Stellate Cells Aid Growth-Permissive Metabolic Reprogramming and Promote Gemcitabine Chemoresistance in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC), also known as pancreatic cancer (PC), is characterized by an overall poor prognosis and a five-year survival that is less than 10%. Characteristic features of the tumor are the presence of a prominent desmoplastic stromal response, an altered metabolism, and profound resistance to cancer drugs including gemcitabine, the backbone of PDAC chemotherapy. The pancreatic stellate cells (PSCs) constitute the major cellular component of PDAC stroma. PSCs are essential for extracellular matrix assembly and form a supportive niche for tumor growth. Various cytokines and growth factors induce activation of PSCs through autocrine and paracrine mechanisms, which in turn promote overall tumor growth and metastasis and induce chemoresistance. To maintain growth and survival in the nutrient-poor, hypoxic environment of PDAC, tumor cells fulfill their high energy demands via several unconventional ways, a process generally referred to as metabolic reprogramming. Accumulating evidence indicates that activated PSCs not only contribute to the therapy-resistant phenotype of PDAC but also act as a nutrient supplier for the tumor cells. However, the precise molecular links between metabolic reprogramming and an acquired therapy resistance in PDAC remain elusive. This review highlights recent findings indicating the importance of PSCs in aiding growth-permissive metabolic reprogramming and gemcitabine chemoresistance in PDAC.

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IL-17B/RB Activation in Pancreatic Stellate Cells Promotes Pancreatic Cancer Metabolism and Growth

Cancers ◽

10.3390/cancers13215338 ◽

2021 ◽

Vol 13 (21) ◽

pp. 5338

Author(s):

Jiahui Li ◽

Xiaolin Wu ◽

Lars Schiffmann ◽

Thomas MacVicar ◽

Chenghui Zhou ◽

...

Keyword(s):

Oxidative Phosphorylation ◽

Tumor Growth ◽

Tumor Cells ◽

Feedback Loop ◽

Cancer Metabolism ◽

Cell Mass ◽

Stellate Cells ◽

Pancreatic Stellate Cells ◽

Ductal Adenocarcinoma ◽

Metabolic Cooperation

In pancreatic ductal adenocarcinoma (PDAC), the tumor stroma constitutes most of the cell mass and contributes to therapy resistance and progression. Here we show a hitherto unknown metabolic cooperation between pancreatic stellate cells (PSCs) and tumor cells through Interleukin 17B/Interleukin 17B receptor (IL-17B/IL-17RB) signaling. Tumor-derived IL-17B carrying extracellular vesicles (EVs) activated stromal PSCs and induced the expression of IL-17RB. PSCs increased oxidative phosphorylation while reducing mitochondrial turnover. PSCs activated tumor cells in a feedback loop. Tumor cells subsequently increased oxidative phosphorylation and decreased glycolysis partially via IL-6. In vivo, IL-17RB overexpression in PSCs accelerated tumor growth in a co-injection xenograft mouse model. Our results demonstrate a tumor-to-stroma feedback loop increasing tumor metabolism to accelerate tumor growth under optimal nutritional conditions.

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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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Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor–stroma crosstalk

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1722434115 ◽

2018 ◽

Vol 115 (16) ◽

pp. E3769-E3778 ◽

Cited By ~ 37

Author(s):

Carlos A. Orozco ◽

Neus Martinez-Bosch ◽

Pedro E. Guerrero ◽

Judith Vinaixa ◽

Tomás Dalotto-Moreno ◽

...

Keyword(s):

Pancreatic Cancer ◽

Tumor Cells ◽

Cancer Progression ◽

Pancreatic Tumor ◽

Therapeutic Potential ◽

Tumor Formation ◽

Pancreatic Stellate Cells ◽

Ductal Adenocarcinoma ◽

Migration And Invasion ◽

Regulatory Pathways

Pancreatic ductal adenocarcinoma (PDA) remains one of the most lethal tumor types, with extremely low survival rates due to late diagnosis and resistance to standard therapies. A more comprehensive understanding of the complexity of PDA pathobiology, and especially of the role of the tumor microenvironment in disease progression, should pave the way for therapies to improve patient response rates. In this study, we identify galectin-1 (Gal1), a glycan-binding protein that is highly overexpressed in PDA stroma, as a major driver of pancreatic cancer progression. Genetic deletion of Gal1 in a Kras-driven mouse model of PDA (Ela-KrasG12Vp53−/−) results in a significant increase in survival through mechanisms involving decreased stroma activation, attenuated vascularization, and enhanced T cell infiltration leading to diminished metastasis rates. In a human setting, human pancreatic stellate cells (HPSCs) promote cancer proliferation, migration, and invasion via Gal1-driven pathways. Moreover, in vivo orthotopic coinjection of pancreatic tumor cells with Gal1-depleted HPSCs leads to impaired tumor formation and metastasis in mice. Gene-expression analyses of pancreatic tumor cells exposed to Gal1 reveal modulation of multiple regulatory pathways involved in tumor progression. Thus, Gal1 hierarchically regulates different events implicated in PDA biology including tumor cell proliferation, invasion, angiogenesis, inflammation, and metastasis, highlighting the broad therapeutic potential of Gal1-specific inhibitors, either alone or in combination with other therapeutic modalities.

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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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Tumor Cell Thrombin/PAR-1 Signaling Drives Pancreatic Ductal Adenocarcinoma Growth and Dissemination

Blood ◽

10.1182/blood.v126.23.1070.1070 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1070-1070

Author(s):

Matthew J. Flick ◽

Cheryl Rewerts ◽

Carolina Cruz ◽

Joseph S. Palumbo ◽

James P. Luyendyk ◽

...

Keyword(s):

Pancreatic Cancer ◽

Tumor Growth ◽

Tumor Cell ◽

Tumor Cells ◽

Coagulation System ◽

Ductal Adenocarcinoma ◽

Parental Line ◽

Experimental Metastasis ◽

Primary Tumor Growth ◽

Wild Type

Abstract Pancreatic ductal adenocarcinoma (PDAC) accounts for ~85% of diagnosed pancreatic cancers and is among the most lethal malignancies. The 5-year survival rate for pancreatic cancer patients has improved only marginally in the last 40 years (3% → 7%), with effectively no change in survival profile for patients with metastatic disease (2%). High mortality is linked to the aggressive and invasive nature of the malignancy and poor efficacy of limited treatment options, which collectively highlight the need for novel treatment strategies. Notably, analyses of pancreatic cancer in patients and animal models have demonstrated that PDAC is associated with robust coagulation system activity. Previous work has shown that patient PDAC tumor cells often express high levels of tissue factor (TF) and protease-activated receptor (PAR)-1. To determine the potential contribution of tumor cell derived-TF and PAR-1 to PDAC growth and metastasis, a novel tumor cell line (termed KPC2) was derived from mice in which PDAC tumorigenesis was induced by activation of two established pancreatic cancer alleles, KrasG12D and Trp53R172H. In transplant studies, tumor growth and experimental metastasis were evaluated using KPC2 cells in which TF or PAR-1 expression was suppressed by shRNA knockdown. In addition, the interplay of tumor-derived TF and PAR-1 with host factors in promoting tumor growth and experimental metastasis were evaluated in mice with genetically imposed deficits in coagulation system components. TF knockdown (to ~10% of the parental line) in KPC2 cells resulted in a significant diminution of both primary tumor growth and experimental metastasis. This reduction appeared to be linked to thrombin activity as primary tumor growth and experimental metastasis of parental KPC2 cells were significantly reduced in fIIlow mice (which constitutively express 10% of normal prothrombin) relative to wild-type mice. PAR-1 knockout mice displayed similar KPC2 growth and experimental metastasis to wild-type animals indicating that stromal cell-derived PAR-1 was not significant determinant. In stark contrast, shRNA-mediated knockdown of PAR-1 in KPC2 (to ~10% of the parental line) cells resulted in significantly diminished tumor growth and experimental metastasis. Diminished tumor growth was linked to reduced expression of the macrophage chemokine MCP-1 and the metalloproteinase MMP9 by the tumor cells as well as reduced thrombin-stimulated ERK phosphorylation. Our results suggest that a major mechanism of PDAC growth and dissemination is through TF/thrombin-driven PAR-1 signaling on tumor cells. Disclosures No relevant conflicts of interest to declare.

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N-acetyl Cysteine Induces Quiescent-like Pancreatic Stellate Cells From an Active State and Attenuates Cancer-stroma Interactions

10.21203/rs.3.rs-89408/v1 ◽

2020 ◽

Author(s):

Haimin Feng ◽

Taiki Moriyama ◽

Kenoki Ohuchida ◽

Nan Sheng ◽

Chika Iwamoto ◽

...

Keyword(s):

Pancreatic Cancer ◽

Mouse Model ◽

Tumor Growth ◽

Lipid Droplets ◽

Stellate Cells ◽

Pancreatic Stellate Cells ◽

Type I ◽

Acetyl Cysteine ◽

And Migration

Abstract Background: Pancreatic stellate cells (PSCs) occupy the majority of the pancreatic cancer microenvironment, contributing to an aggressive behavior of pancreatic cancer cells (PCCs). Recently, anti-fibrotic agents have proven to be an effective strategy against cancer, but clinical trials have shown little efficacy and the driving mechanism remains unknown. N-acetyl-cysteine (NAC) is often used for cystic fibrosis. Pioglitazone, an agonist of peroxisome proliferator-activated receptor gamma, was often used for type II diabetes, but recently reported to inhibit metastasis of PCCs. However, few studies have focused on the effects of these two agents on cancer-stromal interactions. Method: We evaluated the expression of α-smooth muscle actin (α-SMA) and the number of lipid droplets in PSCs cultured with or without NAC. We also evaluated changes in invasiveness and proliferation in PSCs and PCCs after NAC treatment. Using an indirect coculture system, we investigated changes in proliferation, invasiveness, and migration of PSCs and PCCs. Combined treatment effects of NAC and pioglitazone were evaluated in PSCs and PCCs. In vivo, PCCs and PSCs were subcutaneously injected into mice to evaluate tumor growth. We co-transplanted KPC-derived organoids and PSCs using a splenic xenografted mouse model and evaluated the effect of combination of NAC and pioglitazone.Results: In vitro, NAC inhibited the proliferation, invasiveness, and migration of PSCs at a low concentration, but not those of PCCs. NAC treatment significantly reduced expression of α-SMA, collagen type I and fibronectin in PSCs. NAC-treated PSCs apparently present quiescent-like state with a high number of lipid droplets. Co-cultured PSCs and PCCs mutually promoted the proliferation, invasiveness, and migration of each other. However, these promotion effects were attenuated by NAC treatment. Pioglitazone maintained the NAC-induced quiescent-like state of PSCs, which were reactivated by PCC-supernatant, and enhanced chemosensitivity of PCCs. In vivo, administration of NAC to mice with subcutaneously implanted PCCs and PSCs significantly reduced tumor growth with less stromal components. The combination of NAC and pioglitazone suppressed liver metastasis in the 3D-organoid xenografted mouse model Conclusion: NAC suppressed activated PSCs and attenuates cancer-stromal interactions. NAC induces quiescent-like PSCs that were maintained in this state by pioglitazone treatment.

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The Role of Stellate Cells in Pancreatic Ductal Adenocarcinoma: Targeting Perspectives

Frontiers in Oncology ◽

10.3389/fonc.2020.621937 ◽

2021 ◽

Vol 10 ◽

Author(s):

Yang Wu ◽

Chun Zhang ◽

Kuirong Jiang ◽

Jens Werner ◽

Alexandr V. Bazhin ◽

...

Keyword(s):

Pancreatic Cancer ◽

Pancreatic Ductal Adenocarcinoma ◽

Stellate Cells ◽

Pancreatic Stellate Cells ◽

Ductal Adenocarcinoma ◽

Gastrointestinal Malignancy ◽

Desmoplastic Reaction ◽

Pancreatic Cancer Cells ◽

Promising Strategy

Pancreatic ductal adenocarcinoma (PDAC) is a gastrointestinal malignancy with a dismal clinical outcome. Accumulating evidence suggests that activated pancreatic stellate cells (PSCs), the major producers of extracellular matrix (ECM), drive the severe stromal/desmoplastic reaction in PDAC. Furthermore, the crosstalk among PSCs, pancreatic cancer cells (PCCs) as well as other stroma cells can establish a growth-supportive tumor microenvironment (TME) of PDAC, thereby enhancing tumor growth, metastasis, and chemoresistance via various pathways. Recently, targeting stroma has emerged as a promising strategy for PDAC therapy, and several novel strategies have been proposed. The aim of our study is to give a profound review of the role of PSCs in PDAC progression and recent advances in stroma-targeting strategies.

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The P2X7 Receptor Stimulates IL-6 Release from Pancreatic Stellate Cells and Tocilizumab Prevents Activation of STAT3 in Pancreatic Cancer Cells

Cells ◽

10.3390/cells10081928 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1928

Author(s):

Lara Magni ◽

Rayhana Bouazzi ◽

Hugo Heredero Olmedilla ◽

Patricia S. S. Petersen ◽

Marco Tozzi ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Cancer Cell ◽

P2x7 Receptor ◽

Stellate Cells ◽

Cell Interaction ◽

Pancreatic Stellate Cells ◽

Ductal Adenocarcinoma ◽

Pancreatic Cancer Cells ◽

Collagen Secretion

Pancreatic stellate cells (PSCs) are important pancreatic fibrogenic cells that interact with pancreatic cancer cells to promote the progression of pancreatic ductal adenocarcinoma (PDAC). In the tumor microenvironment (TME), several factors such as cytokines and nucleotides contribute to this interplay. Our aim was to investigate whether there is an interaction between IL-6 and nucleotide signaling, in particular, that mediated by the ATP-sensing P2X7 receptor (P2X7R). Using human cell lines of PSCs and cancer cells, as well as primary PSCs from mice, we show that ATP is released from both PSCs and cancer cells in response to mechanical and metabolic cues that may occur in the TME, and thus activate the P2X7R. Functional studies using P2X7R agonists and inhibitors show that the receptor is involved in PSC proliferation, collagen secretion and IL-6 secretion and it promotes cancer cell migration in a human PSC-cancer cell co-culture. Moreover, conditioned media from P2X7R-stimulated PSCs activated the JAK/STAT3 signaling pathway in cancer cells. The monoclonal antibody inhibiting the IL-6 receptor, Tocilizumab, inhibited this signaling. In conclusion, we show an important mechanism between PSC-cancer cell interaction involving ATP and IL-6, activating P2X7 and IL-6 receptors, respectively, both potential therapeutic targets in PDAC.

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NF-κB Dependent Chemokine Signaling in Pancreatic Cancer

Cancers ◽

10.3390/cancers11101445 ◽

2019 ◽

Vol 11 (10) ◽

pp. 1445 ◽

Cited By ~ 6

Author(s):

Geismann ◽

Schäfer ◽

Gundlach ◽

Hauser ◽

Egberts ◽

...

Keyword(s):

Pancreatic Cancer ◽

Tumor Cell ◽

Tumor Cells ◽

Target Genes ◽

Therapy Resistance ◽

Resistance Mechanisms ◽

Ductal Adenocarcinoma ◽

Therapeutic Resistance ◽

Intrinsic Resistance ◽

Chemokine Signaling

Pancreatic cancer is one of the carcinomas with the worst prognoses, as shown by its five-year survival rate of 9%. Although there have been new therapeutic innovations, the effectiveness of these therapies is still limited, resulting in pancreatic ductal adenocarcinoma (PDAC) becoming the second leading cause of cancer-related death in 2020 in the US. In addition to tumor cell intrinsic resistance mechanisms, this disease exhibits a complex stroma consisting of fibroblasts, immune cells, neuronal and vascular cells, along with extracellular matrix, all conferring therapeutic resistance by several mechanisms. The NF-κB pathway is involved in both the tumor cell-intrinsic and microenvironment-mediated therapeutic resistance by regulating the transcription of a plethora of target genes. These genes are involved in nearly all scenarios described as the hallmarks of cancer. In addition to classical regulators of apoptosis, NF-κB regulates the expression of chemokines and their receptors, both in the tumor cells and in cells of the microenvironment. These chemokines mediate autocrine and paracrine loops among tumor cells but also cross-signaling between tumor cells and the stroma. In this review, we will focus on NF-κB-mediated chemokine signaling, with an emphasis on therapy resistance in pancreatic cancer.

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