Chondroitin Sulfate Proteoglycan CSPG4 as a Novel Hypoxia-Sensitive Marker in Pancreatic Tumors

Keleg, Shereen; Titov, Alexandr; Heller, Anette; Giese, Thomas; Tjaden, Christine; Ahmad, Sufian S.; Gaida, Matthias M.; Bauer, Andrea S.; Werner, Jens; Giese, Nathalia A.

doi:10.1371/journal.pone.0100178

Cited by 22 publications

(20 citation statements)

References 61 publications

(83 reference statements)

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“…In macrophages however, a more recent study demonstrated an increase in the proteoglycans versican and perlecan, mediated trough the HIF-pathway [ 57 ]. Furthermore, the novel hypoxia-sensitive chondroitin sulfate proteoglycan CSPG4, important in proliferation, is also increased in hypoxia [ 58 ].…”

Section: Discussionmentioning

confidence: 99%

Serglycin in Quiescent and Proliferating Primary Endothelial Cells

et al. 2015

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Proteoglycans are fundamental components of the endothelial barrier, but the functions of the proteoglycan serglycin in endothelium are less described. Our aim was to describe the roles of serglycin in processes relevant for endothelial dysfunction. Primary human umbilical vein endothelial cells (HUVEC) were cultured in vitro and the expression of proteoglycans was investigated. Dense cell cultures representing the quiescent endothelium coating the vasculature was compared to sparse activated cell cultures, relevant for diabetes, cancer and cardiovascular disease. Secretion of 35S- proteoglycans increased in sparse cultures, and we showed that serglycin is a major component of the cell-density sensitive proteoglycan population. In contrast to the other proteoglycans, serglycin expression and secretion was higher in proliferating compared to quiescent HUVEC. RNAi silencing of serglycin inhibited proliferation and wound healing, and serglycin expression and secretion was augmented by hypoxia, mechanical strain and IL-1β induced inflammation. Notably, the secretion of the angiogenic chemokine CCL2 resulting from IL-1β activation, was increased in serglycin knockdown cells, while angiopoietin was not affected. Both serglycin and CCL2 were secreted predominantly to the apical side of polarized HUVEC, and serglycin and CCL2 co-localized both in perinuclear areas and in vesicles. These results suggest functions for serglycin in endothelial cells trough interactions with partner molecules, in biological processes with relevance for diabetic complications, cardiovascular disease and cancer development.

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Section: Discussionmentioning

confidence: 99%

Serglycin in Quiescent and Proliferating Primary Endothelial Cells

et al. 2015

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“…Esophageal RNA was purchased from BioCat (Heidelberg, Germany) and was used as a positive control for SLURP1 expression. All instruments and reagents for qRT-PCR analysis were purchased from Roche Applied Biosciences AG (Mannheim, Germany) and applied as described previously [ 77 , 78 ]. In brief, mRNA extraction was performed with the MagNA Pure ® System; cDNA was synthesized with the First Strand cDNA synthesis kit and PCR analysis was performed using the LightCycler ® 480.…”

Section: Methodsmentioning

confidence: 99%

Endogenous CHRNA7-ligand SLURP1 as a potential tumor suppressor and anti-nicotinic factor in pancreatic cancer

et al. 2018

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Smoking is associated with increased risk and poorer prognosis of pancreatic ductal adenocarcinoma (PDAC). Nicotine acts through cholinergic nicotinic receptors, preferentially α7 (CHRNA7) that also binds the endogenous ligand SLURP1 (Secreted Ly-6/uPAR-Related Protein 1). The clinical significance of SLURP1 and its interaction with nicotine in PDAC are unclear. We detected similar levels of SLURP1 in sera from healthy donors and patients with chronic pancreatitis or PDAC; higher preoperative values were associated with significantly better survival in patients with resected tumors. Pancreatic tissue was not a source of circulating SLURP1 but contained diverse CHRNA7-expressing cells, preferentially epithelial and immune, whereas stromal stellate cells and a quarter of the tumor cells lacked CHRNA7. The CHRNA7 mRNA levels were decreased in PDAC, and CHRNA7high-PDAC patients lived longer. In CHRNA7high COLO357 and PANC-1 cultures, opposing activities of SLURP1 (anti-malignant/CHRNA7-dependent) and nicotine (pro-malignant/CHRNA7-infidel) were exerted without reciprocally interfering with receptor binding or downstream signaling. These data suggested that the ligands act independently and abolish each other’s effects through a mechanism resembling functional antagonism. Thus, SLURP1 might represent an inborn anti-PDAC defense being sensitive to and counteracting nicotine. Boosting SLURP1-CHRNA7 interaction might represent a novel strategy for treatment in high-risk individuals, i.e., smokers with pancreatic cancer.

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“…Acinar, stromal and immune cells were visualised with antibodies targeting amylase‐A2‐alpha (AMY2A; sheep IgG, abcam #ab18934; Abcam, Camridge, UK), smooth muscle actin alpha (SMACTA2; mIgG2a, DAKO #M 0851; Dako, Hamburg, Germany) and common leucocyte antigen CD45 (mIgG1, DAKO #N1514), respectively. Formalin‐fixed, paraffin‐embedded (FFPE) sections were stained according to a standard protocol . In brief, 4 µm‐thick sections were heated to 96°C in citrate buffer (pH 6) for 30 min to retrieve the antigens.…”

Section: Methodsmentioning

confidence: 99%

“…Formalin-fixed, paraffin-embedded (FFPE) sections were stained according to a standard protocol. 13 In brief, 4 mm-thick sections were heated to 968C in citrate buffer (pH 6) for 30 min to retrieve the antigens. They were blocked with methanol containing 3% H 2 O 2 and universal blocking reagent (BioGenex, San Ramon) and exposed to primary antibodies at 48C overnight.…”

Section: Immunohistochemistrymentioning

confidence: 99%

Transcriptional variations in the wider peritumoral tissue environment of pancreatic cancer

Bauer

Nazarov

Giese

et al. 2017

Intl Journal of Cancer

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Transcriptional profiling was performed on 452 RNA preparations isolated from various types of pancreatic tissue from tumour patients and healthy donors, with a particular focus on peritumoral samples. Pancreatic ductal adenocarcinomas (PDAC) and cystic tumours were most different in these non‐tumorous tissues surrounding them, whereas the actual tumours exhibited rather similar transcript patterns. The environment of cystic tumours was transcriptionally nearly identical to normal pancreas tissue. In contrast, the tissue around PDAC behaved a lot like the tumour, indicating some kind of field defect, while showing far less molecular resemblance to both chronic pancreatitis and healthy tissue. This suggests that the major pathogenic difference between cystic and ductal tumours may be due to their cellular environment rather than the few variations between the tumours. Lack of correlation between DNA methylation and transcript levels makes it unlikely that the observed field defect in the peritumoral tissue of PDAC is controlled to a large extent by such epigenetic regulation. Functionally, a strikingly large number of autophagy‐related transcripts was changed in both PDAC and its peritumoral tissue, but not in other pancreatic tumours. A transcription signature of 15 autophagy‐related genes was established that permits a prognosis of survival with high accuracy and indicates the role of autophagy in tumour biology.

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Chondroitin Sulfate Proteoglycan CSPG4 as a Novel Hypoxia-Sensitive Marker in Pancreatic Tumors

Cited by 22 publications

References 61 publications

Serglycin in Quiescent and Proliferating Primary Endothelial Cells

Serglycin in Quiescent and Proliferating Primary Endothelial Cells

Endogenous CHRNA7-ligand SLURP1 as a potential tumor suppressor and anti-nicotinic factor in pancreatic cancer

Transcriptional variations in the wider peritumoral tissue environment of pancreatic cancer

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