Desmoplastic Reaction in Pancreatic Cancer

Apte, Minoti V.; Park, S.; Phillips, Phoebe A.; Santucci, Nicole; Goldstein, David; Kumar, Rakesh K.; Ramm, Grant A.; Büchler, Markus W.; Frieß, Helmut; McCarroll, Joshua A.; Keogh, G.; Merrett, Neil D.; Pirola, Romano C.; Wilson, Jeremy S.

doi:10.1097/00006676-200410000-00002

Cited by 560 publications

(519 citation statements)

References 29 publications

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“…PSC (on which primary cilia have been detected) have been linked to the initiation of stromal reaction in PDAC and CP [36], therefore it would seem logical that the increase of PC in PDAC and CP stroma may be triggered through pancreatic stellate cells, since these cells also promote tumor cell proliferation [43,52]. This is consistent with our remarkable observation of very long and numerous PC in fibrotic areas/tubular complexes of CP.…”

Section: Discussionsupporting

confidence: 88%

“…Given the PC re-distribution from the epithelium to the stroma, and since pancreatic stellate cells (PSC) play an important role with regard to the desmoplastic stroma-reaction in PDAC [36], we next examined whether PSC express PC and therefore may be able to transfer HH signals. Immunohistochemistry demonstrated that PC are formed by PSC as shown in Fig 7D. …”

Section: Primary Cilia On Pancreatic Stellate Cells and Cancer Cell Lmentioning

confidence: 99%

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Epithelial to stromal redistribution of primary cilia during pancreatic carcinogenesis

et al. 2012

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Section: Discussionsupporting

confidence: 88%

Section: Primary Cilia On Pancreatic Stellate Cells and Cancer Cell Lmentioning

confidence: 99%

Epithelial to stromal redistribution of primary cilia during pancreatic carcinogenesis

et al. 2012

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“…In pancreatic cancer, a dense stroma forms around the tumor cells and collagen synthesis by PSCs increases after exposure to inflammatory cytokines such as TGF-β, TNF-α and IL-10 [31,32]. In fact, prior studies have shown decreased response to gemcitabine and radiation when cancer cells were exposed to PSCs [7]. In addition, interactions between the tumor and surrounding stromal cells have been linked with tumorigenesis, metastasis, and an increased expression of cancer stem cell-related genes [6,33].…”

Section: Discussionmentioning

confidence: 99%

“…Pancreatic stellate cells (PSCs) are primarily responsible for the desmoplastic response observed in pancreatic cancer [7,8]. PSCs are myofibroblast-like cells residing in the periacinar spaces that are typically quiescent under normal physiological conditions, but can become activated in response to pancreatic injury.…”

Section: Introductionmentioning

confidence: 99%

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Paracrine Activation of Chemokine Receptor CCR9 Enhances The Invasiveness of Pancreatic Cancer Cells

Heinrich

Arrington

et al. 2013

Cancer Microenvironment

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Chemokine receptors mediate cancer progression and metastasis. We have previously examined chemokine receptor CCR9 expression in pancreatic cancer. Here, our objective was to evaluate pancreatic stellate cells (PSCs) as a source of CCL25, the CCR9 ligand, and as an activator of CCL25-CCR9 signaling in pancreatic cancer cells. CCL25 and CCR9 expression levels in human pancreatic cancer tissues and normal human pancreas were assessed by immunohistochemsitry. In vitro secretion of CCL25 in PSCs and PANC-1 cells was verified by enzyme-linked immunosorbent assay. Pancreatic cancer cell invasion was measured using a modified Boyden chamber assay with CCL25, PSC secreted proteins, and PANC-1 secreted proteins as the chemoattractant. There was immunostaining for CCR9 expression in human pancreatic tumor tissues, but not in normal pancreatic tissue. CCL25 expression was absent in the normal pancreatic tissue sample, but was observed in cancer cells and in the stromal cells surrounding the tumor. In vitro, both PANC-1 cells and PSCs secreted CCL25. In an invasion assay, exposure to CCL25, PSC-and PANC-1-conditioned media significantly increased the invasiveness of PANC-1 cells. Inclusion of a CCR9-neutralizing antibody in the invasion assay blocked the increase in invading cells elicited by the chemoattractants. Our studies show that pancreatic cancer invasiveness is enhanced by autocrine and paracrine stimulation of CCR9. PSCs in the tumor microenvironment appear to contribute to paracrine activation of CCR9. Investigations into CCR9 as a potential therapeutic target in pancreatic cancer must consider cancer cell autocrine signaling and also paracrine signaling from interactions in the tumor microenvironment.

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Hypoxia‐driven paracrine osteopontin/integrin αvβ3 signaling promotes pancreatic cancer cell epithelial–mesenchymal transition and cancer stem cell‐like properties by modulating forkhead box protein M1

Cao

Sun

et al. 2018

Molecular Oncology

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Pancreatic stellate cells (PSCs), a key component of the tumor microenvironment, contribute to tumor invasion, metastasis, and chemoresistance. Osteopontin (OPN), a phosphorylated glycoprotein, is overexpressed in pancreatic cancer. However, OPN expression in PSCs and its potential roles in tumor–stroma interactions remain unclear. The present study first showed that OPN is highly expressed and secreted in activated PSCs driven by hypoxia, and this process is in a ROS‐dependent manner; in addition, OPN was shown to be involved in the PSC‐induced epithelial–mesenchymal transition (EMT) and cancer stem cell (CSC)‐like properties of pancreatic cancer cells (PCCs). Mechanistically, OPN from activated PSCs interacts with the transmembrane receptor integrin αvβ3 on PCCs to upregulate forkhead box protein M1 (FOXM1) expression and induce malignant phenotypes of PCCs. Moreover, the Akt and Erk pathways participate in OPN/integrin αvβ3 axis‐induced FOXM1 expression of PCCs. Our further analysis showed that OPN and FOXM1 are significantly upregulated in pancreatic cancer tissues and are associated with poor clinical outcome, indicating that OPN and FOXM1 might be considered as diagnostic and prognostic biomarkers for patients with pancreatic cancer. In conclusion, we show here for the first time that OPN promotes the EMT and CSC‐like properties of PCCs by activating the integrin αvβ3‐Akt/Erk‐FOXM1 cascade in a paracrine manner, suggesting that targeting the tumor microenvironment represents a promising therapeutic strategy in pancreatic cancer.

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Desmoplastic Reaction in Pancreatic Cancer

Cited by 560 publications

References 29 publications

Epithelial to stromal redistribution of primary cilia during pancreatic carcinogenesis

Epithelial to stromal redistribution of primary cilia during pancreatic carcinogenesis

Paracrine Activation of Chemokine Receptor CCR9 Enhances The Invasiveness of Pancreatic Cancer Cells

Hypoxia‐driven paracrine osteopontin/integrin αvβ3 signaling promotes pancreatic cancer cell epithelial–mesenchymal transition and cancer stem cell‐like properties by modulating forkhead box protein M1

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