Cancer Research：胰腺肿瘤生长的蛋白质

美国斯坦福大学医学院研究人员日前发现一种对胰腺癌生长至关重要的蛋白质，抑制这种蛋白质的表达可以显著放缓甚至阻止胰腺肿瘤的生长。
这种蛋白质名为CCN2，是一种结缔组织生长因子。研究人员将CCN2表达水平各异的人类胰腺癌细胞注入不同实验鼠的皮下后发现，CCN2表达水平较高的胰腺癌细胞生长迅速，而CCN2表达被抑制的胰腺癌细胞基本不能在实验鼠体内生成肿瘤。
研究人员还发现，CCN2表达水平较高的癌细胞比表达水平低的癌细胞生长和转移速度都快，注射前种癌细胞的实验鼠很快就不治而死。
研究人员说，实体胰腺肿瘤常常会面对缺氧状况，此时肿瘤细胞会通过一系列信号来调节多种基因并促进肿瘤血管生成，使肿瘤细胞在适应缺氧微环境的同时，引起肿瘤自身的侵袭性增加以及对放射治疗的抵抗性增加。研究人员推测，CCN2可能在这一过程中发挥了重要作用。
研究人员表示，他们希望利用这项成果开发出治疗人类胰腺癌的新方法。这一成果已刊登在最新一期美国《癌症研究》杂志上。（生物谷Bioon.com）
生物谷推荐原始出处：
Cancer Research 69, 775-784, February 1, 2009. doi: 10.1158/0008-5472.CAN-08-0987
The Role of Tumor Cell–Derived Connective Tissue Growth Factor (CTGF/CCN2) in Pancreatic Tumor Growth
Kevin L. Bennewith1, Xin Huang1, Christine M. Ham1,2, Edward E. Graves1, Janine T. Erler1, Neeraja Kambham3, Jonathan Feazell1, George P. Yang2, Albert Koong1 and Amato J. Giaccia1
Departments of 1 Radiation Oncology, 2 Surgery, and 3 Pathology, Stanford University School of Medicine, Stanford, California
Pancreatic cancer is highly aggressive and refractory to existing therapies. Connective tissue growth factor (CTGF/CCN2) is a fibrosis-related gene that is thought to play a role in pancreatic tumor progression. However, CCN2 can be expressed in a variety of cell types, and the contribution of CCN2 derived from either tumor cells or stromal cells as it affects the growth of pancreatic tumors is unknown. Using genetic inhibition of CCN2, we have discovered that CCN2 derived from tumor cells is a critical regulator of pancreatic tumor growth. Pancreatic tumor cells derived from CCN2 shRNA–expressing clones showed dramatically reduced growth in soft agar and when implanted s.c. We also observed a role for CCN2 in the growth of pancreatic tumors implanted orthotopically, with tumor volume measurements obtained by positron emission tomography imaging. Mechanistically, CCN2 protects cells from hypoxia-mediated apoptosis, providing an in vivo selection for tumor cells that express high levels of CCN2. We found that CCN2 expression and secretion was increased in hypoxic pancreatic tumor cells in vitro, and we observed colocalization of CCN2 and hypoxia in pancreatic tumor xenografts and clinical pancreatic adenocarcinomas. Furthermore, we found increased CCN2 staining in clinical pancreatic tumor tissue relative to stromal cells surrounding the tumor, supporting our assertion that tumor cell–derived CCN2 is important for pancreatic tumor growth. Taken together, these data improve our understanding of the mechanisms responsible for pancreatic tumor growth and progression, and also indicate that CCN2 produced by tumor cells represents a viable therapeutic target for the treatment of pancreatic cancer.