AGE modified basement membrane cooperates with Endo180 to promote epithelial cell invasiveness and decrease prostate cancer survival
Rodríguez-Teja, Mercedes; Gronau, Julián H; Breit, Claudia; Zhi Zhang, Yu; Minamidate, Ai; Caley, Matthew P; McCarthy, Afshan; Cox, Thomas R; Erler, Janine T; Gaughen, Luke; Darby, Steven; Robson, Craig; Mauri, Francesco; Waxman, Jonathan; Sturge, Justin.
J Pathol
; 235: 581-592, 2014.
Artículo
en Inglés
| URUCAN | ID: bcc-4857
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 hypothesised 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 endproduct (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 recognise 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, where increased basal lamina thickness and tissue stiffness are driving factors(AU)
Biblioteca responsable:
UY78.1
Ubicación: UY78.1 BN-1932
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