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

Rodriguez-Teja, Mercedes; Gronau, Julian H.; Breit, Claudia; Zhang, Yu Zhi; Minamidate, Ai; Caley, Matthew P.; McCarthy, Afshan; Cox, Thomas R; Erler, Janine T; Gaughan, Luke; Darby, Steven; Robson, Craig; Mauri, Francesco; Waxman, Jonathan; Sturge, Justin

Authors

Mercedes Rodriguez-Teja

Julian H. Gronau

Claudia Breit

Yu Zhi Zhang

Ai Minamidate

Matthew P. Caley

Afshan McCarthy

Thomas R Cox

Janine T Erler

Luke Gaughan

Steven Darby

Craig Robson

Francesco Mauri

Jonathan Waxman

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 Endo180ΔEx2–6/ΔEx2–6 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.

Publication Date 2015-03
Journal Journal of Pathology
Print ISSN 0022-3417
Electronic ISSN 1096-9896
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 235
Issue 4
Pages 581-592
Institution Citation Rodriguez-Teja, M., Gronau, J. H., Breit, C., Zhang, Y. Z., Minamidate, A., Caley, M. P., …Sturge, J. (2015). AGE-modified basement membrane cooperates with Endo180 to promote epithelial cell invasiveness and decrease prostate cancer survival. Journal of Pathology, 235(4), 581-592. https://doi.org/10.1002/path.4485
DOI https://doi.org/10.1002/path.4485
Keywords Advanced glycation endproducts; Ageing; Basement membrane; Cell contractility; Collagen crosslinking; C-type lectin domain; Epithelium; Invasion; Matrix stiffness; Prostate cancer
Publisher URL http://onlinelibrary.wiley.com/doi/10.1002/path.4485/abstract;jsessionid=540E40968B236F7C219633A37690474C.f01t04
Copyright Statement © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Additional Information This is a copy of an open access article published in Journal of Pathology, 2015, v.235 issue 4.

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Copyright Statement
© 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.



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