Molecular Profiling of Direct Xenograft Tumors Established from Human Pancreatic Adenocarcinoma After Neoadjuvant Therapy

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• 作者：Michael P. Kim MD (1) (2)
  Mark J. Truty MD (1)
  Woonyoung Choi PhD (2)
  Ya’an Kang MD (1)
  Xavier Chopin-Lally MD (1)
  Gary E. Gallick PhD (3)
  Huamin Wang MD (4)
  David J. McConkey PhD (2)
  Rosa Hwang MD (1)
  Craig Logsdon PhD (2)
  James Abbruzzesse MD (5)
  Jason B. Fleming MD (1)
  
• 刊名：Annals of Surgical Oncology
• 出版年：2012
• 出版时间：July 2012
• 年：2012
• 卷：19
• 期：3-supp
• 页码：395-403
• 全文大小：862KB
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• 作者单位：Michael P. Kim MD (1) (2)
  Mark J. Truty MD (1)
  Woonyoung Choi PhD (2)
  Ya’an Kang MD (1)
  Xavier Chopin-Lally MD (1)
  Gary E. Gallick PhD (3)
  Huamin Wang MD (4)
  David J. McConkey PhD (2)
  Rosa Hwang MD (1)
  Craig Logsdon PhD (2)
  James Abbruzzesse MD (5)
  Jason B. Fleming MD (1)
  
  1. Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
  2. Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
  3. Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
  4. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
  5. Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
  

文摘

Background Pancreatic adenocarcinoma is among the most resistant of human cancers, yet specific mechanisms of treatment resistance remain poorly understood. Models to study pancreatic cancer resistance remain limited and should reflect in vivo changes that occur within patient tumors. We sought to identify consistent, differentially expressed genes between treatment of naive pancreatic tumors and those exposed to neoadjuvant therapy using a strict, in vivo direct xenograft model system. Methods Over a 42-week period, 12 untreated and treated patient tumors were successfully engrafted into NOD/SCID mice. RNA from each treatment group (5 untreated and 4 treated) was isolated in triplicate and subjected to global gene expression analysis. Consistent gene expression changes with treatment were identified and confirmed using RT-PCR and immunohistochemistry. Results Engraftment of untreated patient tumors was more frequent than treated tumors (17 of 21 versus 16 of 49, P?=?.0002) but without differences in observed time until tumor formation. The histology of patient tumors was recapitulated in direct xenograft tumors. Relative to untreated tumors, treated tumors consistently demonstrated more than a 2-fold reduction in TGFβ-R2 mRNA expression and more than a 5-fold increase in IGFBP3 expression (P?<?.0218) and were confirmed by immunohistochemistry. Conclusion Engraftment of human pancreatic tumors into immunodeficient mice prior to and following neoadjuvant therapy is possible and provides an in vivo platform for comparison of global gene expression patterns. The decreased TGFβ-R2 expression and increased IGFBP3 expression among direct xenograft tumors derived from treated tumors relative to untreated tumors suggests a role in therapy resistance and warrants further study.