title: AGE-modified basement membrane cooperates with Endo180 to promote epithelial cell invasiveness and decrease prostate cancer survival.
abstract: Biomechanical strain imposed by age-related thickening of the basal lamina and augmented tissue stiffness in the prostate gland coincides with increased cancer risk. Here we hypothesized that the structural alterations in the basal lamina associated with age can induce mechanotransduction pathways in prostate epithelial cells (PECs) to promote invasiveness and cancer progression. To demonstrate this, we developed a 3D model of PEC acini in which thickening and stiffening of basal lamina matrix was induced by advanced glycation end-product (AGE)-dependent non-enzymatic crosslinking of its major components, collagen IV and laminin. We used this model to demonstrate that antibody targeted blockade of CTLD2, the second of eight C-type lectin-like domains in Endo180 (CD280, CLEC13E, KIAA0709, MRC2, TEM9, uPARAP) that can recognize glycosylated collagens, reversed actinomyosin-based contractility [myosin-light chain-2 (MLC2) phosphorylation], loss of cell polarity, loss of cell-cell junctions, luminal infiltration and basal invasion induced by AGE-modified basal lamina matrix in PEC acini. Our in vitro results were concordant with luminal occlusion of acini in the prostate glands of adult Endo180(Δ) (Ex2-6/) (Δ) (Ex2-6) mice, with constitutively exposed CTLD2 and decreased survival of men with early (non-invasive) prostate cancer with high epithelial Endo180 expression and levels of AGE. These findings indicate that AGE-dependent modification of the basal lamina induces invasive behaviour in non-transformed PECs via a molecular mechanism linked to cancer progression. This study provides a rationale for targeting CTLD2 in Endo180 in prostate cancer and other pathologies in which increased basal lamina thickness and tissue stiffness are driving factors. © 2014 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
authors.affiliation: Department of Surgery and Cancer, Imperial College London, UK; Departamento de Genética, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Rodriguez-Teja
authors.forename: Julian H
authors.initials: JH
authors.lastname: Gronau
authors.forename: Claudia
authors.initials: C
authors.lastname: Breit
authors.forename: Yu Zhi
authors.initials: YZ
authors.lastname: Zhang
authors.forename: Ai
authors.initials: A
authors.lastname: Minamidate
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Caley
authors.forename: Afshan
authors.initials: A
authors.lastname: McCarthy
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Cox
authors.forename: Janine T
authors.initials: JT
authors.lastname: Erler
authors.forename: Luke
authors.initials: L
authors.lastname: Gaughan
authors.forename: Steven
authors.initials: S
authors.lastname: Darby
authors.forename: Craig
authors.initials: C
authors.lastname: Robson
authors.forename: Francesco
authors.initials: F
authors.lastname: Mauri
authors.forename: Jonathan
authors.initials: J
authors.lastname: Waxman
authors.forename: Justin
authors.initials: J
authors.lastname: Sturge
mesh_terms: D000818:Animals; D001485:Basement Membrane / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D002470:Cell Survival; D004548:Elasticity; D004847:Epithelial Cells / Q000378:metabolism*; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D053208:Kaplan-Meier Estimate; D037181:Lectins, C-Type / Q000378:metabolism; D008297:Male; D037241:Mannose-Binding Lectins / Q000378:metabolism*; D040542:Mechanotransduction, Cellular; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018345:Mice, Knockout; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011975:Receptors, Mitogen / Q000378:metabolism*; D013997:Time Factors
chemical_list: C408294:Endo180; D017127:Glycation End Products, Advanced; D037181:Lectins, C-Type; C404106:MRC2 protein, human; D037241:Mannose-Binding Lectins; D008562:Membrane Glycoproteins; C474081:Mrc2 protein, mouse; D011956:Receptors, Cell Surface; D011975:Receptors, Mitogen
keywords: C-type lectin domain; advanced glycation endproducts; ageing; basement membrane; cell contractility; collagen crosslinking; epithelium; invasion; matrix stiffness; prostate cancer