressive tumor formation, while individual pathway activation supports cell persistence.
The combinatorial activation of the PI3K and Ras/MAPK pathways is sufficient for aggressive tumor formation, while individual pathway activation supports cell persistence.
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DOI：
10.18632/oncotarget.6159
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发表时间：
2015-11-03
期刊：
影响因子：
--
通讯作者：
Vitolo MI
中科院分区：
文献类型：
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作者：
Thompson KN;Whipple RA;Yoon JR;Lipsky M;Charpentier MS;Boggs AE;Chakrabarti KR;Bhandary L;Hessler LK;Martin SS;Vitolo MI
高比例的人类肿瘤维持PI 3 K和Ras/MAPK途径两者的活化。在基底样乳腺癌（BBC）中，超过50%的病例中PTEN表达降低/丢失，导致PI 3 K通路的异常激活。此外，BBC细胞系和肿瘤模型已显示出致癌Ras样基因转录特征，表明Ras/MAPK途径的激活。为了直接测试PI 3 K和Ras/MAPK通路如何促进肿瘤发生，我们在非致瘤性MCF-10A乳腺细胞内删除了PTEN并激活了KRas。两种单独的突变都不足以促进肿瘤发生，但组合促进了小鼠肿瘤的稳健生长。然而，在体内生物发光显示，每个突变有能力促进一个持久的表型。肿瘤细胞休眠是一个存在残留疾病但仍无症状的阶段，具有每个个体突变的活细胞在潜伏期内可以在体内持续存在。从小鼠中切除持久性细胞，与积极生长的PTEN−/−KRAS（G12 V）细胞相比，细胞周期阻滞蛋白p21和p27的水平增加。此外，当这些持久性细胞被置于生长促进条件下时，它们能够重新进入细胞周期并增殖。这些结果突出了PTEN缺失或KRAS激活促进体内细胞存活的潜力，以及组合突变产生快速肿瘤生长的独特能力。这可能对确定这些突变常见的肿瘤亚型的复发风险和疾病进展具有重要意义。
A high proportion of human tumors maintain activation of both the PI3K and Ras/MAPK pathways. In basal-like breast cancer (BBC), PTEN expression is decreased/lost in over 50% of cases, leading to aberrant activation of the PI3K pathway. Additionally, BBC cell lines and tumor models have been shown to exhibit an oncogenic Ras-like gene transcriptional signature, indicating activation of the Ras/MAPK pathway. To directly test how the PI3K and Ras/MAPK pathways contribute to tumorigenesis, we deleted PTEN and activated KRas within non-tumorigenic MCF-10A breast cells. Neither individual mutation was sufficient to promote tumorigenesis, but the combination promoted robust tumor growth in mice. However, in vivo bioluminescence reveals that each mutation has the ability to promote a persistent phenotype. Inherent in the concept of tumor cell dormancy, a stage in which residual disease is present but remains asymptomatic, viable cells with each individual mutation can persist in vivo during a period of latency. The persistent cells were excised from the mice and showed increased levels of the cell cycle arrest proteins p21 and p27 compared to the aggressively growing PTEN−/−KRAS(G12V) cells. Additionally, when these persistent cells were placed into growth-promoting conditions, they were able to re-enter the cell cycle and proliferate. These results highlight the potential for either PTEN loss or KRAS activation to promote cell survival in vivo, and the unique ability of the combined mutations to yield rapid tumor growth. This could have important implications in determining recurrence risk and disease progression in tumor subtypes where these mutations are common.