Tissue microarrays of human tumor xenografts: characterization of proteins involved in migration and angiogenesis for applications in the development of targeted anticancer agents.
As new target-directed anticancer agents emerge, preclinical efficacy studies need to integrate target-driven model systems. This approach to drug development requires rapid and reliable characterization of the new targets in established tumor models, such as xenografts and cell lines. Here, we have applied tissue microarray technology to patient-derived, re-growable human tumor xenografts. We have profiled the expression of five proteins involved in cell migration and/or angiogenesis: vascular endothelial growth factor (VEGF), matrix metalloproteinase 1 (MMP1), protease activated receptor (PAR1), cathepsin B, and beta1 integrin in a panel of over 150 tumors and compared their expression levels to available patient outcome data. For each protein, several target overexpressing xenografts were identified. They represent a subset of tumor models prone to respond to specific inhibitors and are available for future preclinical efficacy trials. In a "proof of concept" experiment, we have employed tissue microarrays to select in vivo models for therapy and for the analysis of molecular changes occurring after treatment with the anti-VEGF antibody HuMV833 and gemcitabine. Whereas the less angiogenic pancreatic cancer PAXF736 model proved to be resistant, the highly vascularized PAXF546 xenograft responded to therapy. Parallel analysis of arrayed biopsies from the different treatment groups revealed a down-regulation of Ki-67 and VEGF, an altered tissue morphology, and a decreased vessel density. Our results demonstrate the multiple advantages of xenograft tissue microarrays for preclinical drug development.
Smith
Victoria
V
Institute for Experimental Oncology, Oncotest GmbH, Freiburg, Germany.
Wirth
Gregory J
GJ
Fiebig
Heinz-Herbert
HH
Burger
Angelika M
AM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D002401:Cathepsin B / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics*; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism; D020781:Matrix Metalloproteinase 1 / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000235:genetics*; D009389:Neovascularization, Pathologic / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000235:genetics*; D044463:Receptor, PAR-1 / Q000235:genetics; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors; D046888:Tissue Array Analysis / Q000379:methods*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000964:Antimetabolites, Antineoplastic; D019012:Integrin beta1; C466953:MV833 monoclonal antibody, human; D009363:Neoplasm Proteins; D044463:Receptor, PAR-1; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D003841:Deoxycytidine; D012264:Ribonucleotide Reductases; D002401:Cathepsin B; D020781:Matrix Metalloproteinase 1; D000093542:Gemcitabine