JCI：早期和末期黑色素瘤的分子差异有助于研发新药

生物谷

科学家发现，细胞信号分子Akt是皮肤表面的恶性黑色素瘤开始垂直向下生长，并且变成致命的转移性癌症的主要诱发因子。

一旦了解不同阶段的黑色素瘤之Akt分子的差异，就可以研发出新的药物，以治疗末期的黑色素瘤。

根据美国癌症协会的数据显示，还未转移到皮肤下的黑色素瘤可经由外科手术切除，且患者五年存活率高达百分之98。但是当黑色素瘤向下生长，肿瘤对于化疗及放射线治疗具有高度抵抗性，如果疾病转移到淋巴结，五年存活率迅速地下降至百分之64，若是转移到其它器官，则只剩下百分之16。

当科学家将Akt基因引入辐射状生长的黑色素瘤细胞，细胞表现的生长因子蛋白质VEGF的量高达八倍。已知VEGF是血管新生的强力刺激剂，可以使得供应肿瘤养分的血管生长。

此外，当过度表现Akt的黑色素瘤细胞引入不具免疫力的裸鼠体内，小鼠便发生表现大量VEGF 的恶性肿瘤，但是控制组的小鼠并未长出肿瘤。

这项研究是由Emory 大学医学院皮肤学科的研究人员发表，将刊载于3月号的Journal of Clinical Investigation中。

(资料来源 : Bio.com)

部分英文原文：

Overexpression of Akt converts radial growth melanoma to vertical growth melanoma

Baskaran Govindarajan1, James E. Sligh2, Bethaney J. Vincent2, Meiling Li2, Jeffrey A. Canter2, Brian J. Nickoloff3, Richard J. Rodenburg4, Jan A. Smeitink4, Larry Oberley5, Yuping Zhang5, Joyce Slingerland6, Rebecca S. Arnold7, J. David Lambeth7, Cynthia Cohen7, Lu Hilenski8, Kathy Griendling8, Marta Martínez-Diez9, José M. Cuezva9 and Jack L. Arbiser1

1Department of Dermatology, Emory University School of Medicine, and Atlanta Veterans Administration Medical Center, Atlanta, Georgia, USA. 2Division of Dermatology and Center for Human Genetics Research, Vanderbilt University Medical Center and VA Tennessee Valley Healthcare System, Nashville, Tennessee, USA. 3Cardinal Bernardin Cancer Center, Loyola University Health System, Chicago, Illinois, USA. 4Nijmegen Centre for Mitochondrial Disorders, Department of Paediatrics, Radboud University Medical Centre Nijmegen, Nijmegen, The Netherlands. 5Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa, Iowa City, Iowa, USA. 6Department of Medicine, University of Miami Leonard M. Miller School of Medicine, Miami, Florida, USA. 7Department of Pathology and Laboratory Medicine and 8Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia, USA. 9Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid, Madrid, Spain.

Abstract

Melanoma is the cancer with the highest increase in incidence,and transformation of radial growth to vertical growth (i.e.,noninvasive to invasive) melanoma is required for invasive diseaseand metastasis. We have previously shown that p42/p44 MAP kinaseis activated in radial growth melanoma, suggesting that furthersignaling events are required for vertical growth melanoma.The molecular events that accompany this transformation arenot well understood. Akt, a signaling molecule downstream ofPI3K, was introduced into the radial growth WM35 melanoma inorder to test whether Akt overexpression is sufficient to accomplishthis transformation. Overexpression of Akt led to upregulationof VEGF, increased production of superoxide ROS, and the switchto a more pronounced glycolytic metabolism. Subcutaneous implantationof WM35 cells overexpressing Akt led to rapidly growing tumorsin vivo, while vector control cells did not form tumors. Wedemonstrated that Akt was associated with malignant transformationof melanoma through at least 2 mechanisms. First, Akt may stabilizecells with extensive mitochondrial DNA mutation, which can generateROS. Second, Akt can induce expression of the ROS-generatingenzyme NOX4. Akt thus serves as a molecular switch that increasesangiogenesis and the generation of superoxide, fostering moreaggressive tumor behavior. Targeting Akt and ROS may be of therapeuticimportance in treatment of advanced melanoma.