collagen xviii
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2022 ◽  
Author(s):  
Raman Devarajan ◽  
Hellevi Peltoketo ◽  
Valerio Izzi ◽  
Heli Johanna Ruotsalainen ◽  
Saila Kauppila ◽  
...  

The tumor extracellular matrix (ECM) is a critical regulator of cancer progression and metastasis, significantly affecting the treatment response. Expression of collagen XVIII (ColXVIII), a ubiquitous component of basement membranes, is induced in many solid tumors, but its involvement in tumorigenesis has remained elusive. We show here that ColXVIII is markedly upregulated in human breast cancer (BC) cells and is closely associated with a poor prognosis in high-grade BC, especially in human epidermal growth factor receptor 2 (HER2)-positive and basal/triple-negative cases. We identified a novel mechanism of action for ColXVIII as a modulator of epidermal growth factor receptor (EGFR/ErbB) signaling and show that it forms a complex with EGFR, HER2 and alpha6 integrin to promote cancer cell proliferation in a pathway involving its N-terminal portion and the MAPK/ERK1/2 and PI3K/Akt cascades. In vivo studies with Col18a1 mouse models crossed with the MMTV-PyMT mammary carcinogenesis model showed that the short ColXVIII isoform promotes BC growth and metastasis in a tumor cell-autonomous manner. Moreover, the number of mammary cancer stem cells was significantly reduced in both mouse and human cell models upon ColXVIII inhibition. Finally, ablation of ColXVIII in human BC cells and the MMTV-PyMT model substantially improved the efficacy of certain EGFR/ERbB-targeting therapies, even abolishing resistance to EGFR/ErbB inhibitors in some cell lines. In summary, a new function is revealed for ColXVIII in sustaining the stemness properties of BC cells, and tumor progression and metastasis through EGFR/ErbB signaling, suggesting that targeting ColXVIII in the tumor milieu may have significant therapeutic potential.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yi-Jun Wang ◽  
Matthew A. Downey ◽  
Sungwoon Choi ◽  
Timothy M. Shoup ◽  
David R. Elmaleh

AbstractNeurodegenerative diseases are characterized by chronic neuroinflammation and may perpetuate ongoing fibrotic reactions within the central nervous system. Unfortunately, there is no therapeutic available that treats neurodegenerative inflammation and its sequelae. Here we utilize cromolyn, a mast cell inhibitor with anti-inflammatory capabilities, and its fluorinated analogue F-cromolyn to study fibrosis-related protein regulation and secretion downstream of neuroinflammation and their ability to promote microglial phagocytosis and neurite outgrowth. In this report, RNA-seq analysis shows that administration of the pro-inflammatory cytokine TNF-α to HMC3 human microglia results in a robust upregulation of fibrosis-associated genes. Subsequent treatment with cromolyn and F-cromolyn resulted in reduced secretion of collagen XVIII, fibronectin, and tenascin-c. Additionally, we show that cromolyn and F-cromolyn reduce pro-inflammatory proteins PLP1, PELP1, HSP90, IL-2, GRO-α, Eotaxin, and VEGF-Α, while promoting secretion of anti-inflammatory IL-4 in HMC3 microglia. Furthermore, cromolyn and F-cromolyn augment neurite outgrowth in PC12 neuronal cells in concert with nerve growth factor. Treatment also differentially altered secretion of neurogenesis-related proteins TTL, PROX1, Rab35, and CSDE1 in HMC3 microglia. Finally, iPSC-derived human microglia more readily phagocytose Aβ42 with cromolyn and F-cromolyn relative to controls. We propose the cromolyn platform targets multiple proteins upstream of PI3K/Akt/mTOR, NF-κB, and GSK-3β signaling pathways to affect cytokine, chemokine, and fibrosis-related protein expression.


2021 ◽  
pp. 1-14
Author(s):  
Mei Li ◽  
Zoran Popovic ◽  
Chang Chu ◽  
Bernhard K. Krämer ◽  
Berthold Hocher

Endostatin, a protein derived from the cleavage of collagen XVIII by the action of proteases, is an endogenous inhibitor known for its ability to inhibit proliferation and migration of endothelial cells, angiogenesis, and tumor growth. Angiogenesis is defined as the formation of new blood vessels from pre-existing vasculature, which is crucial in many physiological processes, such as embryogenesis, tissue regeneration, and neoplasia. <b><i>Summary:</i></b> Increasing evidence shows that dysregulation of angiogenesis is crucial for the pathogenesis of renal and cardiovascular diseases. Endostatin plays a pivotal role in the regulation of angiogenesis. Recent studies have provided evidence that circulating endostatin increases significantly in patients with kidney and heart failure and may also contribute to disease progression. <b><i>Key Message:</i></b> In the current review, we summarize the latest findings on preclinical and clinical studies analyzing the impact of endostatin on renal and cardiovascular diseases.


2021 ◽  
Author(s):  
Yi-Jun Wang ◽  
Matthew A. Downey ◽  
Sungwoon Choi ◽  
Timothy M. Shoup ◽  
David R. Elmaleh

Abstract Neurodegenerative diseases are characterized by chronic neuroinflammation and may perpetuate ongoing fibrotic reactions within the central nervous system. In this report, RNA-seq analysis shows that administration of the pro-inflammatory cytokine TNF-α to HMC3 human microglia results in a robust upregulation of fibrosis-associated genes. Subsequent treatment with cromolyn and its fluorinated analogue F-cromolyn resulted in reduced secretion of collagen XVIII, fibronectin, and tenascin-c. Additionally, we show that cromolyn and F-cromolyn reduce secretion of pro-inflammatory proteins PLP1, PELP1, HSP90, IL-2, GRO-α, Eotaxin, and VEGF-Α, while promoting secretion of anti-inflammatory IL-4 in HMC3 microglia. Neurite outgrowth in PC12 neuronal cells is augmented by cromolyn and F-cromolyn in concert with nerve growth factor. Treatment also differentially altered secretion of neurogenesis-related proteins TTL, PROX1, Rab35, and CSDE1 in HMC3 microglia. Finally, iPSC-derived human microglia more readily phagocytose Aβ42 with cromolyn and F-cromolyn relative to controls. We propose the cromolyn platform targets multiple proteins upstream of PI3K/Akt/mTOR, NF-κB, and GSK-3β signaling pathways to affect cytokine, chemokine, and fibrosis-related protein expression.


2021 ◽  
Author(s):  
Mia M. Rinta-Jaskari ◽  
Florence Naillat ◽  
Heli J. Ruotsalainen ◽  
Saad U. Akram ◽  
Jarkko T. Koivunen ◽  
...  

ABSTRACTCollagen XVIII (ColXVIII) is a component of the extracellular matrix implicated in embryogenesis and control of homeostasis. We provide evidence that ColXVIII has a specific role in kidney ontogenesis by regulating the interaction between mesenchymal and epithelial tissues as observed in analyses of total and isoform-specific knockout embryos, mice, andex vivoorgan primordia. ColXVIII deficiency, both temporally and spatially, impacts the 3D pattern of ureteric tree branching morphogenesisviaits specific isoforms. Proper development of ureteric tree depends on a tight control of the nephron progenitor cells (NPCs). ColXVIII-deficient NPCs are leaving the NPC pool faster than in controls. Moreover, the data suggests that ColXVIII mediates the kidney epithelial tree patterningviaits N-terminal domains, and especially the Thrombospondin-1-like domain, and that this morphogenetic effect involves ureteric epithelial integrins. Altogether, the results propose a significant role for ColXVIII in a complex signalling network regulating renal progenitors and kidney development.


2020 ◽  
Vol 11 ◽  
Author(s):  
Nicoletta Orlando ◽  
Gabriele Babini ◽  
Patrizia Chiusolo ◽  
Caterina Giovanna Valentini ◽  
Valerio De Stefano ◽  
...  

Defibrotide (DFB) effects on different endothelial cell pathways have been investigated focusing on a limited number of genes or molecules. This study explored the modulation of the gene expression profile of steady-state or lipopolysaccharide (LPS)-activated endothelial cells, following the DFB exposure. Starting from differentially regulated gene expression datasets, we utilized the Ingenuity Pathway Analysis (IPA) to infer novel information about the activity of this drug. We found that effects elicited by LPS deeply differ depending on cells were exposed to DFB and LPS at the same time, or if the DFB priming occurs before the LPS exposure. Only in the second case, we observed a significant down-regulation of various pathways activated by LPS. In IPA, the pathways most affected by DFB were leukocyte migration and activation, vasculogenesis, and inflammatory response. Furthermore, the activity of DFB seemed to be associated with the modulation of six key genes, including matrix-metalloproteinases 2 and 9, thrombin receptor, sphingosine-kinase1, alpha subunit of collagen XVIII, and endothelial-protein C receptor. Overall, our findings support a role for DFB in a wide range of diseases associated with an exaggerated inflammatory response of endothelial cells.


2020 ◽  
Vol 598 (16) ◽  
pp. 3329-3330
Author(s):  
Jessica L. Braun ◽  
Mia S. Geromella ◽  
Sophie I. Hamstra

2020 ◽  
Vol 598 (16) ◽  
pp. 3373-3393 ◽  
Author(s):  
Tiina Petäistö ◽  
David Vicente ◽  
Kari A. Mäkelä ◽  
Mikko A. Finnilä ◽  
Ilkka Miinalainen ◽  
...  

2020 ◽  
Vol 51 (5) ◽  
pp. 373-380
Author(s):  
Chang Chu ◽  
Ahmed A. Hasan ◽  
Mohamed M.S. Gaballa ◽  
Shufei Zeng ◽  
Yingquan Xiong ◽  
...  

Background: Endostatin is a 20-kDa C-terminal fragment of collagen XVIII, known for its ability to inhibit the proliferation of capillary endothelial cells. Previous studies suggested that circulating endostatin independently predicts incident chronic kidney disease. However, the impact of endostatin on graft loss level in kidney transplant recipients (KTRs) remains unknown. Methods: We conducted a prospective observational cohort study in 574 maintenance KTRs. Patients were followed for kidney graft loss and all-cause mortality during a median follow-up of 48 months. Serum-, and urine-samples and clinical data were collected at baseline. Serum Endostatin concentration was analyzed by an ELISA. Results: Among 574 patients, 37 patients had graft loss and 62 patients died. For graft loss, the optimal cut-off value based on receiver operating characteristics analysis (area under the curve 0.79, 95% CI 0.71–0.86, p < 0.001) of endostatin was 147.3 pmol/L. Kaplan-Meier curves revealed that higher serum endostatin concentrations positively correlated with graft loss (p < 0.001). Multivariable Cox regression analyses showed that baseline endostatin concentrations were significantly associated with graft loss after adjusting for graft loss risk factors (adjusted hazard ratio [HR] 8.34; 95% CI 2.19–31.72; p = 0.002). The adjusted HRs for classical graft loss risk factors such as baseline estimated glomerular filtration rate and urinary protein excretion were lower (1.91 and 5.44, respectively). In contrast to graft loss, baseline endostatin concentrations were not associated with all-cause mortality. Conclusion: Increased serum endostatin at baseline is independently associated with the risk of graft loss in KTRs.


2019 ◽  
Vol 38 (5) ◽  
Author(s):  
Mária Rašiová ◽  
Ľudmila Farkašová ◽  
Martin Koščo ◽  
Matej Moščovič ◽  
Ľubomír Špak ◽  
...  

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