Proteome Variations in Pancreatic Stellate Cells upon Stimulation with Proinflammatory Factors

Marzoq, Aseel; Giese, Nathalia A.; Hoheisel, Jörg D.; Alhamdani, Mohamed Saiel Saeed

doi:10.1074/jbc.m113.488387

Cited by 16 publications

(19 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The myofibroblast-like pancreatic stellate cells (PSCs) reside in a quiescent state in the normal pancreas, but transition to an activated state under pathological conditions such as inflammation or cancer [ 5 , 6 , 9 , 10 ]. Numerous studies have shown that PDAC is often associated with the infiltration of immune cells that creates an inflamed microenvironment enriched with growth factors, cytokines, endotoxins, a hypoxic TME and an increased oxidant stress level, all of which contribute to the activation of PSCs [ 11 , 12 ]. Yet, how PSCs activate intercellular signaling in PDAC cells remains to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

Pancreatic stellate cell secreted IL-6 stimulates STAT3 dependent invasiveness of pancreatic intraepithelial neoplasia and cancer cells

et al. 2016

View full text Add to dashboard Cite

Pancreatic ductal adenocarcinoma (PDAC) is a dynamic tumor supported by several stromal elements such as pancreatic stellate cells (PSC). Significant crosstalk exists between PSCs and tumor cells to stimulate oncogenic signaling and malignant progression of PDAC. However, how PSCs activate intercellular signaling in PDAC cells remains to be elucidated. We have previously shown that activated signal transducer and activator of transcription 3 (STAT3) signaling is a key component in the progression of pancreatic neoplasia. We hypothesize that PSC secreted IL-6 activates STAT3 signaling to promote PanIN progression to PDAC. Human PDAC and mouse PanIN cells were treated with PSC-conditioned media (PSC-CM), and phospho- and total-STAT3 levels by immunoblot analysis were determined. IL-6 was quantified in PSC-CM and cell invasion and colony formation assays were performed in the presence or absence of a neutralizing IL-6 antibody and the JAK/STAT3 inhibitor AZD1480. Serum from Ptf1aCre/+;LSL-KrasG12D/+;Tgfbr2flox/flox' (PKT) and LSL-KrasG12D/+; Trp53R172H/+; Pdx1Cre/+ (KPC) mice demonstrated increased levels of IL-6 compared to serum from non-PDAC bearing KC and PK mice. PSC secreted IL-6 activated STAT3 signaling in noninvasive, precursor PanIN cells as well as PDAC cells, resulting in enhanced cell invasion and colony formation in both cell types. There was a significant positive linear correlation between IL-6 concentration and the ratio of phosphorylated STAT3/total STAT3. IL-6 neutralization or STAT3 inhibition attenuated PSC-CM induced activation of STAT3 signaling and tumorigenicity. These data provide evidence that PSCs are directly involved in promoting the progression of PanINs towards invasive carcinoma. This study demonstrates a novel role of PSC secreted IL-6 in transitioning noninvasive pancreatic precursor cells into invasive PDAC through the activation of STAT3 signaling.

show abstract

Section: Introductionmentioning

confidence: 99%

Pancreatic stellate cell secreted IL-6 stimulates STAT3 dependent invasiveness of pancreatic intraepithelial neoplasia and cancer cells

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Few other proteomic studies of similar kind have reported the expression of proteins related to inflammation, fibrosis, apoptosis, wound healing and proliferation[ 116 ]. The change in the expression profile of the proteome in response to various (TNF-α, FGF-2, CCL4 and IL-6) proinflammatory factors on immortalized human PSCs described their unique functions[ 117 ].…”

Section: Molecular Pathways Micrornas Transcription Factors and Promentioning

confidence: 99%

Pancreatic stellate cell: Pandora's box for pancreatic disease biology

Bynigeri¹,

Jakkampudi²,

Jangala³

et al. 2017

WJG

145

View full text Add to dashboard Cite

Pancreatic stellate cells (PSCs) were identified in the early 1980s, but received much attention after 1998 when the methods to isolate and culture them from murine and human sources were developed. PSCs contribute to a small proportion of all pancreatic cells under physiological condition, but are essential for maintaining the normal pancreatic architecture. Quiescent PSCs are characterized by the presence of vitamin A laden lipid droplets. Upon PSC activation, these perinuclear lipid droplets disappear from the cytosol, attain a myofibroblast like phenotype and expresses the activation marker, alpha smooth muscle actin. PSCs maintain their activated phenotype via an autocrine loop involving different cytokines and contribute to progressive fibrosis in chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC). Several pathways (e.g., JAK-STAT, Smad, Wnt signaling, Hedgehog etc.), transcription factors and miRNAs have been implicated in the inflammatory and profibrogenic function of PSCs. The role of PSCs goes much beyond fibrosis/desmoplasia in PDAC. It is now shown that PSCs are involved in significant crosstalk between the pancreatic cancer cells and the cancer stroma. These interactions result in tumour progression, metastasis, tumour hypoxia, immune evasion and drug resistance. This is the rationale for therapeutic preclinical and clinical trials that have targeted PSCs and the cancer stroma.

show abstract

“…For simplicity, we assumed that the cytokines are produced (by PSCs or macrophages) at a constant rate, and they undergo a natural decay with constant rates (9,10,24,25,27). However, in the production of IL-6, we also included enhancement of IL-6 production by TGF-β (24).…”

Section: Mathematical Modelmentioning

confidence: 99%

“…PSCs are myofibroblast-like cells that reside in the periacinar regions of the pancreas in a quiescent state (4,9). Quiescent PSCs contribute to maintenance of proper tissue architecture by regulating the synthesis of extracellular matrix (ECM) (10).…”

mentioning

confidence: 99%

“…For example, PSC activation may be enhanced by autocrine and paracrine of TGF-β (in addition to IL-6 and TNF-α) (9,10,27). TNF-α and PDGF increase proliferation of active PSCs (APSCs) (9,10,12,(29)(30)(31)(32)(33), whereas TGF-β and IL-6 decrease the proliferation of APSCs (9,10). Conversely, the production of matrix metalloproteinases (MMPs) (34) and tissue inhibitors of metalloproteinase (TIMP) was enhanced by these same cytokines (34).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Mathematical model of chronic pancreatitis

Hao

Komar

Hart

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Chronic pancreatitis (CP) is a progressive inflammatory disease of the pancreas, leading to its fibrotic destruction. There are currently no drugs that can stop or slow the progression of the disease. The etiology of the disease is multifactorial, whereas recurrent attacks of acute pancreatitis are thought to precede the development of CP. A better understanding of the pathology of CP is needed to facilitate improved diagnosis and treatment strategies for this disease. The present paper develops a mathematical model of CP based on a dynamic network that includes macrophages, pancreatic stellate cells, and prominent cytokines that are present at high levels in the CP microenvironment. The model is represented by a system of partial differential equations. The model is used to explore in silico potential drugs that could slow the progression of the disease, for example infliximab (anti-TNF-α) and tocilizumab or siltuximab (anti-IL-6/IL-6R).mathematical model | chronic pancreatitis | drug studies

show abstract

Proteome Variations in Pancreatic Stellate Cells upon Stimulation with Proinflammatory Factors

Cited by 16 publications

References 64 publications

Pancreatic stellate cell secreted IL-6 stimulates STAT3 dependent invasiveness of pancreatic intraepithelial neoplasia and cancer cells

Pancreatic stellate cell secreted IL-6 stimulates STAT3 dependent invasiveness of pancreatic intraepithelial neoplasia and cancer cells

Pancreatic stellate cell: Pandora's box for pancreatic disease biology

Mathematical model of chronic pancreatitis

Contact Info

Product

Resources

About