院士《Science》癌细胞偏爱什么环境？

　　

生物通报道，Luding癌症研究中心，霍华休斯医学研究所，德州大学西南分校医学中心的研究者在最新的Science上发表细胞癌变的研究成果，Glucose Deprivation Contributes to the Development of KRAS Pathway Mutations in Tumor Cells。

 

肿瘤发生是个极其复杂的过程，当中牵涉多种基因多种转录因子，以及一些表观遗传学的突变。世人却忽视了细胞外在的环境变化，究竟是哪种外在的变化会激起细胞发生深刻的变化，导致癌变？

 

霍华休斯医学院教授，美国科学院院士Bert Vogelstein首次剖析细胞癌变的外环境的选择机制。相关成果文章发表在Science杂志上，文章通讯作者就是院士Bert Vogelstein。

 

研究发现，结肠癌和直肠癌细胞常常伴随KRAS或BRAF的突变，深入分析发现，两个基因变异的过程中伴随GLUT1的高表达，GLUT1是编码葡萄糖转换子1的基因。发生癌变的细胞中GLUT1都表现出GLUT1的高表达。癌变细胞对葡萄糖的摄入升高，并且葡萄糖的酵解也加速，这些癌细胞适应存活在这种低糖环境下。

 

这些研究数据表明，葡萄糖缺乏是促使KRAS信号通路变异的外在环境，肿瘤细胞就在这样的环境中滋生。

（生物通 小茜）

生物通推荐原文检索

Glucose Deprivation Contributes to the Development of KRAS Pathway Mutations in Tumor Cells

Jihye Yun 1, Carlo Rago 1, Ian Cheong 1, Ray Pagliarini 2, Philipp Angenendt 1, Harith Rajagopalan 3, Kerstin Schmidt 1, James K. V. Wilson 4, Sandy Markowitz 5, Shibin Zhou 1, Luis A. Diaz Jr.1, Victor Velculescu 1, Christoph Lengauer 6, Kenneth W. Kinzler 1, Bert Vogelstein 1*, Nickolas Papadopoulos 1

1 The Ludwig Center for Cancer Genetics and Therapeutics and The Howard Hughes Medical Institute at the Johns Hopkins Kimmel Cancer Center, Batimore, MD 21231, USA.

2 The Ludwig Center for Cancer Genetics and Therapeutics and The Howard Hughes Medical Institute at the Johns Hopkins Kimmel Cancer Center, Batimore, MD 21231, USA. ; Present address: Novartis Institute for Biomedical Research, Cambridge, MA 02139, USA.

3 The Ludwig Center for Cancer Genetics and Therapeutics and The Howard Hughes Medical Institute at the Johns Hopkins Kimmel Cancer Center, Batimore, MD 21231, USA.; Present address: Cardiovascular Medicine Brigham and Women’s Hospital, Boston, MA 02115, USA.

4 Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

5 Department of Medicine and Ireland Cancer Center, Case Western Reserve University and Case Medical Center of University Hospitals of Cleveland and Howard Hughes Medical Institute, Cleveland, OH 44106, USA.

6 The Ludwig Center for Cancer Genetics and Therapeutics and The Howard Hughes Medical Institute at the Johns Hopkins Kimmel Cancer Center, Batimore, MD 21231, USA.; Present address: Sanofi-Aventis, 13 Quai Jules Guesde, 94400 Vitry-sur-Seine, France.

 

 

【Abstract】

Tumor progression is driven by genetic mutations, but little is known about the environmental conditions that select for these mutations. Studying the transcriptomes of paired colorectal cancer cell lines that differed only in the mutational status of their KRAS or BRAF genes, we found that GLUT1, encoding glucose transporter-1, was one of three genes consistently upregulated in cells with KRAS or BRAF mutations. The mutant cells exhibited enhanced glucose uptake and glycolysis and survived in low glucose conditions, phenotypes that all required GLUT1 expression. In contrast, when cells with wild-type KRAS alleles were subjected to a low glucose environment, very few cells survived. Most surviving cells expressed high levels of GLUT1, and 4% of these survivors had acquired new KRAS mutations. The glycolysis inhibitor 3-bromopyruvate preferentially suppressed the growth of cells with KRAS or BRAF mutations. Together, these data suggest that glucose deprivation can drive the acquisition of KRAS pathway mutations in human tumors