CD248(TEM1/CD164L1/Endosialin): A new molecular target for anti-angiogenic therapy in Pancreatic ductal adenocarcinoma

Abstract Background: Pancreatic ductal adenocarcinoma (PDCA) is one of the malignant tumors with the worst prognosis with a 5-year survival rate of <1%, which is known as the "king of cancers". At present, there is a lack of effective early diagnosis and treatment plan for pancreatic cancer. Therefore, there is an urgent need to understand the molecular mechanisms of pancreatic cancer to generate innovative approaches for the development of effective early diagnosis and treatment strategies.Methods: In this study, we performed single gene pan-cancer analysis, gene co-expression analysis and gene regulatory correlation analysis to understand the molecular mechanism of CD248 in pancreatic cancer using bioinformatics tools. Additionally, we provided potential molecular targets for pancreatic cancer treatment by constructing the lncRNA-miRNA-gene network axis.Results: The results showed that CD248 is differentially expressed in normal and tumor tissues, and abnormally high expression predicts poor prognosis, is a proto-oncogene in pancreatic cancer. Besides, CD248 is associated with angiogenesis of tumors. We obtained three new lncRNA-miRNA-gene network axes, namely AC008040.1-hsa-miR-200c-3p-CD248 axis, AC055822.1-hsa-miR-200c-3p-CD248 axis, RRN3P2-hsa-miR-200c-3p-CD248 axis that provide promising molecular targets for anti-angiogenic therapy and diagnostic biomarkers for pancreatic cancer.Conclusion: In conclusion, this study shows that over-expression of CD248 (TEM1/CD164L1/Endosialin) is always present in breast cancer and predicts a poor prognosis, associated with tumor angiogenesis, suggesting it as an attractive therapeutic target for pancreatic cancer.

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Metabonomic alterations from pancreatic intraepithelial neoplasia to pancreatic ductal adenocarcinoma facilitate the identification of biomarkers in serum for early diagnosis of pancreatic cancer

Molecular BioSystems ◽

10.1039/c6mb00381h ◽

2016 ◽

Vol 12 (9) ◽

pp. 2883-2892 ◽

Cited By ~ 7

Author(s):

Xianchao Lin ◽

Bohan Zhan ◽

Shi Wen ◽

Zhishui Li ◽

Heguang Huang ◽

...

Keyword(s):

Pancreatic Cancer ◽

Early Diagnosis ◽

Pancreatic Ductal Adenocarcinoma ◽

Poor Prognosis ◽

Malignant Disease ◽

Early Stage ◽

Intraepithelial Neoplasia ◽

Ductal Adenocarcinoma ◽

Pancreatic Intraepithelial Neoplasia

Pancreatic cancer is a highly malignant disease with a poor prognosis and it is essential to diagnose and treat the disease at an early stage.

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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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Aberrant MicroRNAs in Pancreatic Cancer: Researches and Clinical Implications

Gastroenterology Research and Practice ◽

10.1155/2014/386561 ◽

2014 ◽

Vol 2014 ◽

pp. 1-11 ◽

Cited By ~ 13

Author(s):

Tao Sun ◽

Xiangyu Kong ◽

Yiqi Du ◽

Zhaoshen Li

Keyword(s):

Pancreatic Cancer ◽

Pancreatic Ductal Adenocarcinoma ◽

Poor Prognosis ◽

Vital Role ◽

High Rate ◽

Ductal Adenocarcinoma ◽

Clinical Implications ◽

Circulating Mirnas ◽

Current Review ◽

Wide Range

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a high rate of mortality and poor prognosis. Numerous studies have proved that microRNA (miRNA) may play a vital role in a wide range of malignancies, including PDAC, and dysregulated miRNAs, including circulating miRNAs, are associated with PDAC proliferation, invasion, chemosensitivity, and radiosensitivity, as well as prognosis. Greater understanding of the roles of miRNAs in PDAC could provide insights into this disease and identify potential diagnostic markers and therapeutic targets. The current review focuses on recent advances with respect to the roles of miRNAs in PDAC and their practical value.

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Advances in Early Detection of Pancreatic Cancer

Diagnostics ◽

10.3390/diagnostics9010018 ◽

2019 ◽

Vol 9 (1) ◽

pp. 18 ◽

Cited By ~ 7

Author(s):

Atsushi Kanno ◽

Atsushi Masamune ◽

Keiji Hanada ◽

Masataka Kikuyama ◽

Masayuki Kitano

Keyword(s):

Pancreatic Cancer ◽

Early Detection ◽

Early Diagnosis ◽

Pancreatic Ductal Adenocarcinoma ◽

Early Stage ◽

Epidemiological Data ◽

The United States ◽

Ductal Adenocarcinoma ◽

Intraductal Papillary Mucinous Neoplasms ◽

Mucinous Neoplasms

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease. PDAC is the fourth leading cause of death in the United States and Japan based on epidemiological data. Early detection of PDAC is very important to improve the prognosis of PDAC. Early detection of pancreatic ductal adenocarcinoma (PDAC) requires further examination after selecting cases with risk factors for the condition, such as family history, hereditary pancreatic carcinoma syndrome, intraductal papillary mucinous neoplasms, or chronic pancreatitis. The Japan Study Group on the Early Detection of Pancreatic Cancer has investigated and clarified the clinicopathological features for the early diagnosis of PDAC. In Japan, an algorithm for the early diagnosis of PDAC, which utilized the cooperation of local clinics and regional general hospitals, has been a breakthrough in the detection of early-stage PDAC. Further approaches for the early diagnosis of PDAC are warranted.

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Gene Co-expression Network Characterizing Microenvironmental Heterogeneity and Intercellular Communication in Pancreatic Ductal Adenocarcinoma: Implications of Prognostic Significance and Therapeutic Target

10.21203/rs.3.rs-1054804/v2 ◽

2021 ◽

Author(s):

Chengsi Wu ◽

Yizhen Liu ◽

Kun Cai ◽

Li Tao ◽

Dianhui Wei ◽

...

Keyword(s):

Neural Network ◽

Pancreatic Cancer ◽

Pancreatic Ductal Adenocarcinoma ◽

Gene Network ◽

Cell Communication ◽

Ductal Adenocarcinoma ◽

Marker Genes ◽

Cell Component ◽

Gene Modules

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is characterized by intensive stroma involvement and heterogeneity. Pancreatic cancer cells interplay with surrounding tumor micro-environment (TME), leading to exacerbated tumorigenesis, dismal prognosis and tenacious therapy resistance. Herein, we aim to ascertain a gene-network indicative of vicious features of TME, then find a vulnerability for pancreatic cancer. Methods Single cell RNA sequencing data was processed by Seurat package, retrieving the cell component marker genes (CCMGs). Correlation networks/modules of CCMGs were determined by WGCNA algorithm in a combined PDAC mRNA expression dataset. The gene modules that statistically associate with prognosis were chosen for classifying TME subgroups, constructing neural network and designing the risk score system. Cell-cell communication analysis was achieved by NATMI software. The tumor suppressive effect of ITGA2 inhibitor was evaluated in vivo by using a Kras G12D -driven murine pancreatic cancer model.Results WGCNA analysis categorized cell component marker genes into eight co-expression networks. From gene modules with the maximum and minimum hazard ratio, we stratify PDAC samples based on TME gene patterns, resulting in two main TME subclasses with contrasting survival periods. Furthermore, we generated a neural network model and a risk score model which robustly predict prognosis and therapeutic outcomes. The hub genes in both gene modules were also gathered for functional enrichment analysis, elucidating a crucial role of cell communication-mediating integrins in TME associated PDAC malignancy. To perform a confirmatory experiment underpinning the significance of hub gene targeting, the mice with spontaneously developed pancreatic cancer were orally treated with an integrin inhibitor. The in vivo assays unraveled that pharmacologically inhibiting ITGA2 counteracts cancer-promoting micro-environment, and ameliorates pancreatic lesions. Conclusions By recapitulating gene-network across various cell types, we exploited novel PDAC prognosis-predicting strategies. Medically interfering ITGA2, a key factor guiding cellular reciprocal interaction, attenuated tumor development. These findings may open new avenue about PDAC targeting therapy.

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Recent development of gene therapy for pancreatic cancer using the non-viral nanovectors

Biomaterials Science ◽

10.1039/d1bm00748c ◽

2021 ◽

Author(s):

Yu Liu ◽

Wei Wu ◽

Wang Yiyao ◽

Shi-Song Han ◽

Yuanyuan Yuan ◽

...

Keyword(s):

Pancreatic Cancer ◽

Gene Therapy ◽

Pancreatic Ductal Adenocarcinoma ◽

Poor Prognosis ◽

Ductal Adenocarcinoma ◽

The World ◽

Desmoplastic Stroma

Pancreatic ductal adenocarcinoma (PDAC), characterized by its dense desmoplastic stroma and hypovascularity, is one of the most lethal cancer with poor prognosis in the world. Traditional treatments such as chemotherapy,...

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Low expression of tRF‐Pro‐CGG predicts poor prognosis in pancreatic ductal adenocarcinoma

Journal of Clinical Laboratory Analysis ◽

10.1002/jcla.23742 ◽

2021 ◽

Author(s):

Jun Li ◽

Lei Jin ◽

Yuan Gao ◽

Peng Gao ◽

Le Ma ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Poor Prognosis ◽

Ductal Adenocarcinoma ◽

Low Expression

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Liquid Biopsy in Pancreatic Cancer: Are We Ready to Apply It in the Clinical Practice?

Cancers ◽

10.3390/cancers13081986 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1986

Author(s):

Victoria Heredia-Soto ◽

Nuria Rodríguez-Salas ◽

Jaime Feliu

Keyword(s):

Pancreatic Cancer ◽

Clinical Practice ◽

Early Diagnosis ◽

Minimally Invasive ◽

Liquid Biopsy ◽

Genetic Material ◽

Current Status ◽

Ductal Adenocarcinoma ◽

Disease Monitoring ◽

Global Status

Pancreatic ductal adenocarcinoma (PDAC) exhibits the poorest prognosis of all solid tumors, with a 5-year survival of less than 10%. To improve the prognosis, it is necessary to advance in the development of tools that help us in the early diagnosis, treatment selection, disease monitoring, evaluation of the response and prognosis. Liquid biopsy (LB), in its different modalities, represents a particularly interesting tool for these purposes, since it is a minimally invasive and risk-free procedure that can detect both the presence of genetic material from the tumor and circulating tumor cells (CTCs) in the blood and therefore distantly reflect the global status of the disease. In this work we review the current status of the main LB modalities (ctDNA, exosomes, CTCs and cfRNAs) for detecting and monitoring PDAC.

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Roles of autophagy and metabolism in pancreatic cancer cell adaptation to environmental challenges

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00138.2017 ◽

2017 ◽

Vol 313 (5) ◽

pp. G524-G536 ◽

Cited By ~ 12

Author(s):

Sandrina Maertin ◽

Jason M. Elperin ◽

Ethan Lotshaw ◽

Matthias Sendler ◽

Steven D. Speakman ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cell Proliferation ◽

Cell Growth ◽

Oxidative Phosphorylation ◽

Pancreatic Ductal Adenocarcinoma ◽

Environmental Stresses ◽

Ductal Adenocarcinoma ◽

Cell Adaptation ◽

Autophagy Inhibition ◽

Dependent Mechanism

Pancreatic ductal adenocarcinoma (PDAC) displays extensive and poorly vascularized desmoplastic stromal reaction, and therefore, pancreatic cancer (PaCa) cells are confronted with nutrient deprivation and hypoxia. Here, we investigate the roles of autophagy and metabolism in PaCa cell adaptation to environmental stresses, amino acid (AA) depletion, and hypoxia. It is known that in healthy cells, basal autophagy is at a low level, but it is greatly activated by environmental stresses. By contrast, we find that in PaCa cells, basal autophagic activity is relatively high, but AA depletion and hypoxia activate autophagy only weakly or not at all, due to their failure to inhibit mechanistic target of rapamycin. Basal, but not stress-induced, autophagy is necessary for PaCa cell proliferation, and AA supply is even more critical to maintain PaCa cell growth. To gain insight into the underlying mechanisms, we analyzed the effects of autophagy inhibition and AA depletion on PaCa cell metabolism. PaCa cells display mixed oxidative/glycolytic metabolism, with oxidative phosphorylation (OXPHOS) predominant. Both autophagy inhibition and AA depletion dramatically decreased OXPHOS; furthermore, pharmacologic inhibitors of OXPHOS suppressed PaCa cell proliferation. The data indicate that the maintenance of OXPHOS is a key mechanism through which autophagy and AA supply support PaCa cell growth. We find that the expression of oncogenic activation mutation in GTPase Kras markedly promotes basal autophagy and stimulates OXPHOS through an autophagy-dependent mechanism. The results suggest that approaches aimed to suppress OXPHOS, particularly through limiting AA supply, could be beneficial in treating PDAC. NEW & NOTEWORTHY Cancer cells in the highly desmoplastic pancreatic ductal adenocarcinoma confront nutrient [i.e., amino acids (AA)] deprivation and hypoxia, but how pancreatic cancer (PaCa) cells adapt to these conditions is poorly understood. This study provides evidence that the maintenance of mitochondrial function, in particular, oxidative phosphorylation (OXPHOS), is a key mechanism that supports PaCa cell growth, both in normal conditions and under the environmental stresses. OXPHOS in PaCa cells critically depends on autophagy and AA supply. Furthermore, the oncogenic activation mutation in GTPase Kras upregulates OXPHOS through an autophagy-dependent mechanism.

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