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

TY - JOUR

T1 - AGE-modified basement membrane cooperates with Endo180 to promote epithelial cell invasiveness and decrease prostate cancer survival

AU - Rodriguez-Teja, Mercedes

AU - Gronau, Julian H

AU - Breit, Claudia

AU - Zhang, Yu Zhi

AU - Minamidate, Ai

AU - Caley, Matthew P

AU - McCarthy, Afshan

AU - Cox, Thomas R

AU - Erler, Janine T

AU - Gaughan, Luke

AU - Darby, Steven

AU - Robson, Craig

AU - Mauri, Francesco

AU - Waxman, Jonathan

AU - Sturge, Justin

N1 - © 2014 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

PY - 2015/3/1

Y1 - 2015/3/1

N2 - 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.

AB - 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.

KW - Animals

KW - Basement Membrane

KW - Cell Line, Tumor

KW - Cell Movement

KW - Cell Survival

KW - Elasticity

KW - Epithelial Cells

KW - Glycosylation End Products, Advanced

KW - Humans

KW - Kaplan-Meier Estimate

KW - Lectins, C-Type

KW - Male

KW - Mannose-Binding Lectins

KW - Mechanotransduction, Cellular

KW - Membrane Glycoproteins

KW - Mice, Knockout

KW - Neoplasm Invasiveness

KW - Prostatic Neoplasms

KW - Protein Structure, Tertiary

KW - Receptors, Cell Surface

KW - Receptors, Mitogen

KW - Time Factors

U2 - 10.1002/path.4485

DO - 10.1002/path.4485

M3 - Journal article

C2 - 25408555

SN - 0022-3417

VL - 235

SP - 581

EP - 592

JO - Journal of Pathology

JF - Journal of Pathology

IS - 4

ER -