Extracellular Vesicles and Pancreatic Cancer: Insights on the Roles of miRNA, lncRNA, and Protein Cargos in Cancer Progression

Pancreatic cancer (PC) is among the most devastating digestive tract cancers worldwide. This cancer is characterized by poor diagnostic detection, lack of therapy, and difficulty in predicting tumorigenesis progression. Although mutations of key oncogenes and oncosuppressor involved in tumor growth and in immunosurveillance escape are known, the underlying mechanisms that orchestrate PC initiation and progression are poorly understood or still under debate. In recent years, the attention of many researchers has been concentrated on the role of extracellular vesicles and of a particular subset of extracellular vesicles, known as exosomes. Literature data report that these nanovesicles are able to deliver their cargos to recipient cells playing key roles in the pathogenesis and progression of many pancreatic precancerous conditions. In this review, we have summarized and discussed principal cargos of extracellular vesicles characterized in PC, such as miRNAs, lncRNAs, and several proteins, to offer a systematic overview of their function in PC progression. The study of extracellular vesicles is allowing to understand that investigation of their secretion and analysis of their content might represent a new and potential diagnostic and prognostic tools for PC.

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Elucidating the Role of Extracellular Vesicles in Pancreatic Cancer

Cancers ◽

10.3390/cancers13225669 ◽

2021 ◽

Vol 13 (22) ◽

pp. 5669

Author(s):

Akbar Lulu Marzan ◽

Sarah Elizabeth Stewart

Keyword(s):

Drug Delivery ◽

Pancreatic Cancer ◽

Survival Rate ◽

Extracellular Vesicles ◽

Cancer Progression ◽

Current Knowledge ◽

Treatment Options ◽

Metabolic Dysfunction ◽

Underlying Mechanisms

Pancreatic cancer is one of the deadliest cancers worldwide, with a 5-year survival rate of less than 10%. This dismal survival rate can be attributed to several factors including insufficient diagnostics, rapid metastasis and chemoresistance. To identify new treatment options for improved patient outcomes, it is crucial to investigate the underlying mechanisms that contribute to pancreatic cancer progression. Accumulating evidence suggests that extracellular vesicles, including exosomes and microvesicles, are critical players in pancreatic cancer progression and chemoresistance. In addition, extracellular vesicles also have the potential to serve as promising biomarkers, therapeutic targets and drug delivery tools for the treatment of pancreatic cancer. In this review, we aim to summarise the current knowledge on the role of extracellular vesicles in pancreatic cancer progression, metastasis, immunity, metabolic dysfunction and chemoresistance, and discuss their potential roles as biomarkers for early diagnosis and drug delivery vehicles for treatment of pancreatic cancer.

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Annexin A1 May Induce Pancreatic Cancer Progression as a Key Player of Extracellular Vesicles Effects as Evidenced in the In Vitro MIA PaCa-2 Model System

International Journal of Molecular Sciences ◽

10.3390/ijms19123878 ◽

2018 ◽

Vol 19 (12) ◽

pp. 3878 ◽

Cited By ~ 18

Author(s):

Emanuela Pessolano ◽

Raffaella Belvedere ◽

Valentina Bizzarro ◽

Paola Franco ◽

Iolanda De Marco ◽

...

Keyword(s):

Pancreatic Cancer ◽

Endothelial Cells ◽

Extracellular Vesicles ◽

Cancer Progression ◽

Umbilical Vein ◽

Annexin A1 ◽

Mesenchymal Transition ◽

Tumour Metastasis

Pancreatic Cancer (PC) is one of the most aggressive malignancies worldwide. As annexin A1 (ANXA1) is implicated in the establishment of tumour metastasis, the role of the protein in PC progression as a component of extracellular vesicles (EVs) has been investigated. EVs were isolated from wild type (WT) and ANXA1 knock-out (KO) PC cells and then characterised by multiple approaches including Western blotting, Field Emission-Scanning Electron Microscopy, and Dynamic Light Scattering. The effects of ANXA1 on tumour aggressiveness were investigated by Wound-Healing and invasion assays and microscopic analysis of the Epithelial to Mesenchymal Transition (EMT). The role of ANXA1 on angiogenesis was also examined in endothelial cells, using similar approaches. We found that WT cells released more EVs enriched in exosomes than those from cells lacking ANXA1. Notably, ANXA1 KO cells recovered their metastatic potential only when treated by WT EVs as they underwent EMT and a significant increase of motility. Similarly, human umbilical vein endothelial cells (HUVEC) migrated and invaded more rapidly when treated by WT EVs whereas ANXA1 KO EVs weakly induced angiogenesis. This study suggests that EVs-related ANXA1 is able to promote cell migration, invasion, and angiogenesis, confirming the relevance of this protein in PC progression.

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MIB1 Upregulates IQGAP1 and Promotes Pancreatic Cancer Progression by inducing ST7 Degradation

10.21203/rs.3.rs-76668/v1 ◽

2020 ◽

Author(s):

Tao Liu ◽

Bin Zhang ◽

xin jin ◽

Xiang Cheng

Keyword(s):

Pancreatic Cancer ◽

Tumor Growth ◽

Cancer Cells ◽

Western Blotting ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Pancreatic Tumors ◽

Pancreatic Cancer Cells ◽

The Relationship

Abstract BackgroundPancreatic cancer is a highly heterogeneous and has a poor prognosis. Elucidating the molecular mechanisms underlying pancreatic cancer progression is essential for improving patient survival. Although the E3 ubiquitin ligase mind bomb 1 (MIB1) is involved in cancer cell proliferation and is often overexpressed in pancreatic cancer, the role of MIB1 in pancreatic cancer progression remains unclear.Methods The relationship of MIB1 with the clinicopathological features of pancreatic tumors was bioinformatically investigated in different datasets. The protein levels of MIB1 and ST7 were assessed by Western blotting and immunohistochemistry. The role of MIB1 and ST7 in pancreatic cancer growth was assessed by MTS assays, colony formation assays, and experiments in mouse xenograft models. The interaction between MIB1 and ST7 was investigated by co-immunoprecipitation. The relationship between MIB1, ST7, and IQGAP1 levels was explored by Western blotting and quantitative real-time PCR.ResultsMIB1 expression was elevated in pancreatic cancer tissues, and its expression levels were associated with unfavorable prognosis. MIB1 overexpression enhanced pancreatic cancer proliferation and invasion in vitro and in vivo. We identified ST7 as a novel MIB1 target for proteasomal degradation. Further, we found that ST7 suppressed tumor growth by downregulating IQGAP1 in pancreatic cancer cells.ConclusionsThese data suggest that MIB1 promotes pancreatic cancer progression by inducing ST7 degradation. ST7 suppresses tumor growth by downregulating IQGAP1 in pancreatic cancer cells. Therefore, the MIB1/ST7/IQGAP1 axis is essential for pancreatic cancer progression, and MIB1 inhibition may improve the survival of pancreatic cancer patients.

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Abstract 2679: Role of TH2 cells in pancreatic cancer progression

10.1158/1538-7445.am2021-2679 ◽

2021 ◽

Author(s):

Aftab Alam ◽

Maulasri Bhatta ◽

Parker Denz ◽

Eric Levanduski ◽

Prasenjit Dey

Keyword(s):

Pancreatic Cancer ◽

Cancer Progression ◽

Th2 Cells

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Hypoxia-inducible factor (HIF): fuel for cancer progression

Current Molecular Pharmacology ◽

10.2174/1874467214666210120154929 ◽

2021 ◽

Vol 14 ◽

Author(s):

Saurabh Satija ◽

Harpreet Kaur ◽

Murtaza M. Tambuwala ◽

Prabal Sharma ◽

Manish Vyas ◽

...

Keyword(s):

Biological Sciences ◽

Tumor Microenvironment ◽

Tumor Cells ◽

Cancer Progression ◽

Oxygen Deficiency ◽

Hypoxia Inducible Factor ◽

Transcription Factor Activation ◽

Underlying Mechanisms ◽

Adaptive Reactions

Hypoxia is an integral part of tumor microenvironment, caused primarily due to rapidly multiplying tumor cells and a lack of proper blood supply. Among the major hypoxic pathways, HIF-1 transcription factor activation is one of the widely investigated pathways in the hypoxic tumor microenvironment (TME). HIF-1 is known to activate several adaptive reactions in response to oxygen deficiency in tumor cells. HIF-1 has two subunits, HIF-1β (constitutive) and HIF-1α (inducible). The HIF-1α expression is largely regulated via various cytokines (through PI3K-ACT-mTOR signals), which involves the cascading of several growth factors and oncogenic cascades. These events lead to the loss of cellular tumor suppressant activity through changes in the level of oxygen via oxygen-dependent and oxygen-independent pathways. The significant and crucial role of HIF in cancer progression and its underlying mechanisms have gained much attention lately among the translational researchers in the fields of cancer and biological sciences, which have enabled them to correlate these mchanisms with various other disease modalities. In the present review, we have summarized the key findings related to the role of HIF in the progression of tumors.

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An Evidence for a Novel Antiviral Mechanism of Teleost Fish: Serum-Derived Exosomes Inhibit Virus Replication Through Incorporating Mx1 Protein

10.20944/preprints202107.0160.v1 ◽

2021 ◽

Author(s):

Changjun Guo ◽

Jian He ◽

Zhi-Min Li ◽

Yuanyuan Wang ◽

Chen nan nan ◽

...

Keyword(s):

Cancer Progression ◽

Teleost Fish ◽

Protein Composition ◽

Underlying Mechanism ◽

Antiviral Effect ◽

Mandarin Fish ◽

Underlying Mechanisms ◽

Antiviral Mechanism ◽

Fish Serum

Exosomes are associated with cancer progression, pregnancy, cardiovascular diseases, central nervous system–related diseases, immune responses and viral pathogenicity. However, study on the role of exosomes in the immune response of teleost fish, especially antiviral immunity, is limited. Herein, serum-derived exosomes from mandarin fish were used to investigate antiviral effect for the exosomes of teleost fish. Exosomes were isolated from mandarin fish serum by ultracentrifugation could internalize into Mandarin fish fry (MFF-1) cells and inhibited Infectious spleen and kidney necrosis virus (ISKNV) infection. To further investigated the underlying mechanisms of exosomes in inhibiting ISKNV infection. The protein composition of serum-derived exosomes was by analysis mass spectrometry and found that myxovirus resistance 1 (Mx1) was incorporated in the exosomes. Furthermore, the scMx1 protein was proved transferred to the recipient cells though the exosomes. Our results found that the serum-derived exosomes from mandarin fish could inhibit ISKNV replication and suggested an underlying mechanism of the serum-derived exosomes antivirus is that serum-derived exosomes incorporation of the Mx1 protein into exosomes and delivery into recipient cells. This study provided an evidence for the important antiviral role of exosomes in the immune system of teleost fish.

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The cholesterol metabolite 27-hydroxycholesterol increases the secretion of extracellular vesicles which promote breast cancer progression

Endocrinology ◽

10.1210/endocr/bqab095 ◽

2021 ◽

Author(s):

Amy E Baek ◽

Natalia Krawczynska ◽

Anasuya Das Gupta ◽

Svyatoslav Victorovich Dvoretskiy ◽

Sixian You ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Growth ◽

Cancer Cells ◽

Extracellular Vesicles ◽

Cancer Progression ◽

Myeloid Cells ◽

Breast Cancer Progression ◽

Label Free ◽

Tumor Growth And Metastasis ◽

Promote Breast Cancer

Abstract Cholesterol has been implicated in the clinical progression of breast cancer, a disease that continues to be the most commonly diagnosed cancer in women. Previous work has identified the cholesterol metabolite, 27-hydroxycholesterol (27HC), as a major mediator of the effects of cholesterol on breast tumor growth and progression. 27HC can act as an estrogen receptor (ER) modulator to promote the growth of ERα+ tumors, and a liver x receptor (LXR) ligand in myeloid immune cells to establish an immune-suppressive program. In fact, the metastatic properties of 27HC require the presence of myeloid cells, with neutrophils (PMNs) being essential for the increase in lung metastasis in murine models. In an effort to further elucidate the mechanisms by which 27HC alters breast cancer progression, we made the striking finding that 27HC promoted the secretion of extracellular vesicles (EVs), a diverse assortment of membrane bound particles that include exosomes. The resulting EVs had a size distribution that was skewed slightly larger, compared to EVs generated by treating cells with vehicle. The increase in EV secretion and size was consistent across three different subtypes: primary murine PMNs, RAW264.7 monocytic cells and 4T1 murine mammary cancer cells. Label-free analysis of 27HC-EVs indicated that they had a different metabolite composition to those from vehicle-treated cells. Importantly, 27HC-EVs from primary PMNs promoted tumor growth and metastasis in two different syngeneic models, demonstrating the potential role of 27HC induced EVs in the progression of breast cancer. EVs from PMNs were taken up by cancer cells, macrophages and PMNs, but not T cells. Since EVs did not alter proliferation of cancer cells, it is likely that their pro-tumor effects are mediated through interactions with myeloid cells. Interestingly, RNA-seq analysis of tumors from 27HC-EV treated mice do not display significantly altered transcriptomes, suggesting that the effects of 27HC-EVs occur early on in tumor establishment and growth. Future work will be required to elucidate the mechanisms by which 27HC increases EV secretion, and how these EVs promote breast cancer progression. Collectively however, our data indicate that EV secretion and content can be regulated by a cholesterol metabolite, which may have detrimental effects in terms of disease progression, important findings given the prevalence of both breast cancer and hypercholesterolemia.

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The Emerging Role of GC-MSCs in the Gastric Cancer Microenvironment: From Tumor to Tumor Immunity

Stem Cells International ◽

10.1155/2019/8071842 ◽

2019 ◽

Vol 2019 ◽

pp. 1-9 ◽

Cited By ~ 1

Author(s):

Zhaoji Pan ◽

Yiqing Tian ◽

Guoping Niu ◽

Chengsong Cao

Keyword(s):

Gastric Cancer ◽

Tumor Microenvironment ◽

Cancer Progression ◽

Wound Repair ◽

Critical Role ◽

The Novel ◽

Potential Biomarker ◽

Underlying Mechanisms ◽

Gastric Cancer Progression

Mesenchymal stem cells (MSCs) have been declared to not only participate in wound repair but also affect tumor progression. Tumor-associated MSCs, directly existing in the tumor microenvironment, play a critical role in tumor initiation, progression, and development. And different tumor-derived MSCs have their own unique characteristics. In this review, we mainly describe and discuss recent advances in our understanding of the emerging role of gastric cancer-derived MSC-like cells (GC-MSCs) in regulating gastric cancer progression and development, as well as the bidirectional influence between GC-MSCs and immune cells of the tumor microenvironment. Moreover, we also discuss the potential biomarker and therapeutic role of GC-MSCs. It is anticipated that new and deep insights into the functionality of GC-MSCs and the underlying mechanisms will promote the novel and promising therapeutic strategies against gastric cancer.

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Extracellular Vesicles-Mediated Transfer of miRNA Let-7b from PC3 Cells to Macrophages

Genes ◽

10.3390/genes11121495 ◽

2020 ◽

Vol 11 (12) ◽

pp. 1495

Author(s):

Egidia Costanzi ◽

Rita Romani ◽

Paolo Scarpelli ◽

Ilaria Bellezza

Keyword(s):

Prostate Cancer ◽

Extracellular Vesicles ◽

Cancer Progression ◽

Inflammatory Responses ◽

Target Cells ◽

Prostate Cell ◽

Prostate Cancer Therapy ◽

Reverse Transcription Quantitative Pcr ◽

Pc3 Cells

Prostate-derived extracellular vesicles (pEVs) may represent a way to selectively transport cargo molecules from the producing cells to the target cells to allow biological events, both in physiological and pathological circumstances. pEVs cargo participates in the modulation of the inflammatory responses in physiological conditions and during cancer progression. In the present study, we examined the expression levels of miRNA Let-7b, in both precursor and mature forms, in noncancerous and cancerous prostate cell lines, PNT2 and PC3 respectively, and in their extracellular vesicles (EVs) using reverse-transcription quantitative PCR strategies. We showed that miRNA Let-7b was highly expressed in noncancerous cells and strongly decreased in cancerous PC3 cells, while the opposite was observed in the respective EVs, thus supporting the tumor suppressor role of miRNA Let7-b. We also demonstrated that miRNA Let-7b can be transferred to THP-1 cells via EVs, which are known to induce TAM-like polarization. Our results support the view that miRNA Let-7 b, contained in PC3-derived EVs, is associated with the increase in the miRNA Let7-b observed in TAM-like macrophages. Overall, our results indicate that circulating EV-loaded miRNA might be useful biomarkers for prostate cancer progression and might also support a possible use of pEVs as targets for prostate cancer therapy.

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