Survival Outcome and EMT Suppression Mediated by a Lectin Domain Interaction of Endo180 and CD147

Rodriguez-Teja, Mercedes; Gronau, Julian Hendrik; Minamidate, Ai; Darby, Steven; Gaughan, Luke; Robson, Craig; Mauri, Francesco; Waxman, Jonathan; Sturge, Justin

doi:10.1158/1541-7786.mcr-14-0344-t

Cited by 20 publications

(40 citation statements)

References 40 publications

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“…In line with our previous studies, where Endo180 has been shown to play a role in EMT and prostate cancer progression , and the spatiotemporal activation of actinomyosin‐based contractile signals and cell migration , we propose a model in which two functional CTLDs in Endo180, CTLD2 and CTLD4, are responsible for directly modulating PEC invasiveness (see supplementary material, Figure S6). We believe that the molecular basis of this regulation involves a switch between the closed and open conformation of Endo180's ectodomain .…”

Section: Discussionsupporting

confidence: 86%

“…The mechanisms underpinning this phenomenon could involve activation of proteases that degrade the basal lamina or defective production and organization of its matrix components. The first mechanism is supported by the finding that Endo180 forms an EMT‐suppressor complex with the extracellular matrix metalloproteinase inducer CD147 , and its targeted blockade results in down‐regulation of MT1‐MMP and uPA (see supplementary material, Figure S5), which both drive basal lamina matrix degradation . The latter mechanism is supported from the finding in a different cellular context, whereby Endo180 orchestrates collagen deposition by primary human osteoblasts .…”

Section: Discussionmentioning

confidence: 81%

“…In support of this theory, immunostaining with a mouse anti‐human Endo180 monoclonal antibody (mAb), A5/158, that recognizes CTLD2 (Figure B) , revealed that endogenously expressed Endo180 is strongly localized at the basal surface of PEC acini in native rBM (Figure C), where it is able to bind to extracellular glycated collagens. Immunostaining with a second mouse anti‐human Endo180 mAb, 39.10, detected Endo180 exclusively in endosomes (Figure C), due to its epitope CTLD4 (Figure B) being masked by its interaction with CD147 at the basal surface of PEC acini . Interestingly, levels of endosomal Endo180 were visibly increased in PECs protruding from the basal surface of acini into stiff rBM (Figure C, arrow).…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2014

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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 iniltration and basal invasion induced by AGE-modiied 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 indings indicate that AGE-dependent modiication 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.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 81%

Section: Resultsmentioning

confidence: 99%

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

et al. 2014

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“…Most researches on MRC2 to date have focused on its role in the development of cancer, as it can promote breast tumor growth, 17 co-operate with the matrix metalloproteinase to remodel of extracellular matrix that attenuate renal fibrosis, 28 and predict prognosis of hepatocellular carcinoma 18 and prostate cancer. 29 Besides, MRC2 is also closely related to collagen turnover. 30 In our study, we found that both estrogen and 1-MT promoted the expression of MRC2 in ESCs, which indicates that MRC2 is downstream to estrogen and IDO1.…”

Section: Discussionmentioning

confidence: 99%

1-Methyl-tryptophan attenuates regulatory T cells differentiation due to the inhibition of estrogen-IDO1-MRC2 axis in endometriosis

et al. 2016

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Foxp3+ regulatory T (Treg) cells contribute to the local dysfunctional immune environment in endometriosis, an estrogen-dependent gynecological disease, which affects the function of ectopic endometrial tissue clearance by the immune system. The reason for the high percentage of peritoneal Treg in endometriosis patients is unknown. Here, we show that the proportion of peritoneal Treg cells increases as endometriosis progresses. To determine the probable mechanism, we established a naive T cell-macrophage-endometrial stromal cell (ESC) co-culture system to mimic the peritoneal cavity microenvironment. After adding 1-methyl-tryptophan (1-MT), a specific inhibitor of indoleamine 2,3-dioxygenase-1 (IDO1), to the co-culture system, we found that the differentiation of Treg cells, mainly IL-10+ Treg cells, decreased. Therefore, 1-MT-pretreated ESCs-educated Treg cells performed impaired suppressive function. Moreover, estrogen promoted the differentiation of Treg cells by elevating IDO1 expression in the ectopic lesion. Subsequently, we examined mannose receptor C, type 2 (MRC2), which is an up-stream molecule of IL-10, by bioinformatics analysis and real-time PCR validation. MRC2 expression in ectopic ESCs was notably lower than that in normal ESCs, which further negatively regulated the expression of IDO1 and Ki-67 in ESCs. Furthermore, MRC2 is required for Treg differentiation in the ectopic lesion, especially that for CD4high Treg. Therefore, MRC2-silenced ESCs-educated Treg manifested a stronger suppressive function in vitro. Consistently, the percentage of Treg increased when MRC2-shRNA was administered in the peritoneal cavity of endometriosis-disease mice model. Besides, 1-MT improved the condition of endometriosis, in terms of reducing the number and weight of total ectopic lesions in vivo. These results indicate that the estrogen-IDO1-MRC2 axis participates in the differentiation and function of Treg and is involved in the development of endometriosis. Thus, blockage of IDO1 in the ectopic lesion, which does not influence physiological functions of estrogen, may be considered a potential therapy for endometriosis.

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“…These acini also have the characteristics of highly organized PECs with apical-to-basal polarity and a visible luminal space 13,20 .…”

Section: Prostate Acini Cultured On Stiff Rbmmentioning

confidence: 99%

How to Study Basement Membrane Stiffness as a Biophysical Trigger in Prostate Cancer and Other Age-related Pathologies or Metabolic Diseases

Rodriguez-Teja

Breit

Clarke

et al. 2016

JoVE

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Here we describe a protocol that can be used to study the biophysical microenvironment related to increased thickness and stiffness of the basement membrane (BM) during age-related pathologies and metabolic disorders (e.g. cancer, diabetes, microvascular disease, retinopathy, nephropathy and neuropathy). The premise of the model is non-enzymatic crosslinking of reconstituted BM (rBM) matrix by treatment with glycolaldehyde (GLA) to promote advanced glycation endproduct (AGE) generation via the Maillard reaction. Examples of laboratory techniques that can be used to confirm AGE generation, non-enzymatic crosslinking and increased stiffness in GLA treated rBM are outlined. These include preparation of native rBM (treated with phosphate-buffered saline, PBS) and stiff rBM (treated with GLA) for determination of: its AGE content by photometric analysis and immunofluorescent microscopy, its non-enzymatic crosslinking by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS PAGE) as well as confocal microscopy, and its increased stiffness using rheometry. The procedure described here can be used to increase the rigidity (elastic moduli, E) of rBM up to 3.2-fold, consistent with measurements made in healthy versus diseased human prostate tissue. To recreate the biophysical microenvironment associated with the aging and diseased prostate gland three prostate cell types were introduced on to native rBM and stiff rBM: RWPE-1, prostate epithelial cells (PECs) derived from a normal prostate gland; BPH-1, PECs derived from a prostate gland affected by benign prostatic hyperplasia (BPH); and PC3, metastatic cells derived from a secondary bone tumor originating from prostate cancer. Multiple parameters can be measured, including the size, shape and invasive characteristics of the 3D glandular acini formed by RWPE-1 and BPH-1 on native versus stiff rBM, and average cell length, migratory velocity and persistence of cell movement of 3D spheroids formed by PC3 cells under the same conditions. Cell signaling pathways and the subcellular localization of proteins can also be assessed.

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Survival Outcome and EMT Suppression Mediated by a Lectin Domain Interaction of Endo180 and CD147

Cited by 20 publications

References 40 publications

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

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

1-Methyl-tryptophan attenuates regulatory T cells differentiation due to the inhibition of estrogen-IDO1-MRC2 axis in endometriosis

How to Study Basement Membrane Stiffness as a Biophysical Trigger in Prostate Cancer and Other Age-related Pathologies or Metabolic Diseases

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