Heterogeneous Pancreatic Stellate Cells Are Powerful Contributors to the Malignant Progression of Pancreatic Cancer

Pancreatic cancer is associated with highly malignant tumors and poor prognosis due to strong therapeutic resistance. Accumulating evidence shows that activated pancreatic stellate cells (PSC) play an important role in the malignant progression of pancreatic cancer. In recent years, the rapid development of single-cell sequencing technology has facilitated the analysis of PSC population heterogeneity, allowing for the elucidation of the relationship between different subsets of cells with tumor development and therapeutic resistance. Researchers have identified two spatially separated, functionally complementary, and reversible subtypes, namely myofibroblastic and inflammatory PSC. Myofibroblastic PSC produce large amounts of pro-fibroproliferative collagen fibers, whereas inflammatory PSC express large amounts of inflammatory cytokines. These distinct cell subtypes cooperate to create a microenvironment suitable for cancer cell survival. Therefore, further understanding of the differentiation of PSC and their distinct functions will provide insight into more effective treatment options for pancreatic cancer patients.

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Immune Cell Modulation of the Extracellular Matrix Contributes to the Pathogenesis of Pancreatic Cancer

Biomolecules ◽

10.3390/biom11060901 ◽

2021 ◽

Vol 11 (6) ◽

pp. 901

Author(s):

Ramiz S. Ahmad ◽

Timothy D. Eubank ◽

Slawomir Lukomski ◽

Brian A. Boone

Keyword(s):

Pancreatic Cancer ◽

Extracellular Matrix ◽

Immune Cells ◽

Immune Cell ◽

Treatment Strategies ◽

Stellate Cells ◽

Pancreatic Stellate Cells ◽

Ductal Adenocarcinoma ◽

Cellular Mechanisms ◽

Novel Treatment Strategies

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a five-year survival rate of only 9%. PDAC is characterized by a dense, fibrotic stroma composed of extracellular matrix (ECM) proteins. This desmoplastic stroma is a hallmark of PDAC, representing a significant physical barrier that is immunosuppressive and obstructs penetration of cytotoxic chemotherapy agents into the tumor microenvironment (TME). Additionally, dense ECM promotes hypoxia, making tumor cells refractive to radiation therapy and alters their metabolism, thereby supporting proliferation and survival. In this review, we outline the significant contribution of fibrosis to the pathogenesis of pancreatic cancer, with a focus on the cross talk between immune cells and pancreatic stellate cells that contribute to ECM deposition. We emphasize the cellular mechanisms by which neutrophils and macrophages, specifically, modulate the ECM in favor of PDAC-progression. Furthermore, we investigate how activated stellate cells and ECM influence immune cells and promote immunosuppression in PDAC. Finally, we summarize therapeutic strategies that target the stroma and hinder immune cell promotion of fibrogenesis, which have unfortunately led to mixed results. An enhanced understanding of the complex interactions between the pancreatic tumor ECM and immune cells may uncover novel treatment strategies that are desperately needed for this devastating disease.

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Multifunctional role of pancreatic stellate cells in pancreatic cancer

Annals of Pancreatic Cancer ◽

10.21037/apc.2019.05.02 ◽

2019 ◽

Vol 2 ◽

pp. 10-10 ◽

Cited By ~ 4

Author(s):

Alpha R. Mekapogu ◽

Srinivasa P. Pothula ◽

Romano C. Pirola ◽

Jeremy S. Wilson ◽

Minoti V. Apte

Keyword(s):

Pancreatic Cancer ◽

Stellate Cells ◽

Pancreatic Stellate Cells

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Pancreatic stellate cells regulate branched-chain amino acid metabolism in pancreatic cancer

Annals of Translational Medicine ◽

10.21037/atm-21-761 ◽

2021 ◽

Vol 9 (5) ◽

pp. 417-417

Author(s):

Wenna Jiang ◽

Lu Qiao ◽

Yawei Han ◽

Aimin Zhang ◽

Haohua An ◽

...

Keyword(s):

Pancreatic Cancer ◽

Amino Acid ◽

Amino Acid Metabolism ◽

Acid Metabolism ◽

Stellate Cells ◽

Pancreatic Stellate Cells ◽

Branched Chain Amino Acid ◽

Branched Chain

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ROLE OF PANCREATIC STELLATE CELLS IN PROGRESSION OF PANCREATIC CANCER

Journal of the Grodno State Medical University ◽

10.25298/2221-8785-2018-16-2-125-131 ◽

2018 ◽

Vol 16 (2) ◽

pp. 125-131

Author(s):

L. A. Mozheiko ◽

Keyword(s):

Pancreatic Cancer ◽

Stellate Cells ◽

Pancreatic Stellate Cells

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Relationship between pancreatic stellate cells and pancreatic cancer

World Chinese Journal of Digestology ◽

10.11569/wcjd.v16.i33.3782 ◽

2008 ◽

Vol 16 (33) ◽

pp. 3782

Author(s):

Jian-Qi Ni ◽

Xiao-Hua Jiang ◽

Wen-Hao Tang

Keyword(s):

Pancreatic Cancer ◽

Stellate Cells ◽

Pancreatic Stellate Cells

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Proton Pump Inhibitors Reduce Pancreatic Adenocarcinoma Progression by Selectively Targeting H+, K+-ATPases in Pancreatic Cancer and Stellate Cells

Cancers ◽

10.3390/cancers12030640 ◽

2020 ◽

Vol 12 (3) ◽

pp. 640 ◽

Cited By ~ 5

Author(s):

Marco Tozzi ◽

Christiane E. Sørensen ◽

Lara Magni ◽

Nynne M. Christensen ◽

Rayhana Bouazzi ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cell Proliferation ◽

Proton Pump Inhibitors ◽

Proton Pump ◽

Human Cancer ◽

Stellate Cells ◽

In Vivo Studies ◽

Pancreatic Stellate Cells ◽

Ductal Adenocarcinoma ◽

Collagen Secretion

Pancreatic duct cells are equipped with acid/base transporters important for exocrine secretion. Pancreatic ductal adenocarcinoma (PDAC) cells may utilize such transporters to acidify extracellular tumor microenvironment, creating a niche favoring cell proliferation, fibrosis and resistance to chemotherapy—all contributing to the notoriously bad prognosis of this disease. Here, we report that gastric and non-gastric H+, K+-ATPases (coded by ATP4A and ATP12A) are overexpressed in human and murine pancreatic cancer and that we can target them specifically with proton pump inhibitors (PPIs) and potassium-competitive acid blockers (P-CABs) in in vitro models of PDAC. Focusing on pantoprazole, we show that it significantly reduced human cancer cell proliferation by inhibiting cellular H+ extrusion, increasing K+ conductance and promoting cyclin D1-dependent cell cycle arrest and preventing STAT3 activation. Pantoprazole also decreased collagen secretion from pancreatic stellate cells. Importantly, in vivo studies show that pantoprazole treatment of tumor-bearing mice reduced tumor size, fibrosis and expression of angiogenic markers. This work provides the first evidence that H+, K+-ATPases contribute to PDAC progression and that these can be targeted by inhibitors of these pumps, thus proving a promising therapeutic strategy.

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