The role of S100A9 in the interaction between pancreatic ductal adenocarcinoma cells and stromal cells

Abstract Background A major feature of the microenvironment in pancreatic ductal adenocarcinoma (PDAC) is the significant amount of extracellular matrix produced by pancreatic stellate cells (PSCs), which have been reported to enhance the invasiveness of pancreatic cancer cells and negatively impact the prognosis. Methods We analyzed the data from two publicly available microarray datasets deposited in the Gene Expression Omnibus and found candidate genes that were differentially expressed in PDAC cells with metastatic potential and PDAC cells cocultured with PSCs. We studied the interaction between PDAC cells and PSCs in vitro and verified our finding with the survival data of patients with PDAC from the website of The Human Protein Atlas. Results We found that PSCs stimulated PDAC cells to secrete S100A9, which attracted circulatory monocytes into cancer tissue and enhanced the expression of programmed death-ligand 1 (PD-L1) on macrophages. When analyzing the correlation of S100A9 and PD-L1 expression with the clinical outcomes of patients with PDAC, we ascertained that high expression of S100A9 and PD-L1 was associated with poor survival in patients with PDAC. Conclusions PSCs stimulated PDAC cells to secrete S100A9, which acts as a chemoattractant to attract circulatory monocytes into cancer microenvironment and induces expression of PD-L1 on macrophages. High expression of S100A9 and PD-L1 was associated with worse overall survival in a cohort of patients with PDAC.

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The Role of S100A9 in the Interaction Between Pancreatic Ductal Adenocarcinoma Cells and Stromal Cells

10.21203/rs.3.rs-105978/v1 ◽

2020 ◽

Author(s):

Pin-Jui Kung ◽

Ting-Yu Lai ◽

Jerry Cao ◽

Li-Chung Hsu ◽

Tsai-Chen Chiang ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Clinical Outcomes ◽

High Expression ◽

Pancreatic Stellate Cells ◽

Ductal Adenocarcinoma ◽

Cancer Tissue ◽

Poor Survival ◽

Programmed Death Ligand 1 ◽

Pancreatic Cancer Cells ◽

Programmed Death

Abstract Background: A major feature of the microenvironment in pancreatic ductal adenocarcinoma (PDAC) is the signiﬁcant amount of extracellular matrix produced by pancreatic stellate cells (PSCs), which have been reported to enhance the invasiveness of pancreatic cancer cells and negatively impact the prognosis. Methods: We analyzed the data from two publicly available microarray datasets deposited in the Gene Expression Omnibus and found that the expression of S100 calcium binding protein A9 (S100A9) was increased in PDAC cells with metastatic potential and PDAC cells cocultured with PSCs. We studied the interaction between PDAC cells and PSCs in vitro and veriﬁed our ﬁnding with the survival data of patients with PDAC from the website of The Human Protein Atlas.Results: We found that PSCs stimulated PDAC cells to secrete S100A9, which attracted circulatory monocytes into cancer tissue and enhanced the expression of programmed death-ligand 1 (PD-L1) on macrophages. When analyzing the correlation of S100A9 and PD-L1 expression with the clinical outcomes of patients with PDAC, we ascertained that high expression of S100A9 and PD-L1 was associated with poor survival in patients with PDAC. Conclusions: We found that PSCs stimulated PDAC cells to secrete S100A9, which attracted circulatory monocytes into cancer tissue and enhanced the expression of programmed death-ligand 1 (PD-L1) on macrophages. When analyzing the correlation of S100A9 and PD-L1 expression with the clinical outcomes of patients with PDAC, we ascertained that high expression of S100A9 and PD-L1 was associated with poor survival in patients with PDAC.

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DNA-Methylation-Caused Downregulation of miR-30 Contributes to the High Expression of XPO1 and the Aggressive Growth of Tumors in Pancreatic Ductal Adenocarcinoma

Cancers ◽

10.3390/cancers11081101 ◽

2019 ◽

Vol 11 (8) ◽

pp. 1101 ◽

Cited By ~ 1

Author(s):

Asfar S. Azmi ◽

Yiwei Li ◽

Amro Aboukameel ◽

Irfana Muqbil ◽

Philip A. Philip ◽

...

Keyword(s):

Pancreatic Cancer ◽

Pancreatic Ductal Adenocarcinoma ◽

Cancer Cells ◽

Nuclear Export ◽

The United States ◽

High Expression ◽

Ductal Adenocarcinoma ◽

Multiple Tumor ◽

Pancreatic Cancer Cells

Pancreatic ductal adenocarcinoma is one of the most aggressive cancers, with high mortality in the United States. One of the important signal transduction proteins involved in the regulation of pancreatic cancer’s aggressive progression is the nuclear export protein (XPO1). High expression of XPO1 has been found in pancreatic, lung, breast and other cancers and lymphomas with a poor prognosis of patients with tumors and high proliferative activity of cancer cells. Because XPO1 exports multiple tumor suppressor proteins simultaneously from the nucleus, the inhibition of XPO1 may retain multiple tumor suppressors in the nucleus, resulting in the suppression of cell proliferation and the induction of apoptosis in tumors. In this study, we found that the high expression of XPO1 in pancreatic cancer cells could be, in part, due to the methylation of the miR-30 gene, leading to the low expression level of the miR-30 family. By co-transfection of the XPO1 3′-UTR-Luc target vector with miR-30 mimic, we found that XPO1 is a direct target of the miR-30 family. We also observed that the enforced expression of the miR-30 family inhibited the expression of XPO1, resulting in the suppression of pancreatic cancer growth both in vitro and in vivo. These findings could help to design a novel therapeutic strategy for the treatment of pancreatic cancer by introducing miR-30 into cancer cells.

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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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Aspartate β-hydroxylase promotes pancreatic ductal adenocarcinoma metastasis through activation of SRC signaling pathway

Journal of Hematology & Oncology ◽

10.1186/s13045-019-0837-z ◽

2019 ◽

Vol 12 (1) ◽

Cited By ~ 5

Author(s):

Kosuke Ogawa ◽

Qiushi Lin ◽

Le Li ◽

Xuewei Bai ◽

Xuesong Chen ◽

...

Keyword(s):

Pancreatic Cancer ◽

Pancreatic Ductal Adenocarcinoma ◽

Stem Cell Marker ◽

Ductal Adenocarcinoma ◽

Physical Interaction ◽

Pancreatic Cancer Cells ◽

Ecm Degradation ◽

Invadopodia Formation ◽

Pdx Models

Abstract Background Signaling pathways critical for embryonic development re-emerge in adult pancreas during tumorigenesis. Aspartate β-hydroxylase (ASPH) drives embryonic cell motility/invasion in pancreatic development/differentiation. We explored if dysregulated ASPH is critically involved in pancreatic cancer pathogenesis. Methods To demonstrate if/how ASPH mediates malignant phenotypes, proliferation, migration, 2-D/3-D invasion, pancreatosphere formation, immunofluorescence, Western blot, co-immunoprecipitation, invadopodia formation/maturation/function, qRT-PCR, immunohistochemistry (IHC), and self-developed in vitro metastasis assays were performed. Patient-derived xenograft (PDX) models of human pancreatic ductal adenocarcinoma (PDAC) were established to illustrate in vivo antitumor effects of the third-generation small molecule inhibitor specifically against ASPH’s β-hydroxylase activity. Prognostic values of ASPH network components were evaluated with Kaplan-Meier plots, log-rank tests, and Cox proportional hazards regression models. Results ASPH renders pancreatic cancer cells more aggressive phenotypes characterized by epithelial–mesenchymal transition (EMT), 2-D/3-D invasion, invadopodia formation/function as demonstrated by extracellular matrix (ECM) degradation, stemness (cancer stem cell marker upregulation and pancreatosphere formation), transendothelial migration (mimicking intravasation/extravasation), and sphere formation (mimicking metastatic colonization/outgrowth at distant sites). Mechanistically, ASPH activates SRC cascade through direct physical interaction with ADAM12/ADAM15 independent of FAK. The ASPH-SRC axis enables invadopodia construction and initiates MMP-mediated ECM degradation/remodeling as executors for invasiveness. Pharmacologic inhibition of invadopodia attenuates in vitro metastasis. ASPH fosters primary tumor development and pulmonary metastasis in PDX models of PDAC, which is blocked by a leading compound specifically against ASPH enzymatic activity. ASPH is silenced in normal pancreas, progressively upregulated from pre-malignant lesions to invasive/advanced stages of PDAC. Expression profiling of ASPH-SRC network components independently/jointly predicts clinical outcome of PDAC patients. Compared to a negative-low level, a moderate-very high level of ASPH, ADAM12, activated SRC, and MMPs correlated with curtailed overall survival (OS) of pancreatic cancer patients (log-rank test, ps < 0.001). The more unfavorable molecules patients carry, the more deleterious prognosis is destinated. Patients with 0–2 (n = 4), 3–5 (n = 8), 6–8 (n = 24), and 9–12 (n = 73) unfavorable expression scores of the 5 molecules had median survival time of 55.4, 15.9, 9.7, and 5.0 months, respectively (p < 0.001). Conclusion Targeting the ASPH-SRC axis, which is essential for propagating multi-step PDAC metastasis, may specifically/substantially retard development/progression and thus improve prognosis of PDAC.

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Biological Effect and Mechanism of the miR-23b-3p/ANXA2 Axis in Pancreatic Ductal Adenocarcinoma

Cellular Physiology and Biochemistry ◽

10.1159/000494468 ◽

2018 ◽

Vol 50 (3) ◽

pp. 823-840 ◽

Cited By ~ 8

Author(s):

Dan-ming Wei ◽

Yi-wu Dang ◽

Zhen-bo Feng ◽

Lu Liang ◽

Lu Zhang ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Chorioallantoic Membrane ◽

Tumor Formation ◽

Ductal Adenocarcinoma ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Chick Chorioallantoic Membrane ◽

Pancreatic Cancer Cells

Background/Aims: Accumulating evidence strongly suggests that microRNAs (miRNAs) modulate the expression of known tumor suppressor genes and oncogenes. In the present study, we found that the proliferation and invasion ability of pancreatic ductal adenocarcinoma (PDAC) cells were significantly suppressed by the overexpression of miR-23b-3p. In addition, there are miR-23b-3p binding sites in annexin A2 (ANXA2). Here, we investigated whether miR-23b-3p had an impact on the progression and metastasis of PDAC by targeting ANXA2. Methods: Cell proliferation, migration, and invasion, and cell cycle assays were performed to explore the effect of miR-23b-3p on various malignant phenotypes of pancreatic cancer cells. The size of tumors was observed following miR-23b-3p overexpression in an in vivo chick chorioallantoic membrane assay. Dual-luciferase reporter, quantitative real-time PCR, western blot, and immunohistochemical analyses were used to validate the relationship between miR-23b-3p and ANXA2 in vitro. Results: We observed that miR-23b-3p could bind specifically to the 3′ untranslated region of ANXA2 and inhibit its expression. MiR-23b-3p overexpression downregulated the expression of ANXA2 mRNA in PDAC cells and limited the size of tumors or even prevented tumor formation. In addition, there was a negative correlation between miR-23b-3p expression and ANXA2 protein expression in clinical specimens. Conclusion: MiR-23b-3p inhibits the development and progression of PDAC by regulating ANXA2 directly.

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Pentraxin 3 is a stromally-derived biomarker for detection of pancreatic ductal adenocarcinoma

npj Precision Oncology ◽

10.1038/s41698-021-00192-1 ◽

2021 ◽

Vol 5 (1) ◽

Author(s):

Michelle R. Goulart ◽

Jennifer Watt ◽

Imran Siddiqui ◽

Rita T. Lawlor ◽

Ahmet Imrali ◽

...

Keyword(s):

Clinical Trial ◽

Pancreatic Ductal Adenocarcinoma ◽

Ex Vivo ◽

Pancreatic Stellate Cells ◽

Ductal Adenocarcinoma ◽

Diagnostic Biomarkers ◽

All Trans Retinoic Acid ◽

Desmoplastic Stroma ◽

Predictive Role

AbstractPancreatic ductal adenocarcinoma (PDAC), characterized by dense desmoplastic stroma laid down by pancreatic stellate cells (PSC), has no reliable diagnostic biomarkers for timely detection. A multi-center cohort of PDAC patients and controls (chronic pancreatitis, intra-ductal papillary neoplasms, gallstones and otherwise healthy) donated serum in an ethically approved manner. Serum PTX3 above 4.34 ng/mL has a higher sensitivity (86%, 95% confidence interval (CI): 65–97%) and specificity (86%, 95% CI: 79–91%), positive predictive value (97%) and likelihood ratio (6.05), and is superior when compared to serum CA19-9 and CEA for detection of PDAC. In vitro and ex vivo analyses of PTX3, in human PDAC samples, PSCs, cell lines and transgenic mouse model for PDAC, suggest that PTX3 originates from stromal cells, mainly PSC. In activated PSC, PTX3 secretion could be downregulated by rendering PSC quiescent using all-trans-retinoic acid (ATRA). PTX3 organizes hyaluronan in conjunction with tumor necrosis factor-stimulated gene 6 (TSG-6) and facilitates stellate and cancer cell invasion. In SCALOP clinical trial (ISRCTN96169987) testing chemo-radiotherapy without stromal targeting, PTX3 had no prognostic or predictive role. However, in STARPAC clinical trial (NCT03307148), stromal modulation by ATRA even at first dose is accompanied with serum PTX3 response in patients who later go on to demonstrate disease control but not those in whom the disease progresses. PTX3 is a putative stromally-derived biomarker for PDAC which warrants further testing in prospective, larger, multi-center cohorts and within clinical trials targeting stroma.

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The Role of Stellate Cells in Pancreatic Ductal Adenocarcinoma: Targeting Perspectives

Frontiers in Oncology ◽

10.3389/fonc.2020.621937 ◽

2021 ◽

Vol 10 ◽

Author(s):

Yang Wu ◽

Chun Zhang ◽

Kuirong Jiang ◽

Jens Werner ◽

Alexandr V. Bazhin ◽

...

Keyword(s):

Pancreatic Cancer ◽

Pancreatic Ductal Adenocarcinoma ◽

Stellate Cells ◽

Pancreatic Stellate Cells ◽

Ductal Adenocarcinoma ◽

Gastrointestinal Malignancy ◽

Desmoplastic Reaction ◽

Pancreatic Cancer Cells ◽

Promising Strategy

Pancreatic ductal adenocarcinoma (PDAC) is a gastrointestinal malignancy with a dismal clinical outcome. Accumulating evidence suggests that activated pancreatic stellate cells (PSCs), the major producers of extracellular matrix (ECM), drive the severe stromal/desmoplastic reaction in PDAC. Furthermore, the crosstalk among PSCs, pancreatic cancer cells (PCCs) as well as other stroma cells can establish a growth-supportive tumor microenvironment (TME) of PDAC, thereby enhancing tumor growth, metastasis, and chemoresistance via various pathways. Recently, targeting stroma has emerged as a promising strategy for PDAC therapy, and several novel strategies have been proposed. The aim of our study is to give a profound review of the role of PSCs in PDAC progression and recent advances in stroma-targeting strategies.

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DDX31: A Novel Functional Oncogene Promotes Migration and Proliferation of Pancreatic Cancer

10.21203/rs.3.rs-520114/v1 ◽

2021 ◽

Author(s):

Yang Liu ◽

Yongjie Xie ◽

Jinsheng Ding ◽

Liangliang Wu

Keyword(s):

Pancreatic Cancer ◽

Western Blot ◽

Pancreatic Ductal Adenocarcinoma ◽

Cancer Cells ◽

Blot Analysis ◽

Western Blot Analysis ◽

Ductal Adenocarcinoma ◽

Rna Helicases ◽

Pancreatic Cancer Cells

Abstract Purpose: Pancreatic cancer is one of the most malignant cancers with rapid disease progression. Pancreatic ductal adenocarcinoma (PDAC) accounts for more than 90% in exocrine pancreatic cancer. DDX31 is one of the Asp-Glu-Ala-Asp (DEAD)-box RNA helicases (DDX) family member, which has never been reported in pancreatic ductal adenocarcinoma. Through comprehensive analysis of bioinformatics screening, clinical pathological data and experiment results verification, we found DDX31 may be a promising oncogene.Patients and methods: The potential correlation between DDX3 expression and clinical feature of PDAC was analyzed, which revealed that patients with high DDX31 expression may have a poor prognosis. Elevated expression levels of DDX31 in PDAC compared with adjacent normal tissues were determined by immunohistochemical and Western blot analyses. Western blot analysis of N-cadherin, Snail, transwell, and wound healing assays was carried out to evaluate the pro-metastasis effects of DDX31 in PDAC. In vitro experiments included colony formation assay. Edu labeling assay, CCK-8, western blot analysis of Ki67, PCNA, and an in vivo subcutaneous mouse model were used to analyze the role of DDX31 in PDAC proliferation.Results: In our research, integrated bioinformatics analysis of the TCGA and GEO databases was performed to identify the metastasis and proliferation-related differentially expressed genes (DEG). DDX31 predicts strong metastasis and proliferation capacity of PDAC, was finally screened. Then, the clinical data identified that highexpression-DDX31 was correlated with pancreatic tumor size, pathological grade, and lymph node metastasis. The in vitro and vivo experiments revealed that overexpression-DDX31 promoted the migration, proliferation and cell viability of pancreatic cancer cells, these functions of DDX31 had also been proved in the knockdown results. Moreover, the EMT related markers and proliferation markers were identified to be positively regulated by DDX31 in pancreatic cancer cells.Conclusion: Thus, our work uncovered that DDX31 promotes migration and proliferation in PDAC and might be a promising therapeutic target in pancreatic cancer.

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Influence of IP-10/CXCL10 induction in human pancreatic cancer stroma on lymphocytes recruitment and correlation with survival.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.3_suppl.290 ◽

2015 ◽

Vol 33 (3_suppl) ◽

pp. 290-290 ◽

Cited By ~ 1

Author(s):

Thomas B Brunner ◽

Serena Lunardi ◽

Nigel B Jamieson ◽

Su Yin Lim ◽

Kristin L Griffiths ◽

...

Keyword(s):

Pancreatic Cancer ◽

T Cells ◽

Pancreatic Ductal Adenocarcinoma ◽

Cancer Patients ◽

Mononuclear Cells ◽

Pancreatic Stellate Cells ◽

Human Pancreatic Cancer ◽

Ductal Adenocarcinoma ◽

Pancreatic Tumors ◽

Pancreatic Cancer Cells

290 Background: Pancreatic ductal adenocarcinoma is characterized by an abundant desmoplastic reaction driven by pancreatic stellate cells (PSCs) that contributes to tumor progression. Here we sought to characterize the interactions between pancreatic cancer cells (PCCs) and PSCs that affect the inflammatory and immune response in pancreatic tumors. Methods: Conditioned media from mono- and cocultures of PSCs and PCCs were assayed for expression of cytokines, chemokines and growth factors. Gene expression analysis of human pancreatic ductal adenocarcinoma samples was used to verify expression of cytokines and their correlation with markers of immunoresponse and with clinical outcome. Finally, we tested chemotaxis of leukocytes isolated from peripheral blood mononuclear cells of pancreatic cancer patients. Results: IP-10/CXCL10 was the most highly induced chemokine in coculture of PSCs and PCCs. Its expression was induced in the PSCs by PCCs. IP-10 expression was consistently upregulated in human pancreatic cancer specimens, and positively correlated with high stroma content. Furthermore, expression of IP-10 and its receptor CXCR3 were significantly associated with the intratumoral presence of regulatory T cells (Tregs). In an independent cohort of 48 patients with resectable pancreatic ductal adenocarcinoma, the survival of patients with high IP-10 levels was 18.1 months less than those with low IP-10 levels (HR=2.14, 95% CI 1.05 -4.42). Importantly, IP-10 stimulated the ex vivo recruitment of CXCR3+ effector T cells as well as CXCR3+ Tregs derived from patients with pancreatic cancer. Conclusions: Our findings suggest that, in pancreatic cancer patients, CXCR3+ Tregs are recruited by IP-10 expressed by PSCs in the tumor stroma, leading to immunosuppressive and tumor-promoting effects.

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