Vimentin Expression in Tumor Microenvironment Predicts Survival in Pancreatic Ductal Adenocarcinoma: Heterogeneity in Fibroblast Population

Maehira, Hiromitsu; Miyake, Toru; Iida, Hiroya; Tokuda, Aya; Mori, Haruki; Yasukawa, Daiki; Mukaisho, Ken‐ichi; Shimizu, Tomoharu; Tani, Masaji

doi:10.1245/s10434-019-07891-x

Cited by 18 publications

(14 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In our study cohort, a key issue is that vimentin has started to be evaluated as a DS marker in patients with PDAC, 59 because it has mainly been described as an EMT marker; 48 , 60 , 61 however, we detected its expression in stromal tissue surrounding tumor glands, in line with previous observations. 62 In contrast to other studies which have reported the expression of pan-cytokeratin in tumor buddings, 46 , 63 we detected pan-cytokeratin expression in glands and scattered tumor cells surrounded by DS in PDAC samples.…”

Section: Discussionsupporting

confidence: 88%

High expression of both desmoplastic stroma and epithelial to mesenchymal transition markers associate with shorter survival in pancreatic ductal adenocarcinoma

et al. 2022

View full text Add to dashboard Cite

Desmoplastic stroma (DS) and the epithelial-to-mesenchymal transition (EMT) play a key role in pancreatic ductal adenocarcinoma (PDAC) progression. To date, however, the combined expression of DS and EMT markers, and their association with variations in survival within each clinical stage and degree of tumor differentiation is unknown. The purpose of this study was to investigate the association between expression of DS and EMT markers and survival variability in patients diagnosed with PDAC. We examined the expression levels of DS markers alpha smooth muscle actin (α-SMA), fibronectin, and vimentin, and the EMT markers epithelial cell adhesion molecule (EPCAM), pan-cytokeratin, and vimentin, by immunohistochemistry using a tissue microarray of a retrospective cohort of 25 patients with PDAC. The results were examined for association with survival by clinical stage and by degree of tumor differentiation. High DS markers expression -α-SMA, fibronectin, and vimentin- was associated with decreased survival at intermediate and advanced clinical stages (p=0.006-0.03), as well as with both poorly and moderately differentiated tumor grades (p=0.01-0.02). Interestingly, the same pattern was observed for EMT markers, i.e., EPCAM, pan-cytokeratin, and vimentin (p=0.00008-0.03). High expression of DS and EMT markers within each clinical stage and degree of tumor differentiation was associated with lower PDAC survival. Evaluation of these markers may have a prognostic impact on survival time variation in patients with PDAC.

show abstract

Section: Discussionsupporting

confidence: 88%

High expression of both desmoplastic stroma and epithelial to mesenchymal transition markers associate with shorter survival in pancreatic ductal adenocarcinoma

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Zhou et al, found that patients whose primary tumors express high vimentin levels with loss of E-cadherin expression were more likely to experience lymph node metastasis, distant metastasis, perineural invasion, and advanced staging (American Joint Committee on Cancer stage) than patients with high or low vimentin expression and preserved E-cadherin expression or low vimentin expression and loss of E-cadherin expression ( Zhou et al, 2021 ). As previously reported ( Maehira et al, 2019 ), increased vimentin expression and loss of E-cadherin expression in the cooperative phenotype of tumor clusters results in metastasis, invasion, radio-resistance, and generation of cancer cells with stem cell-like characteristics in pancreatic cancer. Loss of E-cadherin, and the transition to a more aggressive phenotype, requires the coordinated regulation of both cell-cell (E-cadherin-mediated) adhesions and cell-ECM (integrin-mediated) adhesions, both processes being regulated by a variety of factors within the tumor microenvironment ( Canel et al, 2013 ).…”

Section: Cell-cell (E-cadherin Cdh1) and Cell-ecm (α6 Integrin Cd49f)...supporting

confidence: 75%

“…One protein structural marker for EMT is vimentin, an intermediate filament protein associated with cellular motility, cell shape maintenance, and directional migration of cells ( Ivaska, 2011 ; Maehira et al, 2019 ). Another marker, Epithelial-cadherin (E-cadherin), a cell-surface adhesion molecule, is essential in maintaining apical-basal polarity in epithelial cells (cell-cell adhesion), and is known to decrease during EMT, while also known to be present in metastases ( Petrova et al, 2016 ), suggesting metastasis may not be solely dependent on early EMT, but more likely a result of a hybrid or E-M cooperative phenotype in migrating tumor clusters ( Jolly et al, 2019 ; Sinha et al, 2020 ).…”

Section: Cell-cell (E-cadherin Cdh1) and Cell-ecm (α6 Integrin Cd49f)...mentioning

confidence: 99%

Integrins and Epithelial-Mesenchymal Cooperation in the Tumor Microenvironment of Muscle-Invasive Lethal Cancers

Harryman

Marr

Nagle

et al. 2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Muscle-invasive lethal carcinomas traverse into and through this specialized biophysical and growth factor enriched microenvironment. We will highlight cancers that originate in organs surrounded by smooth muscle, which presents a barrier to dissemination, including prostate, bladder, esophageal, gastric, and colorectal cancers. We propose that the heterogeneity of cell-cell and cell-ECM adhesion receptors is an important driver of aggressive tumor networks with functional consequences for progression. Phenotype heterogeneity of the tumor provides a biophysical advantage for tumor network invasion through the tensile muscle and survival of the tumor network. We hypothesize that a functional epithelial-mesenchymal cooperation (EMC)exists within the tumor invasive network to facilitate tumor escape from the primary organ, invasion and traversing of muscle, and navigation to metastatic sites. Cooperation between specific epithelial cells within the tumor and stromal (mesenchymal) cells interacting with the tumor is illustrated using the examples of laminin-binding adhesion molecules—especially integrins—and their response to growth and inflammatory factors in the tumor microenvironment. The cooperation between cell-cell (E-cadherin, CDH1) and cell-ECM (α6 integrin, CD49f) expression and growth factor receptors is highlighted within poorly differentiated human tumors associated with aggressive disease. Cancer-associated fibroblasts are examined for their role in the tumor microenvironment in generating and organizing various growth factors. Cellular structural proteins are potential utility markers for future spatial profiling studies. We also examine the special characteristics of the smooth muscle microenvironment and how invasion by a primary tumor can alter this environment and contribute to tumor escape via cooperation between epithelial and stromal cells. This cooperative state allows the heterogenous tumor clusters to be shaped by various growth factors, co-opt or evade immune system response, adapt from hypoxic to normoxic conditions, adjust to varying energy sources, and survive radiation and chemotherapeutic interventions. Understanding the epithelial-mesenchymal cooperation in early tumor invasive networks holds potential for both identifying early biomarkers of the aggressive transition and identification of novel agents to prevent the epithelial-mesenchymal cooperation phenotype. Epithelial-mesenchymal cooperation is likely to unveil new tumor subtypes to aid in selection of appropriate therapeutic strategies.

show abstract

“…CAFs can increase vitamin D receptor (VDR) expression and decrease the expression of lipid storage genes in PDAC. Increased stromal expression of α-smooth muscle actin (αSMA) by VDR correlates with aggressive pancreatic cancer biology [ 86 ]. Upon treatment with a synthetic form of vitamin D called calcipotriol, CAFs hindered epithelial-to-mesenchymal transition (EMT), decreased the chemoresistance, increased lipid storage gene expression, and hindered the action of myeloid-derived suppressor cells (MDSCs) [ 87 ].…”

Section: Kras Mutation In Patients With Diabetes Mellitusmentioning

confidence: 99%

Highlights on the Role of KRAS Mutations in Reshaping the Microenvironment of Pancreatic Adenocarcinoma

Hafezi

Saber-Ayad

Abdel‐Rahman

2021

IJMS

View full text Add to dashboard Cite

The most frequent mutated oncogene family in the history of human cancer is the RAS gene family, including NRAS, HRAS, and, most importantly, KRAS. A hallmark of pancreatic cancer, recalcitrant cancer with a very low survival rate, is the prevalence of oncogenic mutations in the KRAS gene. Due to this fact, studying the function of KRAS and the impact of its mutations on the tumor microenvironment (TME) is a priority for understanding pancreatic cancer progression and designing novel therapeutic strategies for the treatment of the dismal disease. Despite some recent enlightening studies, there is still a wide gap in our knowledge regarding the impact of KRAS mutations on different components of the pancreatic TME. In this review, we will present an updated summary of mutant KRAS role in the initiation, progression, and modulation of the TME of pancreatic ductal adenocarcinoma (PDAC). This review will highlight the intriguing link between diabetes mellitus and PDAC, as well as vitamin D as an adjuvant effective therapy via TME modulation of PDAC. We will also discuss different ongoing clinical trials that use KRAS oncogene signaling network as therapeutic targets.

show abstract

Vimentin Expression in Tumor Microenvironment Predicts Survival in Pancreatic Ductal Adenocarcinoma: Heterogeneity in Fibroblast Population

Cited by 18 publications

References 28 publications

High expression of both desmoplastic stroma and epithelial to mesenchymal transition markers associate with shorter survival in pancreatic ductal adenocarcinoma

High expression of both desmoplastic stroma and epithelial to mesenchymal transition markers associate with shorter survival in pancreatic ductal adenocarcinoma

Integrins and Epithelial-Mesenchymal Cooperation in the Tumor Microenvironment of Muscle-Invasive Lethal Cancers

Highlights on the Role of KRAS Mutations in Reshaping the Microenvironment of Pancreatic Adenocarcinoma

Contact Info

Product

Resources

About