S100A10, a novel biomarker in pancreatic ductal adenocarcinoma

Bydoun, Moamen; Sterea, Andra M.; Liptay, Henry; Uzans, Andrea; Huang, Weei‐Yuarn; Rodrigues, Gloria J.; Weaver, Ian C.G.; Gu, Hong; Waisman, David M.

doi:10.1002/1878-0261.12356

Cited by 42 publications

(68 citation statements)

References 53 publications

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“…Our result is in agreement with a previous study, which showed that PDAC patients survival was associated with hypermethylation of several individual genes including SST (HR = 1.63, P = 0.03) (Henriksen et al , 2016). In this regard, Bydoun et al (2018) reported a S100A10 mRNA and methylation status as predictive of pancreatic cancer survival where hypermethylation and lower expression were correlated with better survival. In another study, DNA methylation and altered expression of MET and ITGA2 was associated with patient survival and patients with coordinated hypomethylation and high expression of MET and ITGA2 strongly correlated with poor outcome ( P ‐value = 0.007 and 0.040, respectively) (Nones et al , 2014).…”

Section: Discussionmentioning

confidence: 99%

SST gene hypermethylation acts as a pan‐cancer marker for pancreatic ductal adenocarcinoma and multiple other tumors: toward its use for blood‐based diagnosis

Manoochehri

Giese

et al. 2020

Molecular Oncology

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Aberrant DNA methylation is often involved in carcinogenesis. Our initial goal was to identify DNA methylation biomarkers associated with pancreatic cancer. A genomewide methylation study was performed on DNA from pancreatic ductal adenocarcinoma (PDAC) and endocrine pancreas tumors. Validation of DNA methylation patterns and concomitant alterations in expression of gene candidates was performed on patient samples and pancreatic cancer cell lines. Furthermore, validation was done on independent data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Finally, droplet digital PCR was employed to detect DNA methylation marks in cell-free (cf) DNA isolated from plasma samples of PDAC patients and cancer-free blood donors. Hypermethylation of the SST gene (encoding somatostatin) and concomitant downregulation of its expression were discovered in PDAC and endocrine tumor tissues while not being present in chronic pancreatitis (inflamed) tissues and normal pancreas. Fittingly, treatment with a somatostatin agonist (octreotide) reduced cell proliferation and migration of pancreatic cancer cells. Diagnostic performance of SST methylation in a receiver operating characteristic curve analysis was 100% and 89% for tissue and plasma samples, respectively. A large body of TCGA and GEO data confirmed SST hypermethylation and downregulation in PDAC and showed a similar effect in a broad spectrum of other tumor entities. SST promoter methylation represents a sensitive and promising molecular, pan-cancer biomarker detectable in tumor tissue, and liquid biopsy samples.

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Section: Discussionmentioning

confidence: 99%

SST gene hypermethylation acts as a pan‐cancer marker for pancreatic ductal adenocarcinoma and multiple other tumors: toward its use for blood‐based diagnosis

Manoochehri

Giese

et al. 2020

Molecular Oncology

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“…High S100A10 expression in gall bladder carcinoma is shown to be associated with poor prognosis . Overexpression of S100A10 is also associated with poor prognosis in lung adenocarcinoma and pancreatic ductal adenocarcinoma . For lung squamous cell carcinoma, membranous immunopositivity was found (Fig.…”

Section: The Prognostic Value Of S100a10 For Cancermentioning

confidence: 88%

“…reported that the growth of Panc‐1, S100A10 depleted, in NOD/SCIS mice was hindered showing significant reduction in expression of VEGF and cyclin D1, compared to the scramble control. However, it should be noted that S100A10‐depleted panc‐1 cells have similar proliferation rates compared to the control in vitro . It still remains controversial and unclear whether the reduced tumor growth is plasminogen‐dependent or ‐independent.…”

Section: S100a10 Functions In Therapeutic Burdenmentioning

confidence: 97%

Multiple functions of S100A10, an important cancer promoter

Saiki

Horii

2019

Pathology International

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The S100 group of calcium binding proteins is composed of 21 members that exhibit tissue/cell specific expressions. These S100 proteins bind a diverse range of targets and regulate multiple cellular processes, including proliferation, migration and differentiation. S100A10, also known as p11, binds mainly to annexin A2 and mediates the conversion of plasminogen to an active protease, plasmin. Higher S100A10 expression has been reported to link to worse outcome and/or chemoresistance in a number of cancer types in lung, breast, ovary, pancreas, gall bladder and colorectum and leukemia although some discrepancy was reported. In this review, we focused on the roles of the S100A10 in cancer. We summarized its biological functions, role in cancer progression, prognostic value and targeting of S100A10 for cancer therapy.

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“…P11, present on the extracellular surface, is complexed with its binding partner annexin A2 (p36). We have reported that p11 regulates plasminogen activation on the cell surface of many cancer cells including fibrosarcoma, colorectal, lung and pancreatic cells (8,(11)(12)(13)(14)(15)(16). We have also reported that p11 regulates the plasmin production of stromal cells including macrophages and endothelial cells (17)(18)(19) and that p11-dependent plasmin generation is necessary for macrophage infiltration to the site of inflammation in subcutaneous tumor growth.…”

Section: Introductionmentioning

confidence: 99%

“…Several studies have shown correlations between p11 gene expression and poor prognosis and overall survival in lung (20)(21)(22), colorectal, ovarian, kidney, gastric cancers, anaplastic thyroid carcinoma, melanoma and acute lymphoblastic leukemia (reviewed in (12)), and pancreatic ductal adenocarcinoma (PDAC) (16). P11 is upregulated in basal-type breast cancer (23) and during the process of intravasation and epithelial mesenchymal transition (24).…”

Section: Introductionmentioning

confidence: 99%

S100A10 has a Critical Regulatory Function in Mammary Tumor Growth and Metastasis: Insights using MMTV-PyMT Oncomice and Clinical Patient Sample Analysis.

Bharadwaj

Dahn

Liu

et al. 2020

Preprint

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Background: Breast cancer is one of the leading causes of cancer deaths in women worldwide. Significant advances have been made in the diagnosis and treatment of breast cancer, treatment of triple-negative and metastatic breast cancer poses significant challenge. Metastasis is a multi-step cascade that involves activation of proteases such as plasmin to facilitate the invasive escape of tumor cells to distant organs. The rate-limiting step in plasmin generation requires the interaction of plasminogen with cell surface plasminogen binding sites. Our laboratory first demonstrated that the plasminogen receptor, S100A10 (p11) was upregulated in many cancer cells and was responsible for much of their plasmin generation. Recently, it was reported that p11 is one of a few genes that are activated when human breast cancer cells metastasize from the primary tumor into the blood and is upregulated during the conversion of breast cancer cells to invasive phenotype. In the current study we have investigated the role of p11 in breast cancer tumor progression.Methods: We have used MMTV-PyMT a mouse transgenic mammary tumor model to investigate the effects of loss of p11 on spontaneous tumor initiation, growth and progression to invasive carcinoma and metastasis. We used experimental metastasis assays to ascertain the role of stromal p11 in tumor cell extravasation and lung colonization. Genes and cytokines regulated by p11 in the PyMT tumors were assessed by microarray analysis and RT-qPCR. Finally, we employed gene profiling analysis and immunohistochemical staining of breast cancer patient tumors to correlate p11 expression to human breast cancer progression. Results: Genetic deletion of p11 resulted in significantly decreased tumor onset, growth rate, and spontaneous pulmonary metastatic burden in the PyMT/p11-KO mice. This phenotype was accompanied by substantial reduction in Ki67 positivity, macrophage infiltration, decreased vascular density in the primary tumors and decrease in invasive carcinoma and pulmonary metastasis. Surprisingly, immunohistochemical analysis of wild-type MMTV-PyMT mice failed to detect p11 expression in the tumors or metastatic tumor cells and loss of p11 did not decrease plasmin generation in the PyMT tumors and cells. Furthermore, tumor cells expressing p11 displayed dramatically reduced lung metastasis when injected into p11-depleted mice, further strengthening the stromal role of p11 in tumor growth and metastasis. Transcriptome analysis of the PyMT tumors from p11-KO mice showed marked reduction in genes involved in breast cancer development, progression, and inflammation such as AREG, MUC1 and S100A8. The PyMT/p11- KO tumors displayed a remarkable increase in inflammatory cytokines such as IL-6, IL-10 and IFN-γ. Gene expression profiling from 176 primary breast cancer samples obtained through the CBCF tumor bank showed that p11 mRNA levels were significantly higher in tumors compared to normal tissues. P11 mRNA expression was significantly associated with poor patient prognosis (hazard ratio – 3.34) and significantly elevated in high grade, triple negative (TN) tumors, and tumors with high proliferative index. Evaluation of p11 protein expression in a NSHA cohort of patients revealed substantial upregulation of p11 in cancer tissues compared to normal controls. Conclusions: This is the first study demonstrating the crucial role of p11 in breast tumor development and metastasis. The results emphasize the potential of p11 as a diagnostic and prognostic biomarker in breast cancer.

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S100A10, a novel biomarker in pancreatic ductal adenocarcinoma

Cited by 42 publications

References 53 publications

SST gene hypermethylation acts as a pan‐cancer marker for pancreatic ductal adenocarcinoma and multiple other tumors: toward its use for blood‐based diagnosis

SST gene hypermethylation acts as a pan‐cancer marker for pancreatic ductal adenocarcinoma and multiple other tumors: toward its use for blood‐based diagnosis

Multiple functions of S100A10, an important cancer promoter

S100A10 has a Critical Regulatory Function in Mammary Tumor Growth and Metastasis: Insights using MMTV-PyMT Oncomice and Clinical Patient Sample Analysis.

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