title: Humanized anti-hepatocyte growth factor (HGF) antibody suppresses innate irinotecan (CPT-11) resistance induced by fibroblast-derived HGF.
abstract: The growth factors derived from the microenvironment create an environment conducive to tumor growth and survival. HGF deprivation using neutralizing antibody enhanced chemosensitivity in colorectal cancer cells (CRC). We determined secreted HGF in fibroblast conditioned medium (CM). Combination treatment of anti-HGF antibody and irinotecan (CPT-11) directly enhanced CPT-11 sensitivity in CRC. We generated xenograft in NOD/SCID mice inoculating HCT-116 human colorectal cancer cells subcutaneously with or without fibroblast. We found that the combination of CPT-11 and anti-HGF antibody induced marked suppression of tumor development. These results suggest that HGF produced by fibroblast induce CPT-11 resistance, and that anti-HGF antibody abrogate such resistance in vivo. fibroblast-derived HGF is important determinant of chemoresistance. Anti-HGF monoclonal antibody treatment confirmed the importance of this growth factor for chemoresistance in CRC. These results present new options toward the early diagnosis of chemoresistance and suggest novel combinations of chemotherapy and anti-HGF agents to prevent or significantly delay the onset of therapy resistance.
authors.affiliation: College of Pharmacy, Gachon University, Incheon, Republic of Korea.
authors.forename: Jong Kyu
authors.initials: JK
authors.lastname: Woo
authors.affiliation: National Cancer Center, Goyang, Republic of Korea.
authors.forename: Ju-Hee
authors.initials: JH
authors.lastname: Kang
authors.affiliation: National Cancer Center, Goyang, Republic of Korea.
authors.forename: BoRa
authors.initials: B
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Gachon University, Incheon, Republic of Korea.
authors.forename: Byung Hee
authors.initials: BH
authors.lastname: Park
authors.affiliation: iBio, Inc., Seoul, Republic of Korea.
authors.forename: Kum-Joo
authors.initials: KJ
authors.lastname: Shin
authors.affiliation: Yooyoung Pharmaceutical Co., Seoul, Republic of Korea.
authors.forename: Seong-Won
authors.initials: SW
authors.lastname: Song
authors.affiliation: Yooyoung Pharmaceutical Co., Seoul, Republic of Korea.
authors.forename: Jung Ju
authors.initials: JJ
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Gachon University, Incheon, Republic of Korea.
authors.forename: Hwan-Mook
authors.initials: HM
authors.lastname: Kim
authors.affiliation: National Cancer Center, Goyang, Republic of Korea.
authors.forename: Sang-Jin
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Gachon University, Incheon, Republic of Korea.
authors.forename: Seung Hyun
authors.initials: SH
authors.lastname: Oh
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D017209:Apoptosis / Q000502:physiology; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D017077:Culture Media, Conditioned / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004789:Enzyme Activation; D005347:Fibroblasts / Q000378:metabolism; D045325:HCT116 Cells; D019073:HT29 Cells; D017228:Hepatocyte Growth Factor / Q000276:immunology*; D006801:Humans; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000188:drug therapy; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D017077:Culture Media, Conditioned; C066855:HGF protein, human; D017228:Hepatocyte Growth Factor; D000077146:Irinotecan; D019859:Proto-Oncogene Proteins c-met; D002166:Camptothecin
keywords: chemoresistance; colorectal cancer; hepatocyte growth factor (HGF); irinotecan (CPT-11); microenvironment