Isolation of Quiescent Human Pancreatic Stellate Cells: A Promising in vitro Tool for Studies of Human Pancreatic Stellate Cell Biology

Vonlaufen, Alain; Phillips, Phoebe A.; Yang, Lu; Xu, Zhijian; Fiala-Beer, Eva; Zhang, Xuguo; Pirola, Romano C.; Wilson, Jeremy S.; Apte, Minoti V.

doi:10.1159/000260900

Cited by 58 publications

(51 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Histopathologically, PDAC consists of malignant glands infiltrating into fibrotic stroma composed mostly of extracellular matrix, which consists of type 1 collagen, fibronectin, hyaluronan and proteoglycans (20). Pancreatic stellate cells (PSCs) are resident cells of the pancreas, comprise approximately 5% of the pancreatic parenchyma (21) and have the important function of maintaining the balance of extracellular matrix synthesis and degradation (22). PSCs undergo a phenotypic transformation from a quiescent state to a myofibroblast-like state during times of pancreatic injury in response to stressors such as ethanol, oxidants and various cytokines (21)(22)(23)(24).…”

Section: Discussionmentioning

confidence: 99%

“…Pancreatic stellate cells (PSCs) are resident cells of the pancreas, comprise approximately 5% of the pancreatic parenchyma (21) and have the important function of maintaining the balance of extracellular matrix synthesis and degradation (22). PSCs undergo a phenotypic transformation from a quiescent state to a myofibroblast-like state during times of pancreatic injury in response to stressors such as ethanol, oxidants and various cytokines (21)(22)(23)(24). The results of our study suggest that ATGL might mediate an increase in tumor stroma, possibly by increasing free fatty acid content in the tumor microenvironment, thereby contributing to the phenotypic change of PSCs into an extracellular matrixsecreting state.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Adipose Triglyceride Lipase (ATGL) Expression Is Associated with Adiposity and Tumor Stromal Proliferation in Patients with Pancreatic Ductal Adenocarcinoma

Grace

Meeks

Chen

et al. 2017

View full text Add to dashboard Cite

Abstract. Background: Obesity is an established risk factor for the development of pancreatic ductal adenocarcinoma (PDACPancreatic ductal adenocarcinoma (PDAC) carries an extremely poor prognosis, with a 5-year survival rate of less than 6% in the United States (1). The low survival rate is due to the late stage at which patients are usually diagnosed, with only 20% of patients being eligible for tumor resection at the time of diagnosis (1). Several risk factors for PDAC are firmly established, such as chronic pancreatitis (2), cigarette smoking (3), family history of pancreatic cancer (4), and diabetes mellitus (5).Both epidemiological and experimental studies have also linked obesity to the development of PDAC. In a large casecontrol study, Silverman et al. (6) showed obesity portends a 50-60% increased risk of PDAC in both men and women. Similarly, a pooled case-control analysis using data from the Pancreatic Cancer Cohort Consortium (PanScan) comparing 2170 PDAC cases to 2209 controls showed a positive association between increasing body mass index (BMI) and risk of PDAC [adjusted odds ratio (aOR) for the highest vs. lowest BMI quartile=1.33, 95% confidence interval (CI)= 1.12-1.58, p<0.001 (7).The mechanism of how obesity increases PDAC risk is poorly understood. Previous studies have shown that increased peritumoral fat density promotes metastasis and increases mortality in patients with PDAC (8). Adipose triglyceride lipase (ATGL) is a lipase in adipose tissue that catabolizes the first step in triglyceride hydrolysis and is responsible for the release of free fatty acids. Another lipase called monoacylglycerol lipase has been shown to be overexpressed in human cancer cell lines and to promote in vivo tumor growth via 'feeding' cancer cells with free fatty acids (9). Previous studies of breast cancer demonstrated increased peritumoral ATGL expression in fat cells of obese 699 Τhis article is freely accessible online.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Adipose Triglyceride Lipase (ATGL) Expression Is Associated with Adiposity and Tumor Stromal Proliferation in Patients with Pancreatic Ductal Adenocarcinoma

Grace

Meeks

Chen

et al. 2017

View full text Add to dashboard Cite

show abstract

“…These factors play critical roles in the tumor-stromal interactions in pancreatic cancer. PDGF was reported to induce the proliferation and migration of PSCs through paracrine and autocrine pathways (24)(25)(26)(27). We previously reported that irradiated stromal fibroblasts increased the invasiveness of PCCs through the HGF-c-Met pathway (21).…”

Section: Discussionmentioning

confidence: 99%

Pirfenidone Inhibits Pancreatic Cancer Desmoplasia by Regulating Stellate Cells

et al. 2013

View full text Add to dashboard Cite

Pancreatic stellate cells (PSC), which are implicated in desmoplasia in pancreatic cancer, enhance the malignancy of cancer cells and confer resistance to established treatments. We investigated whether the antifibrotic agent pirfenidone can suppress desmoplasia and exert antitumor effects against pancreatic cancer. Primary PSCs were established from pancreatic cancer tissue obtained during surgery. In vitro, pirfenidone inhibited the proliferation, invasiveness, and migration of PSCs in a dose-dependent manner. Although supernatants of untreated PSCs increased the proliferation, invasiveness, and migration of pancreatic cancer cells (PCC), supernatants of pirfenidone-treated PSCs decreased these effects. Exposure to PCC supernatant increased the production of platelet-derived growth factor-A, hepatic growth factor, collagen type I, fibronectin, and periostin in PSCs, which was significantly reduced by pirfenidone. Mice were subcutaneously implanted with PCCs (SUIT-2 cells) and PSCs into the right flank and PCCs alone into the left flank. Oral administration of pirfenidone to these mice significantly reduced tumor growth of co-implanted PCCs and PSCs, but not of PCCs alone. Pirfenidone also decreased the proliferation of PSCs and the deposition of collagen type I and periostin in tumors. In mice with orthotopic tumors consisting of PCCs co-implanted with PSCs, pirfenidone suppressed tumor growth, reduced the number of peritoneal disseminated nodules, and reduced the incidence of liver metastasis. Pirfenidone in combination with gemcitabine more effectively suppressed orthotopic tumor growth compared with pirfenidone or gemcitabine alone. In conclusion, our findings indicate that pirfenidone is a promising antitumor agent for pancreatic cancer, owing to its suppression of desmoplasia through regulating PSCs. Cancer Res; 73(7); 2345-56. Ó2013 AACR.

show abstract

“…This particular pattern of pancreatic cell secretome mediates effects on tumor growth, invasion, metastasis and resistance to chemotherapy and is modulated by CSCs, through release of mitogenic and fibrogenic stimulants, such as Transforming Growth Factor β1 platelet-derived growth factor, sonic hedgehog, galectin 3, endothelin 1 and serine protease inhibitor nexin 2 [97]. Recognition of their importance in tumoral behaviour led efforts to isolate, cultivate and immortalize them for further manipulation with therapeutic purposes [98][99][100]. Upon activation, pancreatic stellate cells suffer a shift of phenotype towards myofibroblast morphology and a subsequent switch of protein expression [101].…”

Section: A Pancreatic Stellate Cellsmentioning

confidence: 99%