科學家發(fā)現(xiàn),，細胞信號分子Akt是皮膚表面的惡性黑色素瘤開始垂直向下生長,，并且變成致命的轉移性癌癥的主要誘發(fā)因子。
一旦了解不同階段的黑色素瘤之Akt分子的差異,，就可以研發(fā)出新的藥物,，以治療末期的黑色素瘤。
根據(jù)美國癌癥協(xié)會的數(shù)據(jù)顯示,，還未轉移到皮膚下的黑色素瘤可經由外科手術切除,，且患者五年存活率高達百分之98,。但是當黑色素瘤向下生長，腫瘤對于化療及放射線治療具有高度抵抗性,，如果疾病轉移到淋巴結,，五年存活率迅速地下降至百分之64，若是轉移到其它器官,，則只剩下百分之16,。
當科學家將Akt基因引入輻射狀生長的黑色素瘤細胞，細胞表現(xiàn)的生長因子蛋白質VEGF的量高達八倍,。已知VEGF是血管新生的強力刺激劑,，可以使得供應腫瘤養(yǎng)分的血管生長。
此外,，當過度表現(xiàn)Akt的黑色素瘤細胞引入不具免疫力的裸鼠體內,，小鼠便發(fā)生表現(xiàn)大量VEGF 的惡性腫瘤，但是控制組的小鼠并未長出腫瘤,。
這項研究是由Emory 大學醫(yī)學院皮膚學科的研究人員發(fā)表,，將刊載于3月號的Journal of Clinical Investigation中。
(資料來源 : 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 disease and metastasis. We have previously shown that p42/p44 MAP kinase is activated in radial growth melanoma, suggesting that further signaling events are required for vertical growth melanoma. The molecular events that accompany this transformation are not well understood. Akt, a signaling molecule downstream of PI3K, was introduced into the radial growth WM35 melanoma in order to test whether Akt overexpression is sufficient to accomplish this transformation. Overexpression of Akt led to upregulation of VEGF, increased production of superoxide ROS, and the switch to a more pronounced glycolytic metabolism. Subcutaneous implantation of WM35 cells overexpressing Akt led to rapidly growing tumors in vivo, while vector control cells did not form tumors. We demonstrated that Akt was associated with malignant transformation of melanoma through at least 2 mechanisms. First, Akt may stabilize cells with extensive mitochondrial DNA mutation, which can generate ROS. Second, Akt can induce expression of the ROS-generating enzyme NOX4. Akt thus serves as a molecular switch that increases angiogenesis and the generation of superoxide, fostering more aggressive tumor behavior. Targeting Akt and ROS may be of therapeutic importance in treatment of advanced melanoma.
