Holloway Shane, Davis Mishel, Jaber Raffat, Fleming Jason
Division of Surgical Oncology, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390-9155, USA.
Int J Gastrointest Cancer. 2003;33(1):61-9. doi: 10.1385/IJGC:33:1:61.
Genetic alterations impacting the TGF-beta/Smad4 pathway are found in nearly all pancreatic adenocarcinomas, and recent reports have identified a relationship between DPC4/Smad4 expression and patient survival. In this study we use a clinically relevant animal model of pancreatic cancer to examine the impact of these genetic changes on the biology of pancreatic cancer.
Using high-density oligonucleotide DNA microarray technology, a comprehensive examination of the components of the TGF-beta/Smad4 pathway was performed on three human pancreatic adenocarcinoma cell lines. The in vitro and in vivo growth characteristics of these cell lines was then compared. Finally, using a clinically relevant orthotopic xenograft model of pancreatic cancer, primary tumor growth and metastases were measured for pancreatic tumors derived from each cell line.
Examination of the TGF-beta/Smad4 pathway components identified that these three cell lines possess molecular profiles consistent with approximately 90% of pancreatic adenocarcinoma tumors in patients. A significant discrepancy between in vitro and in vivo growth characteristics of each cell line was identified. When tumors from each cell line were established in nu/nu mice, each cell line exhibited distinct metastatic profiles. Data from these studies is consistent, with clinical observations concerning DPC4/Smad4 and patient outcome.
Using an orthotopic model of tumor growth and metastasis identifies distinct metastatic profiles associated with molecular alterations of the TGF-beta/Smad4 pathway and provides insight with regard to the biologic consequences of these changes.
几乎在所有胰腺腺癌中都发现了影响转化生长因子-β/ Smad4信号通路的基因改变，最近的报告已经确定了DPC4/ Smad4表达与患者生存率之间的关系。在本研究中，我们使用一种临床相关的胰腺癌动物模型来研究这些基因变化对胰腺癌生物学特性的影响。
使用高密度寡核苷酸DNA微阵列技术，对三种人胰腺腺癌细胞系进行了转化生长因子-β/ Smad4信号通路成分的全面检测。然后比较了这些细胞系的体外和体内生长特性。最后，使用临床相关的胰腺癌原位异种移植模型，测量了源自每个细胞系的胰腺肿瘤的原发肿瘤生长和转移情况。
对转化生长因子-β/ Smad4信号通路成分的检测发现，这三种细胞系的分子特征与患者中约90%的胰腺腺癌肿瘤一致。每个细胞系的体外和体内生长特性之间存在显著差异。当将每个细胞系的肿瘤接种到裸鼠中时，每个细胞系都表现出不同的转移特征。这些研究的数据与关于DPC4/ Smad4和患者预后的临床观察结果一致。
使用肿瘤生长和转移的原位模型可确定与转化生长因子-β/ Smad4信号通路分子改变相关的不同转移特征，并为这些变化的生物学后果提供见解。
