Overexpression of transmembrane protein 2 (TMEM2), a novel hyaluronidase, predicts poor prognosis in pancreatic ductal adenocarcinoma

Kudo, Yuzan; Sato, Norihiro; Adachi, Yasuhiro; Amaike, Takao; Koga, Atsuhiro; Kohi, Shiro; Noguchi, Hirotsugu; Nakayama, Toshiyuki; Hirata, Keiji

doi:10.1016/j.pan.2020.08.026

Cited by 15 publications

(12 citation statements)

References 26 publications

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“…Indeed, the cell surface hyaluronidase TMEM2 is an independent negative prognostic factor in PDAC 52 , demonstrating the importance of HA degradation in PDAC progression. TMEM2 associates to integrins and clears HA to facilitate cancer cell adhesion and migration 53 .…”

Section: Discussionmentioning

confidence: 99%

Stromal hyaluronan accumulation is associated with low immune response and poor prognosis in pancreatic cancer

Tahkola

Ahtiainen

Mecklin∥

et al. 2021

Sci Rep

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Hyaluronan (HA) accumulation has been associated with poor survival in various cancers, but the mechanisms for this phenomenon are still unclear. The aim of this study was to investigate the prognostic significance of stromal HA accumulation and its association with host immune response in pancreatic ductal adenocarcinoma (PDAC). The study material consisted of 101 radically treated patients for PDAC from a single geographical area. HA staining was evaluated using a HA-specific probe, and the patterns of CD3, CD8, CD73 and PD-L1 expression were evaluated using immunohistochemistry. HA staining intensity of tumour stromal areas was assessed digitally using QuPath. CD3- and CD8-based immune cell score (ICS) was determined. High-level stromal HA expression was significantly associated with poor disease-specific survival (p = 0.037) and overall survival (p = 0.013) In multivariate analysis, high-level stromal HA expression was an independent negative prognostic factor together with histopathological grade, TNM stage, CD73 positivity in tumour cells and low ICS. Moreover, high-level stromal HA expression was associated with low ICS (p = 0.017). In conclusion, stromal HA accumulation is associated with poor survival and low immune response in PDAC.

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Section: Discussionmentioning

confidence: 99%

Stromal hyaluronan accumulation is associated with low immune response and poor prognosis in pancreatic cancer

Tahkola

Ahtiainen

Mecklin∥

et al. 2021

Sci Rep

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“…TMEM2 is regulated by the above-mentioned SOX4 protein and has been shown to promote invasion in breast cancer [ 54 ]. It was also suggested to be a poor prognosis factor in pancreatic ductal adenocarcinoma [ 55 ]. In our study, we have analyzed the KRT gene family including KRT4, KRT8, KRT15 and KRT18 , the epithelial terminal differentiation markers.…”

Section: Discussionmentioning

confidence: 99%

Barrett’s Metaplasia Progression towards Esophageal Adenocarcinoma: An Attempt to Select a Panel of Molecular Sensors and to Reflect Clinical Alterations by Experimental Models

Korbut

Krukowska

Magierowski

2022

IJMS

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The molecular processes that predispose the development of Barrett’s esophagus (BE) towards esophageal adenocarcinoma (EAC) induced by gastrointestinal reflux disease (GERD) are still under investigation. In this study, based on a scientific literature screening and an analysis of clinical datasets, we selected a panel of 20 genes covering BE- and EAC-specific molecular markers (FZD5, IFNGR1, IL1A, IL1B, IL1R1, IL1RN, KRT4, KRT8, KRT15, KRT18, NFKBIL1, PTGS1, PTGS2, SOCS3, SOX4, SOX9, SOX15, TIMP1, TMEM2, TNFRSF10B). Furthermore, we aimed to reflect these alterations within an experimental and translational in vitro model of BE to EAC progression. We performed a comparison between expression profiles in GSE clinical databases with an in vitro model of GERD involving a BE cell line (BAR-T) and EAC cell lines (OE33 and OE19). Molecular responses of cells treated with acidified bile mixture (BM) at concentration of 100 and 250 μM for 30 min per day were evaluated. We also determined a basal mRNA expression within untreated, wild type cell lines on subsequent stages of BE and EAC development. We observed that an appropriately optimized in vitro model based on the combination of BAR-T, OE33 and OE19 cell lines reflects in 65% and more the clinical molecular alterations observed during BE and EAC development. We also confirmed previous observations that exposure to BM (GERD in vitro) activated carcinogenesis in non-dysplastic cells, inducing molecular alternations in the advanced stages of BE. We conclude that it is possible to induce, to a high extent, the molecular profile observed clinically within appropriately and carefully optimized experimental models, triggering EAC development. This experimental scheme and molecular marker panel might be implemented in further research, e.g. aiming to develop and evaluate novel compounds and prodrugs targeting GERD as well as BE and EAC prevention and treatment.

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“…Knockout of the gene encoding TMEM2 in BxPC-3, PANC-1, and SUIT-2 cell lines led to increased cell migration without affecting proliferation. When TMEM2 was knocked down, CEMIP gene expression was increased and HA concentration reduced 41 . This highlights the complexity of the balance between proteins that play a role in HA degradation.…”

Section: Hyaluronan Biology: Ha and Ha-related Molecules In Pdacsmentioning

confidence: 97%

Clinically Relevant Biology of Hyaluronic Acid in the Desmoplastic Stroma of Pancreatic Ductal Adenocarcinoma

Jahedi¹,

Ramachandran²,

Windsor³

et al. 2022

Pancreas

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Pancreatic ductal adenocarcinoma (PDAC) is notorious for its poor outcome. The presence of a dense desmoplastic stroma is a hallmark of this malignancy, and abundant hyaluronic acid (HA) within this stroma is a common feature of PDAC. At the end of 2019, an HA-targeting drug, after initial promise, failed phase 3 clinical trials in PDAC. This failure in the face of such strong evidence for biological importance forces us to turn back to the research and seek a better understanding of HA biology in PDAC. Therefore, in this review, we reexamine what is known about HA biology, the methods used to detect and quantify HA, and the ability of the biological models in which HA has been investigated to recapitulate an HA-rich desmoplastic tumor stroma. The role of HA in PDAC relies on its complex interplay with a range of HA-associated molecules, which have not been as extensively investigated as HA itself. Therefore, using large genomic data sets, we cataloged the abundance and activity in PDAC of molecules that modulate HA synthesis, degradation, protein interactions, and receptor binding. Based on their association with clinical characteristics and individual patient outcomes, we suggest a small number of HA-associated molecules that warrant further investigation as biomarkers and drug targets.

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Overexpression of transmembrane protein 2 (TMEM2), a novel hyaluronidase, predicts poor prognosis in pancreatic ductal adenocarcinoma

Cited by 15 publications

References 26 publications

Stromal hyaluronan accumulation is associated with low immune response and poor prognosis in pancreatic cancer

Stromal hyaluronan accumulation is associated with low immune response and poor prognosis in pancreatic cancer

Barrett’s Metaplasia Progression towards Esophageal Adenocarcinoma: An Attempt to Select a Panel of Molecular Sensors and to Reflect Clinical Alterations by Experimental Models

Clinically Relevant Biology of Hyaluronic Acid in the Desmoplastic Stroma of Pancreatic Ductal Adenocarcinoma

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