scholarly journals Pancreatic Cancer Small Extracellular Vesicles (Exosomes): A Tale of Short- and Long-Distance Communication

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4844
Author(s):  
Mareike Waldenmaier ◽  
Tanja Seibold ◽  
Thomas Seufferlein ◽  
Tim Eiseler
Keyword(s):  
Pancreatic Cancer ◽  
Extracellular Vesicles ◽  
Drug Carriers ◽  
Tumor Formation ◽  
Pancreatic Stellate Cells ◽  
Ductal Adenocarcinoma ◽  
Long Distance ◽  
Diagnosis And Prognosis ◽  
Recent Advances ◽  
Biomarker Analysis

Even with all recent advances in cancer therapy, pancreatic cancer still has a dismal 5-year survival rate of less than 7%. The most prevalent tumor subtype is pancreatic ductal adenocarcinoma (PDAC). PDACs display an extensive crosstalk with their tumor microenvironment (TME), e.g., pancreatic stellate cells, but also immune cells to regulate tumor growth, immune evasion, and metastasis. In addition to crosstalk in the local TME, PDACs were shown to induce the formation of pre-metastatic niches in different organs. Recent advances have attributed many of these interactions to intercellular communication by small extracellular vesicles (sEVs, exosomes). These nanovesicles are derived of endo-lysosomal structures (multivesicular bodies) with a size range of 30–150 nm. sEVs carry various bioactive cargos, such as proteins, lipids, DNA, mRNA, or miRNAs and act in an autocrine or paracrine fashion to educate recipient cells. In addition to tumor formation, progression, and metastasis, sEVs were described as potent biomarker platforms for diagnosis and prognosis of PDAC. Advances in sEV engineering have further indicated that sEVs might once be used as effective drug carriers. Thus, extensive sEV-based communication and applications as platform for biomarker analysis or vehicles for treatment suggest a major impact of sEVs in future PDAC research.

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

2018 ◽  
Vol 115 (16) ◽  
pp. E3769-E3778 ◽  
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.

scholarly journals Resveratrol Ameliorates the Malignant Progression of Pancreatic Cancer by Inhibiting Hypoxia-induced Pancreatic Stellate Cell Activation

2020 ◽  
Vol 29 ◽  
pp. 096368972092998
Author(s):  
Ying Xiao ◽  
Tao Qin ◽  
Liankang Sun ◽  
Weikun Qian ◽  
Jie Li ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Tumor Formation ◽  
Malignant Progression ◽  
Pancreatic Stellate Cells ◽  
Ductal Adenocarcinoma ◽  
Antitumor Effects ◽  
Mesenchymal Transition ◽  
Pancreatic Cancer Cells

Pancreatic cancer is characterized by a hypoxic tumor microenvironment, which is primarily caused by massive fibrosis with pancreatic stellate cells (PSCs) as a main component. Our previous studies have shown that resveratrol can significantly inhibit pancreatic cancer. However, whether resveratrol can inhibit hypoxia-induced cancer development remains unclear. The objective of this study was to explore whether PSCs and hypoxia synergistically mediate aggressiveness in pancreatic cancer and detect the potential pleiotropic protective effects of resveratrol on hypoxia-induced pancreatic cancer progression. Human PSCs were treated with vehicle or resveratrol under normoxic or hypoxic conditions (3% O2), and PSC activation was assessed by immunofluorescence staining. SiRNA was used to silence hypoxia-inducible factor 1 (HIF-1) expression. The invasive capacity of Panc-1 and Mia Paca-2 cells cocultured with conditioned medium from PSCs was assessed by Transwell assays. To examine tumor formation kinetics, KPC (LSL-KrasG12D/+, Trp53fl/+, and Pdx1-Cre) mice were sacrificed at different time points. To investigate the antitumor effects of resveratrol in vivo, 8-wk-old KPC mice were divided into two groups and treated daily with or without 50 mg/kg resveratrol. Our data indicate that hypoxia induces PSC activation via HIF-1 and that the interleukin 6, vascular endothelial growth factor A, and stromal cell-derived factor 1 derived from activated PSCs promote both invasion and the epithelial–mesenchymal transition and inhibit apoptosis in pancreatic cancer cells. However, resveratrol inhibits hypoxia-induced PSC activation, blocks the interplay between PSCs and pancreatic cancer cells, and suppresses the malignant progression of pancreatic cancer and stromal desmoplasia in a KPC mouse model. Our data highlight that activated PSCs and intratumoral hypoxia are essential targets for novel strategies to prevent tumor–microenvironment interactions. Furthermore, the polyphenolic compound resveratrol effectively ameliorates the malignant progression of pancreatic ductal adenocarcinoma.

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

Biomolecules ◽  
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.

scholarly journals Tumor-Derived Extracellular Vesicles Inhibit Natural Killer Cell Function in Pancreatic Cancer

Cancers ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 874 ◽  
Author(s):  
Jiangang Zhao ◽  
Hans A. Schlößer ◽  
Zhefang Wang ◽  
Jie Qin ◽  
Jiahui Li ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Nk Cells ◽  
Extracellular Vesicles ◽  
Nk Cell ◽  
Killer Cell ◽  
Pancreatic Cancer Cell Line ◽  
Ductal Adenocarcinoma ◽  
Metastatic Niche ◽  
Niche Formation ◽  
Tgf Β1

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. Tumor-derived extracellular vesicles (EVs) induce pre-metastatic niche formation to promote metastasis. We isolated EVs from a highly-metastatic pancreatic cancer cell line and patient-derived primary cancer cells by ultracentrifugation. The protein content of EVs was analyzed by mass spectrometry. The effects of PDAC-derived EVs on natural kill (NK) cells were investigated by flow cytometry. The serum EVs’ TGF-β1 levels were quantified by ELISA. We found that integrins were enriched in PDAC-derived EVs. The expression of NKG2D, CD107a, TNF-α, and INF-γ in NK cells was significantly downregulated after co-culture with EVs. NK cells also exhibited decreased levels of CD71 and CD98, as well as impaired glucose uptake ability. In addition, NK cell cytotoxicity against pancreatic cancer stem cells was attenuated. Moreover, PDAC-derived EVs induced the phosphorylation of Smad2/3 in NK cells. Serum EVs’ TGF-β1 was significantly increased in PDAC patients. Our findings emphasize the immunosuppressive role of PDAC-derived EVs and provide new insights into our understanding of NK cell dysfunction regarding pre-metastatic niche formation in PDAC.

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

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 640 ◽  
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.

scholarly journals Extracellular vesicles in pancreatic cancer progression and therapies

2021 ◽  
Vol 12 (11) ◽  
Author(s):  
Chao-Hui Chang ◽  
Siim Pauklin
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Extracellular Vesicles ◽  
Cancer Progression ◽  
Delayed Diagnosis ◽  
Cell Types ◽  
Tumour Microenvironment ◽  
Ductal Adenocarcinoma ◽  
Cancer Hallmarks ◽  
Pancreatic Cancers

AbstractPancreatic cancer (PC) is one of the leading causes of cancer-related death worldwide due to delayed diagnosis and limited treatments. More than 90% of all pancreatic cancers are pancreatic ductal adenocarcinoma (PDAC). Extensive communication between tumour cells and other cell types in the tumour microenvironment have been identified which regulate cancer hallmarks during pancreatic tumorigenesis via secretory factors and extracellular vesicles (EVs). The EV-capsuled factors not only facilitate tumour growth locally, but also enter circulation and reach distant organs to construct a pre-metastatic niche. In this review, we delineate the key factors in pancreatic ductal adenocarcinoma derived EVs that mediate different tumour processes. Also, we highlight the factors that are related to the crosstalk with cancer stem cells/cancer-initiating cells (CSC/CIC), the subpopulation of cancer cells that can efficiently metastasize and resist currently used chemotherapies. Lastly, we discuss the potential of EV-capsuled factors in early diagnosis and antitumour therapeutic strategies.

scholarly journals Characterization of Circulating IL-7R Positive Cell Populations for Early Detection of Pancreatic Ductal Adenocarcinoma

2021 ◽  
Vol 10 (18) ◽  
pp. 4157
Author(s):  
Sun-Hee Heo ◽  
Sung Ill Jang ◽  
So Young Kim ◽  
Bongkun Choi ◽  
Dong Ki Lee ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Mouse Model ◽  
Cancer Patients ◽  
Tumor Formation ◽  
Ductal Adenocarcinoma ◽  
Effector Memory ◽  
Discrete Subset ◽  
Normal Individuals ◽  
Syngeneic Mouse Model

(1) Background: Pancreatic cancer is a high devastating disease with the lowest survival rate among all common cancers due to difficulties in early diagnosis. The purpose of this study was to identify and characterize the distinct subset of blood cell population elevated in peripheral blood mononuclear cells (PBMC) of pancreatic cancer to evaluate the potential markers for diagnosis of pancreatic cancer; (2) Methods: We analyzed differential gene expression in PBMC from normal individuals and pancreatic cancer patients utilizing transcriptome analysis. Flow cytometry analysis was applied to identify the discrete subset of interleukin-7 receptor (IL-7R) expressing cells in these cells. The expression of IL-7R during tumorigenesis was determined in syngeneic mouse model of pancreatic cancer in vivo; (3) Results: PBMC from pancreatic cancer patients expressed elevated IL-7R mRNA compared to healthy control individuals. IL-7R expressing cells rapidly appeared from the early stages of the onset of tumor formation in syngeneic pancreatic cancer mouse model in vivo. The discrete subset of IL-7R positive cells mainly consist of naive T, central memory T, and effector memory T cells; (4) Conclusions: Taken together, our present findings suggest that pancreatic cancer patients expressed higher level of IL-7R expression in PBMC that rapidly emerged from the onset of early pancreatic tumor formation in vivo than normal individuals. Thus, it can be used as a novel biological marker for early events of pancreatic cancer development.

scholarly journals Primary Thromboprophylaxis in Pancreatic Cancer Patients: Why Clinical Practice Guidelines Should Be Implemented

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 618 ◽  
Author(s):  
Dominique Farge ◽  
Barbara Bournet ◽  
Thierry Conroy ◽  
Eric Vicaut ◽  
Janusz Rak ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Clinical Practice ◽  
Cancer Patients ◽  
Clinical Practice Guidelines ◽  
Practice Guidelines ◽  
Randomized Trials ◽  
Treatment Options ◽  
Locally Advanced ◽  
Ductal Adenocarcinoma ◽  
Recent Advances

Exocrine pancreatic ductal adenocarcinoma, simply referred to as pancreatic cancer (PC) has the worst prognosis of any malignancy. Despite recent advances in the use of adjuvant chemotherapy in PC, the prognosis remains poor, with fewer than 8% of patients being alive at 5 years after diagnosis. The prevalence of PC has steadily increased over the past decades, and it is projected to become the second-leading cause of cancer-related death by 2030. In this context, optimizing and integrating supportive care is important to improve quality of life and survival. Venous thromboembolism (VTE) is a common but preventable complication in PC patients. VTE occurs in one out of five PC patients and is associated with significantly reduced progression-free survival and overall survival. The appropriate use of primary thromboprophylaxis can drastically and safely reduce the rates of VTE in PC patients as shown from subgroup analysis of non-PC targeted placebo-controlled randomized trials of cancer patients and from two dedicated controlled randomized trials in locally advanced PC patients receiving chemotherapy. Therefore, primary thromboprophylaxis with a Grade 1B evidence level is recommended in locally advanced PC patients receiving chemotherapy by the International Initiative on Cancer and Thrombosis clinical practice guidelines since 2013. However, its use and potential significant clinical benefit continues to be underrecognized worldwide. This narrative review aims to summarize the main recent advances in the field including on the use of individualized risk assessment models to stratify the risk of VTE in each patient with individual available treatment options.

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

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.

Sign in / Sign up

Export Citation Format

Share Document