Microbiome—Friend or Foe of Pancreatic Cancer?

Pancreatic ductal adenocarcinoma is one of the deadliest human neoplasms. Despite the development of new surgical and adjuvant therapies, the prognosis remains very poor, with the overall survival rate not exceeding 9%. There is now increasing evidence that the human microbiome, which is involved in many physiological functions, including the regulation of metabolic processes and the modulation of the immune system, is possibly linked to pancreatic oncogenesis. However, the exact mechanisms of action are poorly understood. Our review summarizes the current understanding of how the microbiome affects pancreatic cancer development and progression. We discuss potential pathways of microbe translocation to the pancreas, as well as the mechanism of their action. We describe the role of the microbiome as a potential marker of pancreatic cancer diagnosis, progression, and survival. Finally, we discuss the possibilities of modifying the microbiome to improve treatment effectiveness for this deadly disease.

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The Role of Autophagy in Pancreatic Cancer—Recent Advances

Biology ◽

10.3390/biology9010007 ◽

2019 ◽

Vol 9 (1) ◽

pp. 7 ◽

Cited By ~ 3

Author(s):

Maria New ◽

Sharon Tooze

Keyword(s):

Pancreatic Cancer ◽

Early Stage ◽

Large Body ◽

Ductal Adenocarcinoma ◽

Improve Treatment ◽

Recent Advances ◽

Dismal Prognosis ◽

Tumor Survival ◽

Metastasis Development

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers with a 5-year survival rate of only 9%, despite ongoing efforts to improve treatment. This dismal prognosis is due to the difficulty of early stage diagnosis, drug resistance, and likelihood of metastasis development. It is therefore of great importance to identify appropriate therapeutic targets and gain a greater understanding of PDAC biology. Autophagy is a membrane-mediated degradation and recycling mechanism, which is crucial for cell homeostasis. There is evidence for both a tumor-suppressive and a tumor-promoting role of autophagy in cancer, and this is likely context dependent. Within PDAC, a large body of evidence points towards autophagy being required for tumor survival and metabolism. In this review, we describe the recent advances in the understanding of the role and regulation of autophagy in PDAC.

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A Proteomic Study on the Personalized Protein Corona of Liposomes. Relevance for Early Diagnosis of Pancreatic DUCTAL Adenocarcinoma and Biomarker Detection

Journal of Nanotheranostics ◽

10.3390/jnt2020006 ◽

2021 ◽

Vol 2 (2) ◽

pp. 82-93

Author(s):

Luca Digiacomo ◽

Francesca Giulimondi ◽

Daniela Pozzi ◽

Alessandro Coppola ◽

Vincenzo La Vaccara ◽

...

Keyword(s):

Pancreatic Cancer ◽

Early Diagnosis ◽

Pancreatic Ductal Adenocarcinoma ◽

Protein Corona ◽

Detection Sensitivity ◽

Ductal Adenocarcinoma ◽

Protein Biomarkers ◽

Ca 19.9 ◽

Proteomic Study

Due to late diagnosis, high incidence of metastasis, and poor survival rate, pancreatic cancer is one of the most leading cause of cancer-related death. Although manifold recent efforts have been done to achieve an early diagnosis of pancreatic cancer, CA-19.9 is currently the unique biomarker that is adopted for the detection, despite its limits in terms of sensitivity and specificity. To identify potential protein biomarkers for pancreatic ductal adenocarcinoma (PDAC), we used three model liposomes as nanoplatforms that accumulate proteins from human plasma and studied the composition of this biomolecular layer, which is known as protein corona. Indeed, plasma proteins adsorb on nanoparticle surface according to their abundance and affinity to the employed nanomaterial, thus even small differences between healthy and PDAC protein expression levels can be, in principle, detected. By mass spectrometry experiments, we quantified such differences and identified possible biomarkers for PDAC. Some of them are already known to exhibit different expressions in PDAC proteomes, whereas the role of other relevant proteins is still not clear. Therefore, we predict that the employment of nanomaterials and their protein corona may represent a useful tool to amplify the detection sensitivity of cancer biomarkers, which may be used for the early diagnosis of PDAC, with clinical implication for the subsequent therapy in the context of personalized medicine.

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Cancer stem cells markers associated with development and aggressive phenotype in pancreatic cancer

Panorama brasileiro de tungstênio (w) entre os anos de 2008 e 2014 ◽

10.32749/nucleodoconhecimento.com.br/health/pancreatic-cancer ◽

2020 ◽

pp. 102-122

Author(s):

Camila Juliano Salvador Rodrigues ◽

Elita Ferreira da Silveira ◽

Rafael da Silveira Vargas ◽

Giordano Gatti de Giacomo ◽

Marino Muxfeldt Bianchin

Keyword(s):

Pancreatic Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Tumor Development ◽

Staining Intensity ◽

Ductal Adenocarcinoma ◽

Clinicopathological Parameters ◽

Tumor Initiating Cells ◽

New Ideas

Background: Cancer stem cells, also known as tumor-initiating cells, are suggested to be responsible for drug resistance and cancer development due in part to their ability to self-renew themselves and differentiate into heterogeneous lineages of cancer cells. Objective: This study was designed to investigate the role of cancer stem cells in pancreatic cancer. Methods: A retrospective clinicopathological analysis was undertaken in 112 patients diagnosed with pancreatic ductal adenocarcinoma between 2005 and 2010, and immunohistochemistry was performed with antibodies against CD133, CD24, and OCT4. Positive nuclear, cytoplasmic or membrane staining for each antibody was rated on staining intensity, being classified into low/moderate or strong staining groups. Results were analyzed relative to each patient’s clinicopathological parameters. Results: There was an established relationship between the staining of the markers with some variables associated with worse prognosis, being the three markers present in most tumor cells and associated with tumor progression. We suppose that cancer stem cells are present from the beginning of tumor initiation and are intrinsically related to tumor development. Although the presence of stem cells has been associated with molecular biology of various tumors, their expression in pancreatic cancer has not yet been clinically reported. Conclusion: The presence of stem cells and their role in pancreatic cancer tumorigenesis may be considered as valuable prognostic factors, although the mechanism involved needs further investigation. Increasing insights into role of cancer stem cells and carcinogenesis can ultimately generate new ideas for molecularly based diagnostic and therapeutic approaches.

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KIF4A Regulates the Progression of Pancreatic Ductal Adenocarcinoma through Proliferation and Invasion

BioMed Research International ◽

10.1155/2021/8249293 ◽

2021 ◽

Vol 2021 ◽

pp. 1-12

Author(s):

Jing Chen ◽

Cui-Cui Zhao ◽

Fei-Ran Chen ◽

Guo-Wei Feng ◽

Fei Luo ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cell Proliferation ◽

Pancreatic Ductal Adenocarcinoma ◽

Disease Free Survival ◽

High Expression ◽

Ductal Adenocarcinoma ◽

Migration And Invasion

Background. Pancreatic cancer is a malignant tumor of the digestive tract, which is difficult to diagnose and treat due to bad early diagnosis. We aimed to explore the role of kinesin superfamily 4A (KIF4A) in pancreatic ductal adenocarcinoma (PDAC). Methods. We first used the bioinformatic website to screen the data of pancreatic cancer in TCGA, and KIF4A protein was detected among the 86 specimens of patients in our hospital combined with clinic-pathological characteristics and survival analysis. KIF4A loss-expression cell lines were established by RNA interference (RNAi). In addition, we performed in vitro cell assays to detect the changes in cell proliferation, migration, and invasion. The proteins involved in the proliferation and metastasis of cancer cells were also detected by western blot. The above results could be proved in vivo. Further, the correlation between KIF4A and CDC5L was analyzed by TCGA and IHC data. Results. We first found a high expression of KIF4A in pancreatic cancer, suggesting a role of KIF4A in the development of pancreatic cancer. KIF4A was found to be differentially expressed ( P < 0.05 ) among the 86 specimens of patients in our hospital and was significantly associated with PDAC TNM stages and tumor size. High KIF4A expression also significantly worsened overall survival (OS) and disease-free survival rate (DFS) ( P < 0.05 , respectively). In addition, cell proliferation, migration, and invasion were inhibited by the KIF4A-shRNA group compared with the control ( P < 0.05 , respectively). In the end, knockdown of KIF4A could inhibit tumor development and metastasis in vivo. Further, the positive correlation between KIF4A and CDC5L existed, and KIF4A might promote pancreatic cancer proliferation by affecting CDC5L expression. Conclusion. In conclusion, the high expression level of KIF4A in PDAC was closely related to poor clinical and pathological status, lymphatic metastasis, and vascular invasion. KIF4A might be involved in promoting the development of PDAC in vitro and in vivo, which might be a new therapeutic target of PDAC.

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Epigenetic Alterations in Pancreatic Cancer Metastasis

10.20944/preprints202106.0629.v1 ◽

2021 ◽

Author(s):

Sarah S Wang ◽

Jihao Xu ◽

Keely Y Ji ◽

Chang-Il Hwang

Keyword(s):

Pancreatic Cancer ◽

Cancer Metastasis ◽

The United States ◽

Genetic Mutation ◽

Therapeutic Interventions ◽

Ductal Adenocarcinoma ◽

Epigenetic Mechanisms ◽

Comprehensive Overview ◽

Nucleosome Remodeling

Pancreatic cancer is the third leading cause of cancer-related deaths in the United States. Pancreatic ductal adenocarcinoma (PDA) is the most common (90%) and aggressive type of pancreatic cancer. Genomic analyses of PDA specimens have identified the recurrent genetic mutations that drive PDA initiation and progression. However, the underlying mechanisms that further drive PDA metastasis remain elusive. Despite many attempts, no recurrent genetic mutation driving PDA metastasis has been found, suggesting that PDA metastasis is driven by epigenetic fluctuations rather than genetic factors. Therefore, establishing epigenetic mechanisms of PDA metastasis would facilitate the development of successful therapeutic interventions. In this review, we provide a comprehensive overview on the role of epigenetic mechanisms in PDA as a critical contributor on PDA progression and metastasis. In particular, we explore the recent advancements elucidating the role of nucleosome remodeling, histone modification, and DNA methylation in the process of cancer metastasis.

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Upregulation of Mobility in Pancreatic Cancer Cells by Secreted S100A11 Through Activation of Surrounding Fibroblasts

Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics ◽

10.3727/096504019x15555408784978 ◽

2019 ◽

Vol 27 (8) ◽

pp. 945-956 ◽

Cited By ~ 3

Author(s):

Yosuke Mitsui ◽

Nahoko Tomonobu ◽

Masami Watanabe ◽

Rie Kinoshita ◽

I Wayan Sumardika ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cell Motility ◽

Cancer Cells ◽

Cellular Migration ◽

Mitogen Activated Protein Kinase ◽

Ductal Adenocarcinoma ◽

Pancreatic Cancer Cells ◽

Mechanistic Investigation

S100A11, a member of the S100 family of proteins, is actively secreted from pancreatic ductal adenocarcinoma (PDAC) cells. However, the role of the extracellular S100A11 in PDAC progression remains unclear. In the present study, we investigated the extracellular role of S100A11 in crosstalking between PDAC cells and surrounding fibroblasts in PDAC progression. An abundant S100A11 secreted from pancreatic cancer cells stimulated neighboring fibroblasts through receptor for advanced glycation end products (RAGE) upon S100A11 binding and was followed by not only an enhanced cancer cell motility in vitro but also an increased number of the PDAC-derived circulating tumor cells (CTCs) in vivo. Mechanistic investigation of RAGE downstream in fibroblasts revealed a novel contribution of a mitogen-activated protein kinase kinase kinase (MAPKKK), tumor progression locus 2 (TPL2), which is required for positive regulation of PDAC cell motility through induction of cyclooxygenase 2 (COX2) and its catalyzed production of prostaglandin E2 (PGE2), a strong chemoattractive fatty acid. The extracellularly released PGE2 from fibroblasts was required for the rise in cellular migration as well as infiltration of their adjacent PDAC cells in a coculture setting. Taken together, our data reveal a novel role of the secretory S100A11 in PDAC disseminative progression through activation of surrounding fibroblasts triggered by the S100A11‐RAGE‐TPL2‐COX2 pathway. The findings of this study will contribute to the establishment of a novel therapeutic antidote to PDACs that are difficult to treat by regulating cancer-associated fibroblasts (CAFs) through targeting the identified pathway.

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Wnt/β-Catenin Signaling: The Culprit in Pancreatic Carcinogenesis and Therapeutic Resistance

International Journal of Molecular Sciences ◽

10.3390/ijms20174242 ◽

2019 ◽

Vol 20 (17) ◽

pp. 4242 ◽

Cited By ~ 20

Author(s):

Monish Ram Makena ◽

Himavanth Gatla ◽

Dattesh Verlekar ◽

Sahithi Sukhavasi ◽

Manoj K. Pandey ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cell Cycle Progression ◽

Patient Survival ◽

Epithelial Mesenchymal Transition ◽

Ductal Adenocarcinoma ◽

Steady Increase ◽

Mesenchymal Transition ◽

Pancreatic Carcinogenesis ◽

Tumor Immune Microenvironment

Pancreatic ductal adenocarcinoma (PDAC) is responsible for 7.3% of all cancer deaths. Even though there is a steady increase in patient survival for most cancers over the decades, the patient survival rate for pancreatic cancer remains low with current therapeutic strategies. The Wnt/β-catenin pathway controls the maintenance of somatic stem cells in many tissues and organs and is implicated in pancreatic carcinogenesis by regulating cell cycle progression, apoptosis, epithelial-mesenchymal transition (EMT), angiogenesis, stemness, tumor immune microenvironment, etc. Further, dysregulated Wnt has been shown to cause drug resistance in pancreatic cancer. Although different Wnt antagonists are effective in pancreatic patients, limitations remain that must be overcome to increase the survival benefits associated with this emerging therapy. In this review, we have summarized the role of Wnt signaling in pancreatic cancer and suggested future directions to enhance the survival of pancreatic cancer patients.

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CCAAT/Enhancer-Binding Protein Delta (C/EBPδ): A Previously Unrecognized Tumor Suppressor that Limits the Oncogenic Potential of Pancreatic Ductal Adenocarcinoma Cells

Cancers ◽

10.3390/cancers12092546 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2546

Author(s):

Leonie Hartl ◽

JanWillem Duitman ◽

Hella L. Aberson ◽

Kan Chen ◽

Frederike Dijk ◽

...

Keyword(s):

Pancreatic Cancer ◽

Tumor Suppressor ◽

Pancreatic Ductal Adenocarcinoma ◽

Binding Protein ◽

Ductal Adenocarcinoma ◽

Ductal Cells ◽

Enhancer Binding Protein ◽

Adenocarcinoma Cells ◽

Ccaat Enhancer Binding Protein

CCAAT/enhancer-binding protein δ (C/EBPδ) is a transcription factor involved in growth arrest and differentiation, which has consequently been suggested to harbor tumor suppressive activities. However, C/EBPδ over-expression correlates with poor prognosis in glioblastoma and promotes genomic instability in cervical cancer, hinting at an oncogenic role of C/EBPδ in these contexts. Here, we explore the role of C/EBPδ in pancreatic cancer. We determined C/EBPδ expression in biopsies from pancreatic cancer patients using public gene-expression datasets and in-house tissue microarrays. We found that C/EBPδ is highly expressed in healthy pancreatic ductal cells but lost in pancreatic ductal adenocarcinoma. Furthermore, loss of C/EBPδ correlated with increased lymph node involvement and shorter overall survival in pancreatic ductal adenocarcinoma patients. In accordance with this, in vitro experiments showed reduced clonogenic capacity and proliferation of pancreatic ductal adenocarcinoma cells following C/EBPδ re-expression, concurrent with decreased sphere formation capacity in soft agar assays. We thus report a previously unrecognized but important tumor suppressor role of C/EBPδ in pancreatic ductal adenocarcinoma. This is of particular interest since only few tumor suppressors have been identified in the context of pancreatic cancer. Moreover, our findings suggest that restoration of C/EBPδ activity could hold therapeutic value in pancreatic ductal adenocarcinoma, although the latter claim needs to be substantiated in future studies.

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The Role of miRNAs in the Regulation of Pancreatic Cancer Stem Cells

Stem Cells International ◽

10.1155/2016/8352684 ◽

2016 ◽

Vol 2016 ◽

pp. 1-7 ◽

Cited By ~ 6

Author(s):

Sabrina Bimonte ◽

Antonio Barbieri ◽

Maddalena Leongito ◽

Giuseppe Palma ◽

Vitale del Vecchio ◽

...

Keyword(s):

Pancreatic Cancer ◽

Stem Cells ◽

Drug Resistance ◽

Cancer Stem Cells ◽

Biological Activities ◽

Biological Properties ◽

Ductal Adenocarcinoma ◽

Small Noncoding Rnas ◽

Pancreatic Cancer Stem Cells

Pancreatic ductal adenocarcinoma is currently one of the deadliest cancers with low overall survival rate. This disease leads to an aggressive local invasion and early metastases and is poorly responsive to treatment with chemotherapy or chemoradiotherapy. Several studies have shown that pancreatic cancer stem cells (PCSCs) play different roles in the regulation of drug resistance and recurrence in pancreatic cancer. MicroRNA (miRNA), a class of newly emerging small noncoding RNAs, is involved in the modulation of several biological activities ranging from invasion to metastases development, as well as drug resistance of pancreatic cancer. In this review, we synthesize the latest findings on the role of miRNAs in regulating different biological properties of pancreatic cancer stem cells.

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Microbiota Alterations and Their Association with Oncogenomic Changes in Pancreatic Cancer Patients

International Journal of Molecular Sciences ◽

10.3390/ijms222312978 ◽

2021 ◽

Vol 22 (23) ◽

pp. 12978

Author(s):

Heidelinde Sammallahti ◽

Arto Kokkola ◽

Sama Rezasoltani ◽

Reza Ghanbari ◽

Hamid Asadzadeh Aghdaei ◽

...

Keyword(s):

Pancreatic Cancer ◽

Immune Responses ◽

Human Microbiome ◽

Drug Efficacy ◽

Oral Microbiota ◽

Complex Interactions ◽

Key Factor ◽

Cancer Mutations ◽

Host Metabolism

Pancreatic cancer (PC) is an aggressive disease with a high mortality and poor prognosis. The human microbiome is a key factor in many malignancies, having the ability to alter host metabolism and immune responses and participate in tumorigenesis. Gut microbes have an influence on physiological functions of the healthy pancreas and are themselves controlled by pancreatic secretions. An altered oral microbiota may colonize the pancreas and cause local inflammation by the action of its metabolites, which may lead to carcinogenesis. The mechanisms behind dysbiosis and PC development are not completely clear. Herein, we review the complex interactions between PC tumorigenesis and the microbiota, and especially the question, whether and how an altered microbiota induces oncogenomic changes, or vice versa, whether cancer mutations have an impact on microbiota composition. In addition, the role of the microbiota in drug efficacy in PC chemo- and immunotherapies is discussed. Possible future scenarios are the intentional manipulation of the gut microbiota in combination with therapy or the utilization of microbial profiles for the noninvasive screening and monitoring of PC.

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