title: Connective tissue growth factor-specific monoclonal antibody therapy inhibits pancreatic tumor growth and metastasis.
abstract: Pancreatic cancer is highly aggressive and refractory to most existing therapies. Past studies have shown that connective tissue growth factor (CTGF) expression is elevated in human pancreatic adenocarcinomas and some pancreatic cancer cell lines. To address whether and how CTGF influences tumor growth, we generated pancreatic tumor cell lines that overexpress different levels of human CTGF. The effect of CTGF overexpression on cell proliferation was measured in vitro in monolayer culture, suspension culture, or soft agar, and in vivo in tumor xenografts. Although there was no effect of CTGF expression on proliferation in two-dimensional cultures, anchorage-independent growth (AIG) was enhanced. The capacity of CTGF to enhance AIG in vitro was linked to enhanced pancreatic tumor growth in vivo when these cells were implanted s.c. in nude mice. Administration of a neutralizing CTGF-specific monoclonal antibody, FG-3019, had no effect on monolayer cell proliferation, but blocked AIG in soft agar. Consistent with this observation, anti-CTGF treatment of mice bearing established CTGF-expressing tumors abrogated CTGF-dependent tumor growth and inhibited lymph node metastases without any toxicity observed in normal tissue. Together, these studies implicate CTGF as a new target in pancreatic cancer and suggest that inhibition of CTGF with a human monoclonal antibody may control primary and metastatic tumor growth.
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Nadja
authors.initials: N
authors.lastname: Dornhöfer
authors.forename: Suzanne
authors.initials: S
authors.lastname: Spong
authors.forename: Kevin
authors.initials: K
authors.lastname: Bennewith
authors.forename: Ali
authors.initials: A
authors.lastname: Salim
authors.forename: Stephen
authors.initials: S
authors.lastname: Klaus
authors.forename: Neeraja
authors.initials: N
authors.lastname: Kambham
authors.forename: Carol
authors.initials: C
authors.lastname: Wong
authors.forename: Fiona
authors.initials: F
authors.lastname: Kaper
authors.forename: Patrick
authors.initials: P
authors.lastname: Sutphin
authors.forename: Randall
authors.initials: R
authors.lastname: Nacamuli
authors.forename: Rendall
authors.initials: R
authors.lastname: Nacalumi
authors.forename: Michael
authors.initials: M
authors.lastname: Höckel
authors.forename: Quynh
authors.initials: Q
authors.lastname: Le
authors.forename: Michael
authors.initials: M
authors.lastname: Longaker
authors.forename: George
authors.initials: G
authors.lastname: Yang
authors.forename: Albert
authors.initials: A
authors.lastname: Koong
authors.forename: Amato
authors.initials: A
authors.lastname: Giaccia
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D000918:Antibody Specificity; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D055513:Connective Tissue Growth Factor; D006801:Humans; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000276:immunology*; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000276:immunology*; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; C526317:CCN2 protein, human; C526318:CCN2 protein, mouse; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D055513:Connective Tissue Growth Factor