title: Integrin α11β1 regulates cancer stromal stiffness and promotes tumorigenicity and metastasis in non-small cell lung cancer.
abstract: Integrin α11β1 is a stromal cell-specific receptor for fibrillar collagens and is overexpressed in carcinoma-associated fibroblasts (CAFs). We have investigated its direct role in cancer progression by generating severe combined immune deficient (SCID) mice deficient in integrin α11 (α11) expression. The growth of A549 lung adenocarcinoma cells and two patient-derived non-small cell lung carcinoma (NSCLC) xenografts in these α11 knockout (α11(-/-)) mice was significantly impeded, as compared with wild-type (α11(+/+)) SCID mice. Orthotopic implantation of a spontaneously metastatic NCI-H460SM cell line into the lungs of α11(-/-) and α11(+/+) mice showed significant reduction in the metastatic potential of these cells in the α11(-/-) mice. We identified that collagen cross-linking is associated with stromal α11 expression, and the loss of tumor stromal α11 expression was correlated with decreased collagen reorganization and stiffness. This study shows the role of integrin α11β1, a receptor for fibrillar collagen in differentiation of fibroblasts into CAFs. Furthermore, our data support an important role for α11 signaling pathway in CAFs, promoting tumor growth and metastatic potential of NSCLC cells and being closely associated with collagen cross-linking and the organization and stiffness of fibrillar collagen matrices.
authors.affiliation: Princess Margaret Cancer Center and Campbell Family Institute for Cancer Research, University Health Network, Toronto, Ontario, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Navab
authors.affiliation: Princess Margaret Cancer Center and Campbell Family Institute for Cancer Research, University Health Network, Toronto, Ontario, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Strumpf
authors.affiliation: Princess Margaret Cancer Center and Campbell Family Institute for Cancer Research, University Health Network, Toronto, Ontario, Canada.
authors.forename: C
authors.initials: C
authors.lastname: To
authors.affiliation: Princess Margaret Cancer Center and Campbell Family Institute for Cancer Research, University Health Network, Toronto, Ontario, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: E
authors.initials: E
authors.lastname: Pasko
authors.affiliation: Department of Chemistry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: K S
authors.initials: KS
authors.lastname: Kim
authors.affiliation: Princess Margaret Cancer Center and Campbell Family Institute for Cancer Research, University Health Network, Toronto, Ontario, Canada.
authors.forename: C J
authors.initials: CJ
authors.lastname: Park
authors.affiliation: Princess Margaret Cancer Center and Campbell Family Institute for Cancer Research, University Health Network, Toronto, Ontario, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Hai
authors.affiliation: Princess Margaret Cancer Center and Campbell Family Institute for Cancer Research, University Health Network, Toronto, Ontario, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.affiliation: Princess Margaret Cancer Center and Campbell Family Institute for Cancer Research, University Health Network, Toronto, Ontario, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Jonkman
authors.affiliation: Department of Biomedicine and Centre of Cancer Biomarkers, University of Bergen, Bergen, Norway.
authors.forename: M
authors.initials: M
authors.lastname: Barczyk
authors.affiliation: Princess Margaret Cancer Center and Campbell Family Institute for Cancer Research, University Health Network, Toronto, Ontario, Canada.
authors.forename: B
authors.initials: B
authors.lastname: Bandarchi
authors.affiliation: Princess Margaret Cancer Center and Campbell Family Institute for Cancer Research, University Health Network, Toronto, Ontario, Canada.
authors.forename: Y H
authors.initials: YH
authors.lastname: Wang
authors.affiliation: Princess Margaret Cancer Center and Campbell Family Institute for Cancer Research, University Health Network, Toronto, Ontario, Canada.
authors.forename: K
authors.initials: K
authors.lastname: Venkat
authors.affiliation: Princess Margaret Cancer Center and Campbell Family Institute for Cancer Research, University Health Network, Toronto, Ontario, Canada.
authors.forename: E
authors.initials: E
authors.lastname: Ibrahimov
authors.affiliation: Princess Margaret Cancer Center and Campbell Family Institute for Cancer Research, University Health Network, Toronto, Ontario, Canada.
authors.forename: N-A
authors.initials: NA
authors.lastname: Pham
authors.affiliation: Princess Margaret Cancer Center and Campbell Family Institute for Cancer Research, University Health Network, Toronto, Ontario, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Ng
authors.affiliation: Princess Margaret Cancer Center and Campbell Family Institute for Cancer Research, University Health Network, Toronto, Ontario, Canada.
authors.forename: N
authors.initials: N
authors.lastname: Radulovich
authors.affiliation: Princess Margaret Cancer Center and Campbell Family Institute for Cancer Research, University Health Network, Toronto, Ontario, Canada.
authors.forename: C-Q
authors.initials: CQ
authors.lastname: Zhu
authors.affiliation: Princess Margaret Cancer Center and Campbell Family Institute for Cancer Research, University Health Network, Toronto, Ontario, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Pintilie
authors.affiliation: Princess Margaret Cancer Center and Campbell Family Institute for Cancer Research, University Health Network, Toronto, Ontario, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Wang
authors.affiliation: Princess Margaret Cancer Center and Campbell Family Institute for Cancer Research, University Health Network, Toronto, Ontario, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Lu
authors.affiliation: Princess Margaret Cancer Center and Campbell Family Institute for Cancer Research, University Health Network, Toronto, Ontario, Canada.|Department of Computer Science, University of Toronto, Toronto, Ontario, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: I
authors.initials: I
authors.lastname: Jurisica
authors.affiliation: Department of Chemistry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: G C
authors.initials: GC
authors.lastname: Walker
authors.affiliation: Department of Biomedicine and Centre of Cancer Biomarkers, University of Bergen, Bergen, Norway.
authors.forename: D
authors.initials: D
authors.lastname: Gullberg
authors.affiliation: Princess Margaret Cancer Center and Campbell Family Institute for Cancer Research, University Health Network, Toronto, Ontario, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: M-S
authors.initials: MS
authors.lastname: Tsao
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D045744:Cell Line, Tumor; D003094:Collagen / Q000378:metabolism; D003433:Crosses, Genetic; D004548:Elasticity; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000502:physiology*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D006801:Humans; D039001:Integrin alpha Chains; D019012:Integrin beta1 / Q000502:physiology*; D016023:Integrins / Q000502:physiology*; D008175:Lung Neoplasms / Q000473:pathology*; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D038981:Receptors, Collagen / Q000502:physiology*; D015398:Signal Transduction; D017154:Stromal Cells / Q000502:physiology*
chemical_list: D016326:Extracellular Matrix Proteins; D039001:Integrin alpha Chains; D019012:Integrin beta1; D016023:Integrins; D009363:Neoplasm Proteins; D038981:Receptors, Collagen; C000610207:integrin alpha11, mouse; C467800:integrin alpha11beta1; D003094:Collagen; D011494:Protein Kinases