HIF-1α-regulated stanniocalcin-1 mediates gemcitabine resistance in pancreatic ductal adenocarcinoma via PI3K/AKT signaling pathway.

Pancreatic ductal adenocarcinoma (PDAC) has a poor response to the first-line chemotherapy drug gemcitabine. We previously identified stanniocalcin-1 as a gemcitabine-resistant-related gene, but its specific role and function in pancreatic cancer remain unclear. RT-qPCR and Western blot were used to evaluate differential protein and mRNA expressions. The biological functions of genes were determined using proliferation and drug-resistance experiments. Subcutaneous tumorigenesis experiment was performed on nude mice. Prognostic analysis was performed using public databases and our clinical data. We found HIF-1α-regulated STC1 expression mediated chemoresistance in pancreatic cancer. Deeper, we explored the action mechanism of STC1 and identified PI3K/AKT as the downstream signaling pathway of STC1. Furthermore, we analyzed clinical data and found that STC1 expression was related to the prognosis of gemcitabine-treated patients after surgery. In general, we proved the HIF-1α/STC1/PI3K-AKT axis participated in PDAC progression and chemoresistance, and STC1 may serve as a potential prognostic factor and therapeutic target for PDAC treatment.

Novel therapies targeting hypoxia mechanism to treat pancreatic cancer.

Pancreatic cancer (PC) is one of the deadliest malignancies. The high mortality rate of PC largely results from delayed diagnosis and early metastasis. Therefore, identifying novel treatment targets for patients with PC is urgently required to improve survival rates. A major barrier to successful treatment of PC is the presence of a hypoxic tumor microenvironment, which is associated with poor prognosis, treatment resistance, increased invasion and metastasis. Recent studies have identified a number of novel molecules and pathways in PC cells that promote cancer cells progression under hypoxic conditions, which may provide new therapy strategies to inhibit the development and metastasis of PC. This review summarizes the latest research of hypoxia in PC and provides an overview of how the current therapies have the capacity to overcome hypoxia and improve PC patient treatment. These findings will eventually provide guidance for future PC management and clinical trials and hopefully improve the survival of patients with PC.

Novel therapeutic strategies and perspectives for pancreatic cancer: Autophagy and apoptosis are key mechanisms to fight pancreatic cancer.

Pancreatic cancer (PC) is the most lethal malignancy of the gastrointestinal tract. The poor prognosis of patients with PC is primarily due to lack of effective treatments against its progressive and metastatic behavior. Hence, figuring out the mechanisms underlying PC development and putting up with effective targeted therapies are of great significance to improve the prognosis of patients with PC. Apoptosis and autophagy serve to maintain tissue homoeostasis. Escaping from apoptosis or autophagy is one of the features of malignancy. PC is seriously resistant to autophagy and apoptosis, which explains its invasiveness and resistance to conventional treatment. Recently, several biological activities and pharmacological functions found in natural product extracts have been reported to inhibit PC progression. The current review focuses on understanding natural product extracts and their derivatives as one kind of novel treatments through affecting the apoptosis or autophagy in PC.

The Role of Mitochondria in the Chemoresistance of Pancreatic Cancer Cells.

The first-line chemotherapies for patients with unresectable pancreatic cancer (PC) are 5-fluorouracil (5-FU) and gemcitabine therapy. However, due to chemoresistance the prognosis of patients with PC has not been significantly improved. Mitochondria are essential organelles in eukaryotes that evolved from aerobic bacteria. In recent years, many studies have shown that mitochondria play important roles in tumorigenesis and may act as chemotherapeutic targets in PC. In addition, according to recent studies, mitochondria may play important roles in the chemoresistance of PC by affecting apoptosis, metabolism, mtDNA metabolism, and mitochondrial dynamics. Interfering with some of these factors in mitochondria may improve the sensitivity of PC cells to chemotherapeutic agents, such as gemcitabine, making mitochondria promising targets for overcoming chemoresistance in PC.

Targeting hypoxic tumor microenvironment in pancreatic cancer.

Attributable to its late diagnosis, early metastasis, and poor prognosis, pancreatic cancer remains one of the most lethal diseases worldwide. Unlike other solid tumors, pancreatic cancer harbors ample stromal cells and abundant extracellular matrix but lacks vascularization, resulting in persistent and severe hypoxia within the tumor. Hypoxic microenvironment has extensive effects on biological behaviors or malignant phenotypes of pancreatic cancer, including metabolic reprogramming, cancer stemness, invasion and metastasis, and pathological angiogenesis, which synergistically contribute to development and therapeutic resistance of pancreatic cancer. Through various mechanisms including but not confined to maintenance of redox homeostasis, activation of autophagy, epigenetic regulation, and those induced by hypoxia-inducible factors, intratumoral hypoxia drives the above biological processes in pancreatic cancer. Recognizing the pivotal roles of hypoxia in pancreatic cancer progression and therapies, hypoxia-based antitumoral strategies have been continuously developed over the recent years, some of which have been applied in clinical trials to evaluate their efficacy and safety in combinatory therapies for patients with pancreatic cancer. In this review, we discuss the molecular mechanisms underlying hypoxia-induced aggressive and therapeutically resistant phenotypes in both pancreatic cancerous and stromal cells. Additionally, we focus more on innovative therapies targeting the tumor hypoxic microenvironment itself, which hold great potential to overcome the resistance to chemotherapy and radiotherapy and to enhance antitumor efficacy and reduce toxicity to normal tissues.

Preclinical models of pancreatic ductal adenocarcinoma: challenges and opportunities in the era of precision medicine.

Pancreatic ductal adenocarcinoma (PDAC) is an extremely lethal malignancy, with an average 5-year survival rate of 9% (Siegel RL, Miller KD, Jemal A. Ca Cancer J Clin. 2019;69(1):7-34). The steady increase in mortality rate indicates limited efficacy of the conventional regimen. The heterogeneity of PDAC calls for personalized treatment in clinical practice, which requires the construction of a preclinical system for generating patient-derived models. Currently, the lack of high-quality preclinical models results in ineffective translation of novel targeted therapeutics. This review summarizes applications of commonly used models, discusses major difficulties in PDAC model construction and provides recommendations for integrating workflows for precision medicine.

CREPT serves as a biomarker of poor survival in pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human malignancies. Cell-cycle-related and expression-elevated protein in tumor (CREPT) plays an important role in the phosphorylation of RNA Pol II, and has been implicated in the development of several types of cancer. As yet, however, there have been no reports on its role in PDAC. Here, we aimed to explore the value of CREPT as a prognostic biomarker in PDAC. METHODS: CREPT expression was assessed by immunohistochemistry (IHC) on a tissue microarray containing samples from 375 PDAC patients. Kaplan-Meier and Cox regression analyses were performed to explore the independent prognostic value of CREPT expression for the disease-free survival (DFS) and overall survival (OS) of PDAC patients. A Cell Counting Kit-8 (CCK8) assay was used to determine the growth rates and gemcitabine sensitivities of PDAC cells, while a Transwell assay was used to determine the migration and invasion abilities of PDAC cells. Subcutaneous xenografts were used to explore the effect of CREPT expression on tumor growth in vivo. RESULTS: We found that CREPT is highly expressed in tumor tissues and may serve as an independent prognostic biomarker for DFS and OS of PDAC patients. In vitro assays revealed that CREPT expression promotes the proliferation, migration, invasion and gemcitabine resistance of PDAC cells, and in vivo assays showed that CREPT expression knockdown led to inhibition of PDAC tumor growth. CONCLUSIONS: We conclude that high CREPT expression enhances the proliferation, migration, invasion and gemcitabine resistance of PDAC cells. In addition, we conclude that CREPT may serve as an independent prognostic biomarker and therapeutic target for PDAC patients.

Do novel treatment strategies enhance T cell-mediated Immunity: Opportunities and challenges in pancreatic cancer immunotherapy.

Although immunotherapy is successful when included as component of treatment strategies for advanced cancers, data are insufficient for evaluating its efficacy for treating patients with pancreatic cancer (PC). PC is remarkably resistant to current immunotherapies because of its strongly immunosuppressive tumor microenvironment comprising immunosuppressive cells such as myeloid-derived suppressor cells and regulatory T cells, which limit the efficacy of T cell infiltration. Thus, the ability to achieve robust and durable intrinsic T cell efficacy may represent the key for improving patients' outcomes. Recent studies show that the efficacy of immunotherapy for treating PC will be significantly improved when combined with novel treatment strategies. This review summarizes the latest research in this rapidly progressing area and provides an overview of how current therapies enhance T cell-mediated immunotherapies that employ immune checkpoint inhibitors, cytokines, cell receptor modulators, tumor microenvironment regulators, vaccines, and gene-targeted immunotherapies. We highlight novel discoveries, which promise to guide future management of PC, and clinical trials aimed to increase the overall survival rate of patients with PC.

MicroRNA-381-A Key Transcriptional Regulator: Its Biological Function and Clinical Application Prospects in Cancer.

MicroRNAs (miRNAs) are small non-coding RNA molecules that function by regulating messenger RNAs. Recent studies have shown that miRNAs play important roles in multiple processes of cancer development. MiR-381 is one of the most important miRNAs in cancer progression. MiR-381 is downregulated in some cancers and upregulated in other cancers, including glioma, epithelial sarcoma, and osteosarcoma. MiR-381 regulates epithelial-mesenchymal transition (EMT), chemotherapeutic resistance, radioresistance, and immune responses. Thus, miR-381 participates in tumor initiation, progression, and metastasis. Moreover, miR-381 functions in various oncogenic pathways, including the Wnt/ß-catenin, AKT, and p53 pathways. Clinical studies have shown that miR-381 could be considered a biomarker or a novel prognostic factor. Here, we summarize the present studies on the role of miR-381 in cancer development, including its biogenesis and various affected signaling pathways, and its clinical application prospects. MiR-381 expression is associated with tumor stage and survival time, making miR-381 a novel prognostic factor.

Comparative [18F]FDG and [18F]DPA714 PET imaging and time-dependent changes of brown adipose tissue in tumour-bearing mice.

Brown adipose tissue (BAT) is important in monitoring energy homeostasis and cancer cachexia. Different from white adipose tissue, BAT is characterized by the presence of a large number of mitochondria in adipocytes. Translocator protein 18 kDa (TSPO), a critical transporter, is expressed in the outer membrane of mitochondria. We speculated that [18F]DPA714, a specific TSPO tracer, may monitor BAT activity in tumor-bearing mice in vivo. We first analyzed the radioactive uptake of positron emission tomography (PET) tracers in BAT of CT26 xenograft mice with 18F-fluorodeoxyglucose ([18F]FDG) and [18F]DPA714. We also studied the BAT uptake of [18F]DPA714 in CT26, A549 and LLC tumor models. The dynamic distribution of [18F]FDG is quite variable among animals, even in mice of the same tumor model (%ID/g-mean: mean ± SDM, 8.61 ± 8.90, n = 16). Contrarily, [18F]DPA714 produced high-quality and stable BAT imaging in different tumor models and different animals of the same model. Interestingly, %ID/g-mean of [18F]DPA714 in BAT was significantly higher on day 26 than that on day 7 in CT26 xenograft model. Taken together, these results strongly indicate the potential feasibility of [18F]DPA714 PET imaging in investigating BAT and energy metabolism during tumor progression in preclinical and clinical study.

Is Invagination Anastomosis More Effective in Reducing Clinically Relevant Pancreatic Fistula for Soft Pancreas After Pancreaticoduodenectomy Under Novel Fistula Criteria: A Systematic Review and Meta-Analysis.

Objective: To define the effectiveness of different anastomosis on clinically relevant postoperative fistula in patients with soft pancreas using the newest version of the fistula definition and criteria. Background: Different criteria of clinically relevant postoperative pancreatic fistula (POPF) result in the optimal anastomosis technique remaining controversial. Methods: PubMed, Embase, Web of Science, the Cochrane Central Library, and ClinicalTrials.gov were systematically searched up to 20 April 2020, and were evaluated by Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. Randomized controlled trials comparing duct-to-mucosa anastomosis vs. invagination anastomosis in pancreatic surgery were included. Result: Seven studies involving 1,110 participants were included. Using the postoperative pancreatic fistula definition provided by the International Study Group of Pancreatic Surgery 2016, the incidence rate of grade B/C pancreatic fistula was significantly lower in patients experiencing invagination anastomosis than in those undergoing duct-to-mucosa anastomosis. Four of seven trials comparing invagination with duct-to-mucosa anastomosis in patients with a soft pancreas showed that invagination was significantly better than duct-to-mucosa anastomosis in controlling pancreatic fistula formation, but no significant difference was detected between the two anastomosis techniques in patients with a hard pancreas. No significant difference in the length of hospital stay or postoperative mortality rate was found between the two methods. Conclusion: This study demonstrated superiority of invagination anastomosis over duct-to-mucosa anastomosis in reducing the risk of Grade B/C postoperative pancreatic fistula using the ISGPS 2016 definition, but it does not significantly reduce the mortality rate or length of hospital stay. The effect of invagination in reducing pancreatic fistula formation is obvious in patients with a soft pancreas, but there is no significant difference between the two anastomosis techniques in patients with a hard pancreas. We found a lower rate of clinically relevant postoperative pancreatic fistula in the invagination group, in patients with a soft pancreas.

MiR-135a biogenesis and regulation in malignancy: a new hope for cancer research and therapy.

MicroRNAs (miRNAs) are evolutionarily conserved small non-coding RNAs that affect posttranscriptional regulation by binding to the 3'-untranslated region of target messenger RNAs. MiR-135a is a critical miRNA that regulates gene expression, and many studies have focused on its function in cancer research. MiR-135a is dysregulated in various cancers and regulates cancer cell proliferation and invasion via several signaling pathways, such as the MAPK and JAK2/STAT3 pathways. MiR-135a has also been found to promote or inhibit the epithelial-mesenchymal transition and chemoresistance in different cancers. Several studies have discovered the value of miR-135a as a novel biomarker for cancer diagnosis and prognosis. These studies have suggested the potential of therapeutically manipulating miR-135a to improve the outcome of cancer patients. Although these findings have demonstrated the role of miR-135a in cancer progression and clinical applications, a number of questions remain to be answered, such as the dual functional roles of miR-135a in cancer. In this review, we summarize the available studies regarding miR-135a and cancer, including background on the biogenesis and expression of miR-135a in cancer and relevant signaling pathways involved in miR-135a-mediated tumor progression. We also focus on the clinical application of miR-135a as a biomarker in diagnosis and as a therapeutic agent or target in cancer treatment, which will provide a greater level of insight into the translational value of miR-135a.

The prospect of serum and glucocorticoid-inducible kinase 1 (SGK1) in cancer therapy: a rising star.

Serum and glucocorticoid-inducible kinase 1 (SGK1) is an AGC kinase that has been reported to be involved in a variety of physiological and pathological processes. Recent evidence has accumulated that SGK1 acts as an essential Akt-independent mediator of phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway in cancer. SGK1 is overexpressed in several tumors, including prostate cancer, colorectal carcinoma, glioblastoma, breast cancer, and endometrial cancer. The functions of SGK1 include regulating tumor growth, survival, metastasis, autophagy, immunoregulation, calcium (Ca2+) signaling, cancer stem cells, cell cycle, and therapeutic resistance. In this review, we introduce the pleiotropic role of SGK1 in the development and progression of tumors, summarize its downstream targets, and integrate the knowledge provided by preclinical studies that the prospect of SGK1 inhibition as a potential therapeutic approach.

Neoantigen-based immunotherapy in pancreatic ductal adenocarcinoma (PDAC).

Neoantigens generated in neoplasms are a type of protein completely absent in healthy tissues. Therefore, anti-tumor immunity targeting neoantigens is highly specific, which provides an optional approach to boost tumor immunotherapy. Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies in humans, with few efficient treatments to improve its prognosis. Therefore, immunotherapies reinforced by neoantigen-based strategies should be considered. In PDAC, the mutational burden is intermediate compared with other common malignancies, while the naturally formed tumor immunity is significantly inferior. Moreover, the high mutation load in PDAC correlates with a poor clinical prognosis, although the combination of a large mutation repertoire and competent T cell population is indispensable for long-term survival. In clinical practice, three strategies have been mainly used: peptide or tumor cell vaccines, neo-epitope-coding nucleotide vaccines, and dendritic cell vaccines. However, three major problems remain to be addressed, including (1) highly personalized protocols after sampling, (2) insufficient neoantigen quantity, and (3) ineffective immunotherapy of PDAC. In summary, neoantigen-based therapy of PDAC is increasing and the treatment methods are accompanied by great challenges. Currently, extensive development is needed for effective neoantigen-based therapy.

Mechanistic target of rapamycin in the tumor microenvironment and its potential as a therapeutic target for pancreatic cancer.

Pancreatic cancer(PC) is a devastating disease with a poor prognosis; however, few treatment options are available and the search continues for feasible molecular therapeutic targets, both in the tumor itself and in the tumor microenvironment. The mechanistic target of rapamycin (mTOR) signaling pathway has emerged as an attractive target due to its regulatory role in multiple cellular processes, including metabolism, proliferation, survival, and differentiation, under physiological and pathological conditions. Although mTOR-regulated events in tumor cells and the tumor microenvironment are known to restrict the development and growth of tumor cells, monotherapy with mTOR inhibitors has shown limited efficacy against PC to date, suggesting the need for alternative approaches. In this review, we describe the mechanisms by which mTOR modulates the PC microenvironment and suggest ways its function in immune cells might be exploited for the treatment of PC. We also discuss preclinical and clinical studies with mTOR inhibitors in combination with other therapeutic strategies, most notably immunotherapy. Finally, we highlight the promise that mTOR combinatorial therapy may hold for the treatment of PC in the near future.

Expression, function and clinical application of stanniocalcin-1 in cancer.

The glycoprotein stanniocalcin-1 functions as a regulatory endocrine hormone that maintains the balance of calcium and phosphorus in bony fish and as a paracrine/autocrine factor involved in many physiological/pathological processes in humans, including carcinogenesis. In this review, we provide an overview of (a) the possible mechanisms through which STC1 affects the malignant properties of cancer, (b) transcriptional and post-transcriptional regulation pathways of STC1 and (c) the potential clinical relevance of STC1 as a cancer biomarker and even a therapeutic target in the future. Exploring the role of STC1 in cancer development may provide a better understanding of the tumorigenesis process in humans and may facilitate finding an effective therapeutic method against cancer.

Novel Discoveries Targeting Pathogenic Gut Microbes and New Therapies in Pancreatic Cancer: Does Pathogenic E. coli Infection Cause Pancreatic Cancer Progression Modulated by TUBB/Rho/ROCK Signaling Pathway? A Bioinformatic Analysis.

Pancreatic cancer (PC) is a pernicious cancer of the digestive system which remains a high degree of malignancy. Increasing studies demonstrated that regulating the gut microbiome may become a brand new strategy to improve the therapeutic outcomes of PC. This study is aimed at obtaining the pathway in the microbial tumorigenesis of PC. Microarray datasets GSE27890, GSE46234, and GSE17610 were downloaded from the GEO (Gene Expression Omnibus) database. Differential analysis was performed for every single gene chip using the R software package ("Limma" package), and functional enrichment analyses were carried out by DAVID (Database for Annotation, Visualization and Integrated Discovery). The PPI (protein-protein interaction) network was constructed with the Search Tool for the Retrieval of Interacting Genes (STRING). The survival analysis was performed by GEPIA and USCS. A total of 84 differentially expressed genes (DEGs) were identified, and 3 of them were extracted (TUBB, TUBA4A, and TLR5). Biological process analysis revealed that these 3 genes were mainly enriched in pathogenic Escherichia coli (E. coli) infection. Survival analysis and pathway analysis revealed that TUBB (tubulin, beta class I) may be associated with the pathogenic E. coli infection, which may be involved in the carcinogenesis and progression of PC by activating the TUBB/Rho/ROCK signaling pathway. Elevated evidence indicated that a specific gut microbe could affect the progression of PC by suppressing immune response. However, little attention has been paid to the relationship and crosstalk between TUBB/Rho/ROCK signaling, microbes, and PC. This article is aimed at deducing that gut and tumor microbes are related to the development of PC by stimulating TUBB/Rho/ROCK signaling, while ablation of microbes by antibiotics cotreated with inhibitors of TUBB/Rho/ROCK signaling were identified as a novel target for PC therapy.

Novel therapeutic strategies and perspectives for metastatic pancreatic cancer: vaccine therapy is more than just a theory.

Pancreatic cancer is an aggressive and malignant tumor with an exceedingly high mortality rate. The quality of life and survival rates of pancreatic cancer patients with metastasis are poor compared with those without metastasis. Thus far, no effective treatment strategy has been established for metastatic pancreatic cancer patients. Therefore, an appropriate therapeutic method based on the elimination of metastatic pancreatic cancer is critical to improve patient outcome. Tumor-targeted vaccines have been widely discussed in recent studies and enabled important breakthroughs in the treatment of pancreatic cancer by preventing the escape of tumor cells from immune surveillance and activating the immune system to eliminate cancer cells. T cells can be activated by the stimulation of tumor-targeted vaccines, but to mount an effective immune response, both immune checkpoint inhibitors and positive costimulatory molecules are required. In this review, we discuss potential tumor-targeted vaccines that can target pancreatic cancer, elaborate the probably appropriate combination of vaccines therapy and evaluate the underlying benefits as well as obstacles in the current therapy for metastatic pancreatic cancer.