Toggle Main Menu Toggle Search

Open Access padlockePrints

AGE-modified basement membrane cooperates with Endo180 to promote epithelial cell invasiveness and decrease prostate cancer survival

Lookup NU author(s): Dr Luke GaughanORCiD, Dr Steven Darby, Professor Craig Robson

Downloads

Full text for this publication is not currently held within this repository. Alternative links are provided below where available.


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(Ex2-6/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. (c) 2014 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


Publication metadata

Author(s): Rodriguez-Teja M, Gronau JH, Breit C, Zhang YZ, Minamidate A, Caley MP, McCarthy A, Cox TR, Erler JT, Gaughan L, Darby S, Robson C, Mauri F, Waxman J, Sturge J

Publication type: Article

Publication status: Published

Journal: Journal of Pathology

Year: 2015

Volume: 235

Issue: 4

Pages: 581-592

Print publication date: 01/03/2015

Online publication date: 24/12/2014

Acceptance date: 08/11/2014

ISSN (print): 0022-3417

ISSN (electronic): 1096-9896

Publisher: Wiley

URL: http://dx.doi.org/10.1002/path.4485

DOI: 10.1002/path.4485


Altmetrics

Altmetrics provided by Altmetric


Funding

Funder referenceFunder name
M41Rosetrees Trust
M40Rosetrees Trust
Imperial College NHS Healthcare Trust
Tony and Rita Gallagher
08-0803Association of International Cancer Research
110632Prostate Cancer Charity

Share