title: Antibody-mediated blockade of integrin alpha v beta 6 inhibits tumor progression in vivo by a transforming growth factor-beta-regulated mechanism.
abstract: The alpha(v)beta(6) integrin is up-regulated on epithelial malignancies and has been implicated in various aspects of cancer progression. Immunohistochemical analysis of alpha(v)beta(6) expression in 10 human tumor types showed increased expression relative to normal tissues. Squamous carcinomas of the cervix, skin, esophagus, and head and neck exhibited the highest frequency of expression, with positive immunostaining in 92% (n = 46), 84% (n = 49), 68% (n = 56), and 64% (n = 100) of cases, respectively. We studied the role of alpha(v)beta(6) in Detroit 562 human pharyngeal carcinoma cells in vitro and in vivo. Prominent alpha(v)beta(6) expression was detected on tumor xenografts at the tumor-stroma interface resembling the expression on human head and neck carcinomas. Nonetheless, coculturing cells in vitro with matrix proteins did not up-regulate alpha(v)beta(6) expression. Detroit 562 cells showed alpha(v)beta(6)-dependent adhesion and activation of transforming growth factor-beta (TGF-beta) that was inhibited >90% with an alpha(v)beta(6) blocking antibody, 6.3G9. Although both recombinant soluble TGF-beta receptor type-II (rsTGF-beta RII-Fc) and 6.3G9 inhibited TGF-beta-mediated Smad2/3 phosphorylation in vitro, there was no effect on proliferation. Conversely, in vivo, 6.3G9 and rsTGF-beta RII-Fc inhibited xenograft tumor growth by 50% (n = 10, P < 0.05) and >90% (n = 10, P < 0.001), respectively, suggesting a role for the microenvironment in this response. However, stromal collagen and smooth muscle actin content in xenograft sections were unchanged with treatments. Although further studies are required to consolidate in vitro and in vivo results and define the mechanisms of tumor inhibition by alpha(v)beta(6) antibodies, our findings support a role for alpha(v)beta(6) in human cancer and underscore the therapeutic potential of function blocking alpha(v)beta(6) antibodies.
authors.affiliation: Department of Discovery Immunology, Biogen Idec, Cambridge, Massachusetts 02142, USA.
authors.forename: Louise A Koopman
authors.initials: LA
authors.lastname: Van Aarsen
authors.forename: Diane R
authors.initials: DR
authors.lastname: Leone
authors.forename: Steffan
authors.initials: S
authors.lastname: Ho
authors.forename: Brian M
authors.initials: BM
authors.lastname: Dolinski
authors.forename: Patricia E
authors.initials: PE
authors.lastname: McCoon
authors.forename: Doreen J
authors.initials: DJ
authors.lastname: LePage
authors.forename: Rebecca
authors.initials: R
authors.lastname: Kelly
authors.forename: Glenna
authors.initials: G
authors.lastname: Heaney
authors.forename: Paul
authors.initials: P
authors.lastname: Rayhorn
authors.forename: Carl
authors.initials: C
authors.lastname: Reid
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Simon
authors.forename: Gerald S
authors.initials: GS
authors.lastname: Horan
authors.forename: Nianjun
authors.initials: N
authors.lastname: Tao
authors.forename: Humphrey A
authors.initials: HA
authors.lastname: Gardner
authors.forename: Marilyn M
authors.initials: MM
authors.lastname: Skelly
authors.forename: Allen M
authors.initials: AM
authors.lastname: Gown
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Thomas
authors.forename: Paul H
authors.initials: PH
authors.lastname: Weinreb
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Fawell
authors.forename: Shelia M
authors.initials: SM
authors.lastname: Violette
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D018450:Disease Progression; D005260:Female; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000494:pharmacology; D039482:Integrin alpha5 / Q000276:immunology* / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008819:Mice, Nude; D008907:Mink; D010610:Pharyngeal Neoplasms / Q000378:metabolism / Q000473:pathology*; D020033:Protein Isoforms / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000494:pharmacology; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000737:chemistry; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000235:genetics; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D007141:Immunoglobulin Fc Fragments; D039482:Integrin alpha5; D020033:Protein Isoforms; D018125:Receptors, Transforming Growth Factor beta; D011993:Recombinant Fusion Proteins; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II