title: Combining molecular targeted drugs to inhibit both cancer cells and activated stromal cells in gastric cancer.
abstract: Recent studies have revealed that PDGF plays a role in promoting progressive tumor growth in several cancers, including gastric cancer. Cancer-associated fibroblasts, pericytes, and lymphatic endothelial cells in stroma express high levels of PDGF receptor (PDGF-R); cancer cells and vascular endothelial cells do not. Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that increases the production of proteins that stimulate key cellular processes such as cell growth and proliferation, cell metabolism, and angiogenesis. In the present study, we examined the effects of PDGF-R tyrosine kinase inhibitor (nilotinib) and mTOR inhibitor (everolimus) on tumor stroma in an orthotopic nude mice model of human gastric cancer. Expression of PDGF-B and PDGF-Rβ mRNAs was associated with stromal volume. Treatment with nilotinib did not suppress tumor growth but significantly decreased stromal reactivity, lymphatic invasion, lymphatic vessel area, and pericyte coverage of tumor microvessels. In contrast, treatment with everolimus decreased tumor growth and microvessel density but not stromal reactivity. Nilotinib and everolimus in combination reduced both the growth rate and stromal reaction. Target molecule-based inhibition of cancer-stromal cell interaction appears promising as an effective antitumor therapy.
authors.affiliation: Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Mieko
authors.initials: M
authors.lastname: Onoyama
authors.affiliation: Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Kitadai
authors.affiliation: Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Yuge
authors.affiliation: Department of Endoscopy, Hiroshima University Hospital, Hiroshima, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Shinagawa
authors.affiliation: Department of Endoscopy, Hiroshima University Hospital, Hiroshima, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Tanaka
authors.affiliation: Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Yasui
authors.affiliation: Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Chayama
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004357:Drug Synergism; D000068338:Everolimus; D005260:Female; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017154:Stromal Cells / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D020574:Proto-Oncogene Proteins c-sis; D011743:Pyrimidines; D000068338:Everolimus; C546842:MTOR protein, human; D020797:Receptor, Platelet-Derived Growth Factor beta; D058570:TOR Serine-Threonine Kinases; C498826:nilotinib; D020123:Sirolimus