Antibody-mediated blockade of integrin alpha v beta 6 inhibits tumor progression in vivo by a transforming growth factor-beta-regulated mechanism.
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.
Van Aarsen
Louise A Koopman
LA
Department of Discovery Immunology, Biogen Idec, Cambridge, Massachusetts 02142, USA.
Leone
Diane R
DR
Ho
Steffan
S
Dolinski
Brian M
BM
McCoon
Patricia E
PE
LePage
Doreen J
DJ
Kelly
Rebecca
R
Heaney
Glenna
G
Rayhorn
Paul
P
Reid
Carl
C
Simon
Kenneth J
KJ
Horan
Gerald S
GS
Tao
Nianjun
N
Gardner
Humphrey A
HA
Skelly
Marilyn M
MM
Gown
Allen M
AM
Thomas
Gareth J
GJ
Weinreb
Paul H
PH
Fawell
Stephen E
SE
Violette
Shelia M
SM
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
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