title: [EGFR-blockade by antibody Cetuximab inhibits the growth of human gastric cancer xenograft in nude mice and its possible mechanism].
abstract: OBJECTIVE
  EGFR-mediated tumor proliferation plays an important role in the development of cancer, and is a key candidate for targeted therapy. The aim of this study is to evaluate the impact of EGFR monoclonal antibody Cetuximab (C225) on the growth, proliferation and apoptsis of gastric cancer xenograft in nude mice, and its possible mechanisms.
  
  
  METHODS
  A gastric cancer cell line SGC-7901 with high EGFR expression level was screened from 7 gastric cancer cell lines. Gastric cancer xenografts in nude mice were established, and randomly divided into C225 treatment group and PBS control group. Tumor growth curves were calculated, the impact of C225 on the tumor growth, proliferation and angiogenesis was evaluated by immunohistochemical (IHC) staining Ki67 and CD34, respectively. The effect of C225 on apoptosis in the gastric cancer cells was evaluated by TUNEL assay. The expression levels of EGFR and its transcription factor Sp1 were detected by IHC staining and Western blot.
  
  
  RESULTS
  After C225 treatment, the proliferation and growth of gastric cancer xenograft in nude mice were significantly decreased. In the contrast, the apopotic indexes in C225 treatment group and PBS control group were (16.4% +/- 0.3%) and (3.1% +/- 0.9%), respectively, with a significant difference (P < 0.001). There was no significant difference of the densities of CD34-positive microvessels between C225 treatment group and control group. Elevated expression of EGFR and Sp1 after C225 treatment was observed by IHC staining and Western blot assay.
  
  
  CONCLUSIONS
  EGFR monoclonal antibody cetuximab (C225) can effectively inhibit the growth of gastric cancer xenografts in nude mice, and trigger its apoptosis. Yet, C225 treatment may upregulate the expression of EGFR and its transcription factor Sp1. A "block-transcription activation-compensation" mechanism may exist to explain the molecular mechanism of acquired resistance of a single target blockade treatment.
authors.affiliation: Division of Biotherapy & Targeted Therapy, Department of Surgery, Shanghai Institute of Digestive Surgery, Rui Jin Hospital, Shanghai Jiaotong University Medical School, Shanghai 200025, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.forename: Jun
authors.initials: J
authors.lastname: Ji
authors.forename: Fei
authors.initials: F
authors.lastname: Yuan
authors.forename: Tao
authors.initials: T
authors.lastname: Ma
authors.forename: Zheng-bao
authors.initials: ZB
authors.lastname: Ye
authors.forename: Ying-yan
authors.initials: YY
authors.lastname: Yu
authors.forename: Bing-ya
authors.initials: BY
authors.lastname: Liu
authors.forename: Zheng-gang
authors.initials: ZG
authors.lastname: Zhu
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D000068818:Cetuximab; D066246:ErbB Receptors / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D055806:Microvessels / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D011897:Random Allocation; D016329:Sp1 Transcription Factor / Q000378:metabolism; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D019394:Ki-67 Antigen; D016329:Sp1 Transcription Factor; D066246:ErbB Receptors; D000068818:Cetuximab