生物
Wnt信号通路
衰老
PLD2型
癌变
肿瘤微环境
细胞生物学
癌症研究
磷脂酶D
癌细胞
癌症
癌症干细胞
溶血磷脂酸
磷脂酸
干细胞
信号转导
磷脂
生物化学
遗传学
受体
膜
作者
Sandra Muñoz-Galván,Antonio Lucena-Cacace,Manuel Pérez,Daniel Otero-Albiol,Julián Gómez-Cambronero,Amancio Carnero
出处
期刊:Oncogene
[Springer Nature]
日期:2018-10-10
卷期号:38 (8): 1309-1323
被引量:34
标识
DOI:10.1038/s41388-018-0527-2
摘要
Cancer cells are in continuous communication with the surrounding microenvironment and this communication can affect tumor evolution. In this work, we show that phospholipase D2 (PLD2) was overexpressed in colon tumors and is secreted by cancer cells, inducing senescence in neighboring fibroblasts. This occurs through its lipase domain. Senescence induced by its product, phosphatidic acid, leads to a senescence-associated secretory phenotype (SASP) able to increase the stem properties of cancer cells. This increase in stemness occurs by Wnt pathway activacion. This closes a feedback loop in which senescence acts as a crosspoint for the generation of CSCs mediated by phospholipid metabolism. We also demonstrate the connexion of both phenomena in mouse models in vivo showing that a high PLD2 expression increased stemness and tumorigenesis. Thus, the patients with colon cancer show high levels of PLD2 and SASP factor genes expression correlating with Wnt pathway activation. Therefore, we demonstrate that tumor cell-secreted PLD2 contributes to tumor development by modifying the microenvironment, making it a possible therapeutic target for cancer treatment. This mechanism may also explain the high levels of Wnt pathway activation in colon cancer.
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