结直肠癌
转移
克拉斯
癌症研究
CXCR4型
癌症
医学
生物
内科学
受体
趋化因子
作者
Jelena Urosevic,Maria Blasco,Alicia Llorente Lope,Anna Bellmunt,Antonio Berenguer,Marc Guiu,Adrià Cañellas‐Socias,Esther Fernández,Ivan Burkov,Maria Clapés,Mireia Cartanà,Cristina Figueras-Puig,Eduard Batlle,Ángel R. Nebreda,Roger R. Gomis
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2020-08-19
卷期号:80 (21): 4668-4680
被引量:44
标识
DOI:10.1158/0008-5472.can-19-4028
摘要
Carcinoma development in colorectal cancer is driven by genetic alterations in numerous signaling pathways. Alterations in the RAS-ERK1/2 pathway are associated with the shortest overall survival for patients after diagnosis of colorectal cancer metastatic disease, yet how RAS-ERK signaling regulates colorectal cancer metastasis remains unknown. In this study, we used an unbiased screening approach based on selection of highly liver metastatic colorectal cancer cells in vivo to determine genes associated with metastasis. From this, an ERK1/2-controlled metastatic gene set (EMGS) was defined. EMGS was associated with increased recurrence and reduced survival in patients with colorectal cancer tumors. Higher levels of EMGS expression were detected in the colorectal cancer subsets consensus molecular subtype (CMS)1 and CMS4. ANGPT2 and CXCR4, two genes within the EMGS, were subjected to gain-of-function and loss-of-function studies in several colorectal cancer cell lines and then tested in clinical samples. The RAS-ERK1/2 axis controlled expression of the cytokine ANGPT2 and the cytokine receptor CXCR4 in colorectal cancer cells, which facilitated development of liver but not lung metastases, suggesting that ANGPT2 and CXCR4 are important for metastatic outgrowth in the liver. CXCR4 controlled the expression of cytokines IL10 and CXCL1, providing evidence for a causal role of IL10 in supporting liver colonization. In summary, these studies demonstrate that amplification of ERK1/2 signaling in KRAS-mutated colorectal cancer cells affects the cytokine milieu of the tumors, possibly affecting tumor-stroma interactions and favoring liver metastasis formation. SIGNIFICANCE: These findings identify amplified ERK1/2 signaling in KRAS-mutated colorectal cancer cells as a driver of tumor-stroma interactions that favor formation of metastases in the liver.
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