Accumulation of FOXP3+T-cells in the tumor microenvironment is associated with an epithelial-mesenchymal-transition-type tumor budding phenotype and is an independent prognostic factor in surgically resected pancreatic ductal adenocarcinoma

652 Background: Tumor budding (TB) represents the epithelial-mesenchymal transition (EMT) and is a novel marker that predicts metastasis and poor survival in patients with colorectal cancer. Although recent preclinical studies have elucidated the interaction between the EMT process and tumor microenvironment (TME), the clinicopathological correlation between TB and TME remains unclear. Methods: Formalin-fixed paraffin-embedded blocks of specimens were obtained from patients with stage III colorectal cancer who underwent surgical resection and adjuvant chemotherapy at our institution between January 2009 and July 2012. TB, tumor stroma percentage (TSP), and inflammatory reaction (IR) graded using the Klintrup-Mäkinen method were evaluated on hematoxylin and eosin sections. The densities of CD8+ T-cells at the tumor centers and invasive margins were analyzed using immunohistochemistry and digital image analysis. Cox proportional hazards models were used to assess the effect of clinicopathological variables on relapse-free survival (RFS). Results: One hundred and ninety-five patients were included in this analysis. The median age was 62 years (range 32–84 years). The median follow-up duration of this study was 5.8 years. High TB ( > 5 buds/0.785 mm2) was observed in 106 patients (54.4%) and was associated with high TSP (P < 0.01), but not with IR and CD8 expression. Multivariate analysis, including clinicopathological factors such as histology, TB, TSP, and IR revealed that high TB was an independent poor prognostic factor (hazard ratio, 1.89; 95% confidence interval, 1.04–3.45; P = 0.04). Patients with high TB and low IR (21.0%) exhibited a shorter survival than others; the 5-year RFS rates were 82.7%, 81.1%, 78.4%, and 40.8% in patients with low TB and high IR, low TB and IR, high TB and high IR, and high TB and low IR, respectively. Conclusions: Our study demonstrated that high TB was an adverse prognostic factor, regardless of TME status. The combined analysis of TB plus IR could improve prognostic value in patients with stage III colorectal cancer. Patients with high TB and low IR may need novel therapeutic approaches.

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Detailed analysis of epithelial-mesenchymal transition and tumor budding identifies predictors of long-term survival in pancreatic ductal adenocarcinoma

Journal of Gastroenterology and Hepatology ◽

10.1111/jgh.12752 ◽

2015 ◽

Vol 30 ◽

pp. 78-84 ◽

Cited By ~ 37

Author(s):

Ilona Kohler ◽

Peter Bronsert ◽

Sylvia Timme ◽

Martin Werner ◽

Thomas Brabletz ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Detailed Analysis ◽

Epithelial Mesenchymal Transition ◽

Tumor Budding ◽

Ductal Adenocarcinoma ◽

Term Survival ◽

Long Term Survival ◽

Mesenchymal Transition

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Role of Epithelial-Mesenchymal Transition in Pancreatic Ductal Adenocarcinoma: Is Tumor Budding the Missing Link?

Frontiers in Oncology ◽

10.3389/fonc.2013.00221 ◽

2013 ◽

Vol 3 ◽

Cited By ~ 28

Author(s):

Eva Karamitopoulou

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Epithelial Mesenchymal Transition ◽

Tumor Budding ◽

Ductal Adenocarcinoma ◽

Missing Link ◽

Mesenchymal Transition

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Tumor-derived exosomal long noncoding RNA LINC01133, regulated by Periostin, contributes to pancreatic ductal adenocarcinoma epithelial-mesenchymal transition through the Wnt/β-catenin pathway by silencing AXIN2

Oncogene ◽

10.1038/s41388-021-01762-0 ◽

2021 ◽

Vol 40 (17) ◽

pp. 3164-3179

Author(s):

Yang Liu ◽

Tianchi Tang ◽

Xiaosheng Yang ◽

Peng Qin ◽

Pusen Wang ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Noncoding Rna ◽

Pancreatic Tumor ◽

Epithelial Mesenchymal Transition ◽

Noncoding Rnas ◽

Ductal Adenocarcinoma ◽

Overall Survival Rate ◽

Poor Overall Survival ◽

Mesenchymal Transition ◽

Pancreatic Cancer Cells

AbstractPancreatic ductal adenocarcinoma (PDAC) is one of the most fatal malignancies and rapidly progressive diseases. Exosomes and long noncoding RNAs (lncRNAs) are emerging as vital mediators in tumor cells and their microenvironment. However, the detailed roles and mechanisms of exosomal lncRNAs in PDAC progression remain unknown. Here, we aimed to clarify the clinical significance and mechanisms of exosomal lncRNA 01133 (LINC01133) in PDAC. We analyzed the expression of LINC01133 in PDAC and found that exosomal LINC01133 expression was high and positively correlated with higher TNM stage and poor overall survival rate of PDAC patients. Further research demonstrated that Periostin could increase exosome secretion and then enhance LINC01133 expression. In addition, Periostin increased p-EGFR, p-Erk, and c-myc expression, and c-myc could bind to the LINC01133 promoter region. These findings suggested that LINC01133 can be regulated by Periostin via EGFR pathway activity. We also observed that LINC01133 promoted the proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT) of pancreatic cancer cells. We subsequently evaluated the effect of LINC01133 on the Wnt/β-catenin pathway and confirmed that LINC01133 can interact with Enhancer Of Zeste Homolog 2 (EZH2) and then promote H3K27 trimethylation. This can further silence AXIN2 and suppress GSK3 activity, ultimately activating β-catenin. Collectively, these data indicate that exosomal LINC01133 plays an important role in pancreatic tumor progression, and targeting LINC01133 may provide a potential treatment strategy for PDAC.

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Pancreatic Cancers with High Grade Tumor Budding Exhibit Hallmarks of Diminished Anti-Tumor Immunity

Cancers ◽

10.3390/cancers13051090 ◽

2021 ◽

Vol 13 (5) ◽

pp. 1090

Author(s):

Hassan Sadozai ◽

Animesh Acharjee ◽

Thomas Gruber ◽

Beat Gloor ◽

Eva Karamitopoulou

Keyword(s):

Gene Expression ◽

Pancreatic Cancer ◽

Disease Progression ◽

Immune Escape ◽

Epithelial Mesenchymal Transition ◽

Tumor Budding ◽

Ductal Adenocarcinoma ◽

Low Grade ◽

High Grade ◽

Mesenchymal Transition

Tumor budding is associated with epithelial-mesenchymal transition and diminished survival in a number of cancer types including pancreatic ductal adenocarcinoma (PDAC). In this study, we dissect the immune landscapes of patients with high grade versus low grade tumor budding to determine the features associated with immune escape and disease progression in pancreatic cancer. We performed immunohistochemistry-based quantification of tumor-infiltrating leukocytes and tumor bud assessment in a cohort of n = 111 PDAC patients in a tissue microarray (TMA) format. Patients were divided based on the ITBCC categories of tumor budding as Low Grade (LG: categories 1 and 2) and High Grade (HG: category 3). Tumor budding numbers and tumor budding grade demonstrated a significant association with diminished overall survival (OS). HG cases exhibit notably reduced densities of stromal (S) and intratumoral (IT) T cells. HG cases also display lower M1 macrophages (S) and increased M2 macrophages (IT). These findings were validated using gene expression data from TCGA. A published tumor budding gene signature demonstrated a significant association with diminished survival in PDAC patients in TCGA. Immune-related gene expression revealed an immunosuppressive TME in PDAC cases with high expression of the budding signature. Our findings highlight a number of immune features that permit an improved understanding of disease progression and EMT in pancreatic cancer.

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