Pancreatic Cancer and Platelets Crosstalk: A Potential Biomarker and Target

Platelets have been recognized as key players in hemostasis, thrombosis, and cancer. Preclinical and clinical researches evidenced that tumorigenesis and metastasis can be promoted by platelets through a wide variety of crosstalk between cancer cells and platelets. Pancreatic cancer is a devastating disease with high morbidity and mortality worldwide. Although the relationship between pancreatic cancer and platelets in clinical diagnosis is described, the interplay between pancreatic cancer and platelets, the underlying pathological mechanism and pathways remain a matter of intensive study. This review summaries recent researches in connections between platelets and pancreatic cancer. The existing data showed different underlying mechanisms were involved in their complex crosstalk. Typically, pancreatic tumor accelerates platelet aggregation which forms thrombosis. Furthermore, extracellular vesicles released by platelets promote communication in a neoplastic microenvironment and illustrate how these interactions drive disease progression. We also discuss the advantages of novel model organoids in pancreatic cancer research. A more in-depth understanding of tumor and platelets crosstalk which is based on organoids and translational therapies may provide potential diagnostic and therapeutic strategies for pancreatic cancer progression.

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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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MicroRNA-7 as a Potential Biomarker for Prognosis in Pancreatic Cancer

Disease Markers ◽

10.1155/2020/2782101 ◽

2020 ◽

Vol 2020 ◽

pp. 1-13 ◽

Cited By ~ 1

Author(s):

Zhi-qiang Ye ◽

Chang-lin Zou ◽

Han-bin Chen ◽

Ming-jie Jiang ◽

Zhu Mei ◽

...

Keyword(s):

Pancreatic Cancer ◽

Tumor Progression ◽

Clinical Significance ◽

Cancer Progression ◽

Cox Proportional Hazards Model ◽

The Cancer Genome Atlas ◽

Cancer Tissue ◽

Advanced Tumor ◽

Potential Biomarker ◽

Tumor Stages

MicroRNAs play critical roles in tumor progression. Our recent study has indicated that microRNA-7 (miR-7) impairs autophagy-derived pools of glucose to suppress the glycolysis in pancreatic cancer progression. However, the roles of miR-7 in clinical significance and chemoresistance of pancreatic cancer remain unexplored. The aim of this study was to assess the expression of miR-7 in patients with pancreatic cancer and to evaluate the possibility of its usage as a prognostic molecular biomarker. MicroRNA array-based quantification analysis of 372 miRNAs was compared in serum between pancreatic cancer and healthy individuals, gemcitabine-sensitive and gemcitabine-resistance patients. We identified miR-7 showed the potential predictive power for gemcitabine-sensitive patients with pancreatic cancer. Then, the results were validated in pancreatic tissue microarray and The Cancer Genome Atlas (TCGA) dataset, demonstrating that lower miR-7 expression was correlated with more advanced tumor stages and worse prognosis in pancreatic cancer. The Cox proportional-hazards model analysis identified miR-7 to be an independent variable for prediction of the survival. Furthermore, the mechanistic exploration suggested the clinical significance of miR-7 involved its interference effect on autophagy and glycolysis in pancreatic cancer using pancreatic cancer tissue microarrays and TCGA data. Therefore, the results of the present study provide evidences that low microRNA-7 expression may contribute to tumor progression and poor prognosis in pancreatic cancer.

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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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Fusobacterium nucleatum infection induces pancreatic cancer cell proliferation and migration through regulation of host cytokine signaling

10.1101/2021.11.19.469245 ◽

2021 ◽

Author(s):

Barath Udayasuryan ◽

Tam T.D. Nguyen ◽

Ariana Umana ◽

LaDeidra Monet Roberts ◽

Raffae A Ahmad ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Cancer Cell ◽

Cancer Progression ◽

Pancreatic Tumor ◽

Pancreatic Cancer Cell ◽

Fusobacterium Nucleatum ◽

Cellular Migration ◽

Gm Csf ◽

Pancreatic Cancer Cells

Pancreatic ductal adenocarcinoma (PDAC) harbors a complex tumor microbiome that has been implicated in cancer progression and resistance to chemotherapy. Recent clinical investigations uncovered a correlation between high loads of intratumor Fusobacterium nucleatum and decreased patient survival. Here we show that pancreatic cancer cell lines harboring intracellular F. nucleatum secrete elevated levels of cancer-associated cytokines including IL-8, CXCL1, GM-CSF, and MIP-3α. We report that GM-CSF directly increases the proliferation of pancreatic cancer cells, and contributes to increased cellular migration, notably in the absence of immune cell participation. This study is the first to investigate the direct impact of F. nucleatum infection on pancreatic cancer cells. Our results suggest that F. nucleatum within the pancreatic tumor microenvironment elicits infection-specific cytokine secretion that directly contributes adversely to cancer progression and warrants further research into therapeutic manipulation of the pancreatic tumor microbiome.

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Linking Tumor Microenvironment to Plasticity of Cancer Stem Cells: Mechanisms and Application in Cancer Therapy

Frontiers in Oncology ◽

10.3389/fonc.2021.678333 ◽

2021 ◽

Vol 11 ◽

Author(s):

Xiaobo Zheng ◽

Chune Yu ◽

Mingqing Xu

Keyword(s):

Stem Cells ◽

Drug Resistance ◽

Tumor Microenvironment ◽

Cancer Stem Cells ◽

Cancer Progression ◽

Immune Escape ◽

Underlying Mechanisms ◽

Novel Therapeutic Strategies ◽

And Function ◽

The Relationship

Cancer stem cells (CSCs) are a minority subset of cancer cells that can drive tumor initiation, promote tumor progression, and induce drug resistance. CSCs are difficult to eliminate by conventional therapies and eventually mediate tumor relapse and metastasis. Moreover, recent studies have shown that CSCs display plasticity that renders them to alter their phenotype and function. Consequently, the varied phenotypes result in varied tumorigenesis, dissemination, and drug-resistance potential, thereby adding to the complexity of tumor heterogeneity and further challenging clinical management of cancers. In recent years, tumor microenvironment (TME) has become a hotspot in cancer research owing to its successful application in clinical tumor immunotherapy. Notably, emerging evidence shows that the TME is involved in regulating CSC plasticity. TME can activate stemness pathways and promote immune escape through cytokines and exosomes secreted by immune cells or stromal cells, thereby inducing non-CSCs to acquire CSC properties and increasing CSC plasticity. However, the relationship between TME and plasticity of CSCs remains poorly understood. In this review, we discuss the emerging investigations on TME and CSC plasticity to illustrate the underlying mechanisms and potential implications in suppressing cancer progression and drug resistance. We consider that this review can help develop novel therapeutic strategies by taking into account the interlink between TME and CSC plasticity.

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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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ALKBH5-mediated m6A demethylation of KCNK15-AS1 inhibits pancreatic cancer progression via regulating KCNK15 and PTEN/AKT signaling

Cell Death and Disease ◽

10.1038/s41419-021-04401-4 ◽

2021 ◽

Vol 12 (12) ◽

Author(s):

Yuan He ◽

HongQin Yue ◽

Ying Cheng ◽

Zhilong Ding ◽

Zhen Xu ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cell Proliferation ◽

Cell Growth ◽

Cancer Progression ◽

Gene Interaction ◽

Migration And Invasion ◽

Cellular Functions ◽

Phosphatase And Tensin Homolog ◽

Tensin Homolog ◽

Potential Biomarker

AbstractLong noncoding RNAs (lncRNAs) are regarded as crucial regulators in tumor progression. Potassium two pore domain channel subfamily K member 15 and WISP2 antisense RNA 1 (KCNK15-AS1) has been confirmed to inhibit the migration and invasion of pancreatic cancer (PC) cells. However, its downstream mechanism and effect on other cellular functions in PC remain unknown. This study probed the function and potential mechanism of KCNK15-AS1 in PC cell growth. RT-qPCR and western blot were employed to measure gene expression in PC cells. ISH was applied to analyze KCNK15-AS1 expression in PC tissues. Functional assays were utilized to evaluate PC cell proliferation, apoptosis, migration and EMT. Mechanical experiments were adopted to detect gene interaction in PC cells. The obtained data indicated that KCNK15-AS1 was down-regulated in PC cells and tissues. Overexpressing KCNK15-AS1 hindered cell proliferation, migration and EMT while facilitated cell apoptosis in PC. Mechanically, alkylation repair homolog protein 5 (ALKBH5) was verified to induce m6A demethylation of KCNK15-AS1 to mediate KCNK15-AS1 up-regulation. KCNK15-AS1 combined with KCNK15 5’UTR to inhibit KCNK15 translation. Moreover, KCNK15-AS1 recruited MDM2 proto-oncogene (MDM2) to promote RE1 silencing transcription factor (REST) ubiquitination, thus transcriptionally upregulating phosphatase and tensin homolog (PTEN) to inactivate AKT pathway. In conclusion, our study first confirmed that KCNK15-AS1 hinders PC cell growth by regulating KCNK15 and PTEN, suggesting KCNK15-AS1 as a potential biomarker of PC.

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PBX1 Participated in Estrogen Mediated Bladder Cancer Progression and Chemo-Resistance through Affecting Estrogen Receptors

10.21203/rs.3.rs-810980/v1 ◽

2021 ◽

Author(s):

Yang Zhao ◽

Jizhong Che ◽

Aimin Tian ◽

Gang Zhang ◽

Yankai Xu ◽

...

Keyword(s):

Bladder Cancer ◽

Estrogen Receptors ◽

Cancer Progression ◽

Epithelial Mesenchymal Transition ◽

High Morbidity ◽

Promoting Effect ◽

Mesenchymal Transition ◽

Survival Status ◽

Underlying Mechanisms ◽

Muscle Invasive

Abstract Bladder cancer (BCa) is a common cancer associated with high morbidity and mortality worldwide. Pre-B-cell leukemia transcription factor 1 (PBX1) has been reported to be involved in tumor progression. The aim of the study was to explore the specific role of PBX1 in BCa and its underlying mechanisms. The relative expressions of PBX1 in muscle-invasive BCa tissues and cell lines were analyzed through RT-qPCR and Western blotting. Kaplan–Meier analysis was used to analyze the relationship between PBX1 levels and survival status. Co-immunoprecipitation (CO-IP) and chromatin immunoprecipitation (ChIP)-qPCR assay were adopted to verify the interaction between PBX1 and Estrogen receptors (ERs), and explore the ER-dependent genes transcription. The results shown that PBX1 was upregulated in invasive BCa patients and BCa cells, positively associated with tumor size, lymph node metastasis, distant metastasis and poorer survival status. Overexpression of PBX1 promoted cell growth, invasion, epithelial-mesenchymal transition (EMT) process and cisplatin resistance in BCa cells, while the silence of PBX1 showed opposite effects. Further, PBX1 interacted with Estrogen receptors (ERs) and was required for the ER function. Overexpression of PBX1 aggravated the tumor-promoting effect of estrogen on BCa cells, while partially suppressed the inhibitory effects of ER antagonist AZD9496 on BCa cells. In summary, this study revealed that PBX1 participated in estrogen mediated BCa progression and chemo-resistance through binding and activating estrogen receptors. Hence, PBX1 may serve as a potential prognostic and therapeutic target for BCa treatment.

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PRSS1 mutation: a possible pathomechanism of pancreatic carcinogenesis and pancreatic cancer

Molecular Medicine ◽

10.1186/s10020-019-0111-4 ◽

2019 ◽

Vol 25 (1) ◽

Cited By ~ 2

Author(s):

Qicai Liu ◽

Ling Guo ◽

Sheng Zhang ◽

Jingwen Wang ◽

Xinhua Lin ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Progression ◽

Tumor Development ◽

Intraepithelial Neoplasia ◽

Migration And Invasion ◽

Antibody Array ◽

Pancreatic Carcinogenesis ◽

Cationic Trypsinogen ◽

Underlying Mechanisms ◽

Job Role

Abstract Background Previous studies revealed somatic mutations of the cationic trypsinogen gene (PRSS1) in patients with chronic pancreatitis and pancreatic cancer. However, whether PRSS1 mutations trigger pancreatic cancer and/or promote malignant proliferation and metastasis in pancreatic cancer remains largely unclear, as well as the potential underlying mechanisms. Methods In the present study, whole-exome sequencing was applied for screening, and the R116C mutation was validated by Sanger sequencing. Phosphorylation antibody array, RNA-Seq, and RT-qPCR were adopted to screen and validate that R116C mutation promoted pancreatic cancer progression via the JAK1-STAT5 pathway. Results It showed that migration and invasion were significantly increased in R116C-bearing PANC-1 cells compared with wild type counterparts. In a transgenic mouse model of iZEG-PRSS1_R116C, primary pancreatic intraepithelial neoplasia (PanINs) was observed in the pancreatic duct. Conclusions These findings suggested a novel pathway mediating pancreatic cancer development, with PRSS1 mutation and overexpression playing an “inside job” role in pancreatic carcinogenesis and tumor development.

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The Roles of Thyroid and Thyroid Hormone in Pancreas: Physiology and Pathology

International Journal of Endocrinology ◽

10.1155/2018/2861034 ◽

2018 ◽

Vol 2018 ◽

pp. 1-14 ◽

Cited By ~ 6

Author(s):

Chaoran Chen ◽

Zhenxing Xie ◽

Yingbin Shen ◽

Shu Fang Xia

Keyword(s):

Pancreatic Cancer ◽

Insulin Secretion ◽

Energy Metabolism ◽

Thyroid Dysfunction ◽

Pancreas Development ◽

Endocrine Glands ◽

Autoimmune Thyroid ◽

Pancreas Function ◽

Underlying Mechanisms ◽

The Relationship

It is widely accepted that thyroid hormones (THs), secreted from the thyroid, play important roles in energy metabolism. It is also known that THs also alter the functioning of other endocrine glands; however, their effects on pancreatic function have not yet been reviewed. One of the main functions of the pancreas is insulin secretion, which is altered in diabetes. Diabetes, therefore, could be related to thyroid dysfunction. Earlier research on this subject focused on TH regulation of pancreas function (such as insulin secretion) or on insulin function through TH-mediated increase of energy metabolism. Afterwards, epidemiological investigations and animal test research found a link between autoimmune diseases, thyroid dysfunction, and pancreas pathology; however, the underlying mechanisms remain unknown. Furthermore, recent studies have shown that THs also play important roles in pancreas development and on islet pathology, both in diabetes and in pancreatic cancer. Therefore, an overview of the effects of thyroid and THs on pancreas physiology and pathology is presented. The topics contained in this review include a summary of the relationship between autoimmune thyroid dysfunction and autoimmune pancreas lesions and the effects of THs on pancreas development and pancreas pathology (diabetes and pancreatic cancer).

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