The hepatic microenvironment essentially determines tumor cell dormancy and metastatic outgrowth of pancreatic ductal adenocarcinoma

ObjectivesTo explore the differences between intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) and diffusion-weighted imaging (DWI) in evaluating the histopathological characters of pancreatic ductal adenocarcinoma (PDAC).MethodsThis retrospective study enrolled 50 patients with PDAC confirmed by pathology from December 2018 to May 2020. All patients underwent DWI and IVIM-DWI before surgeries. Patients were classified into low- and high-fibrosis groups. Apparent diffusion coefficient (ADC), diffusion coefficient (D), false diffusion coefficient (D*), and perfusion fraction (f) were measured by two radiologists, respectively in GE AW 4.7 post-processing station, wherein ADC values were derived by mono-exponential fits and f, D, D* values were derived by biexponential fits. The tumor tissue was stained with Sirius red, CD34, and CK19 to evaluate fibrosis, microvascular density (MVD), and tumor cell density. Furthermore, the correlation between ADC, D, D*, and f values and histopathological results was analyzed.ResultsThe D values were lower in the high-fibrosis group than in the low-fibrosis group, while the f values were opposite. Further, no statistically significant differences were detected in ADC and D* values between the high- and low-fibrosis groups. The AUC of D and f values had higher evaluation efficacy in the high- and low-fibrosis groups than ADC values. A significant negative correlation was established between D values, and fibrosis and a significant positive correlation were observed between f values and fibrosis. No statistical difference was detected between DWI/IVIM parameters values and MVD or tumor cell density except for the positive correlation between D* values and tumor cell density.ConclusionsD and f values derived from the IVIM model had higher sensitivity and diagnostic performance for grading fibrosis in PDAC compared to the conventional DWI model. IVIM-DWI may have the potential as an imaging biomarker for predicting the fibrosis grade of PDAC.

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The ECM and CAFs interact to differentially regulate PDAC parenchymal (CPC) and CSC phenotypes to determine pancreatic ductal adenocarcinoma (PDAC) progression

10.21203/rs.2.13193/v1 ◽

2019 ◽

Author(s):

Stefania Cannone ◽

Maria Rafaella Greco ◽

Hélène Guizouarn ◽

Olivier Soriani ◽

Richard Tomasini ◽

...

Keyword(s):

Tumor Cell ◽

Pancreatic Ductal Adenocarcinoma ◽

Ductal Adenocarcinoma ◽

Metastatic Progression ◽

Cell Type

Abstract Summary CAFs and acellular stromal ECM components interact to drive metastatic progression by stimulating the hallmark behaviors of each tumor cell type that contribute to metastasis: invasion in the CPCs and growth and angiogenesis in the CSCs.

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"Stealth dissemination" of macrophage-tumor cell fusions cultured from blood of patients with pancreatic ductal adenocarcinoma

PLoS ONE ◽

10.1371/journal.pone.0184451 ◽

2017 ◽

Vol 12 (9) ◽

pp. e0184451 ◽

Cited By ~ 14

Author(s):

Gary A. Clawson ◽

Gail L. Matters ◽

Ping Xin ◽

Christopher McGovern ◽

Eric Wafula ◽

...

Keyword(s):

Tumor Cell ◽

Pancreatic Ductal Adenocarcinoma ◽

Ductal Adenocarcinoma ◽

Cell Fusions

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Epithelial-to-Mesenchymal Transition in Pancreatic Ductal Adenocarcinoma and Pancreatic Tumor Cell Lines: The Role of Neutrophils and Neutrophil-Derived Elastase

Clinical and Developmental Immunology ◽

10.1155/2012/720768 ◽

2012 ◽

Vol 2012 ◽

pp. 1-12 ◽

Cited By ~ 71

Author(s):

Thomas Große-Steffen ◽

Thomas Giese ◽

Nathalia Giese ◽

Thomas Longerich ◽

Peter Schirmacher ◽

...

Keyword(s):

Tumor Cell ◽

Pancreatic Ductal Adenocarcinoma ◽

Tumor Cells ◽

Epithelial To Mesenchymal Transition ◽

Pancreatic Tumor ◽

Polymorphonuclear Neutrophils ◽

Nuclear Accumulation ◽

Ductal Adenocarcinoma ◽

Mesenchymal Transition ◽

E Cadherin

Pancreatic ductal adenocarcinoma (PDAC) is frequently associated with fibrosis and a prominent inflammatory infiltrate in the desmoplastic stroma. Moreover, in PDAC, an epithelial-to-mesenchymal transition (EMT) is observed. To explore a possible connection between the infiltrating cells, particularly the polymorphonuclear neutrophils (PMN) and the tumor cell transition, biopsies of patients with PDAC (n=115) were analysed with regard to PMN infiltration and nuclear expression ofβ-catenin and of ZEB1, well-established indicators of EMT. In biopsies with a dense PMN infiltrate, a nuclear accumulation ofβ-catenin and of ZEB1 was observed. To address the question whether PMN could induce EMT, they were isolated from healthy donors and were cocultivated with pancreatic tumor cells grown as monolayers. Rapid dyshesion of the tumor cells was seen, most likely due to an elastase-mediated degradation of E-cadherin. In parallel, the transcription factor TWIST was upregulated,β-catenin translocated into the nucleus, ZEB1 appeared in the nucleus, and keratins were downregulated. EMT was also induced when the tumor cells were grown under conditions preventing attachment to the culture plates. Here, also in the absence of elastase, E-cadherin was downmodulated. PMN as well as prevention of adhesion induced EMT also in liver cancer cell line. In conclusion, PMN via elastase induce EMTin vitro, most likely due to the loss of cell-to-cell contact. Because in pancreatic cancers the transition to a mesenchymal phenotype coincides with the PMN infiltrate, a contribution of the inflammatory response to the induction of EMT and—by implication—to tumor progression is possible.

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Abstract 514: DUOX2-related H2O2production contributes to pro-inflammatory cytokine-related DNA damage and tumor cell growth in models of pancreatic ductal adenocarcinoma

10.1158/1538-7445.sabcs18-514 ◽

2019 ◽

Author(s):

Yongzhong Wu ◽

Jiamo Lu ◽

Smitha Antony ◽

Jennifer L. Meitzler ◽

Agnes Juhasz ◽

...

Keyword(s):

Dna Damage ◽

Cell Growth ◽

Tumor Cell ◽

Pancreatic Ductal Adenocarcinoma ◽

Inflammatory Cytokine ◽

Ductal Adenocarcinoma ◽

Tumor Cell Growth

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IL-1α Expression in Pancreatic Ductal Adenocarcinoma Affects the Tumor Cell Migration and Is Regulated by the p38MAPK Signaling Pathway

PLoS ONE ◽

10.1371/journal.pone.0070874 ◽

2013 ◽

Vol 8 (8) ◽

pp. e70874 ◽

Cited By ~ 20

Author(s):

Vegard Tjomsland ◽

Linda Bojmar ◽

Per Sandström ◽

Charlotte Bratthäll ◽

Davorka Messmer ◽

...

Keyword(s):

Cell Migration ◽

Tumor Cell ◽

Pancreatic Ductal Adenocarcinoma ◽

Signaling Pathway ◽

Ductal Adenocarcinoma ◽

Tumor Cell Migration ◽

P38mapk Signaling

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Overexpression of receptor tyrosine kinase Axl promotes tumor cell invasion and survival in pancreatic ductal adenocarcinoma

Cancer ◽

10.1002/cncr.25483 ◽

2010 ◽

Vol 117 (4) ◽

pp. 734-743 ◽

Cited By ~ 84

Author(s):

Xianzhou Song ◽

Hua Wang ◽

Craig D. Logsdon ◽

Asif Rashid ◽

Jason B. Fleming ◽

...

Keyword(s):

Tyrosine Kinase ◽

Tumor Cell ◽

Pancreatic Ductal Adenocarcinoma ◽

Cell Invasion ◽

Receptor Tyrosine Kinase ◽

Tumor Cell Invasion ◽

Ductal Adenocarcinoma

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Prognostic significance of high mobility group A2 (HMGA2) in pancreatic ductal adenocarcinoma: malignant functions of cytoplasmic HMGA2 expression

Journal of Cancer Research and Clinical Oncology ◽

10.1007/s00432-021-03745-w ◽

2021 ◽

Author(s):

Jan-Paul Gundlach ◽

Charlotte Hauser ◽

Franka Maria Schlegel ◽

Anna Willms ◽

Christine Halske ◽

...

Keyword(s):

Lymph Node ◽

Tumor Cell ◽

Pancreatic Ductal Adenocarcinoma ◽

Primary Tumor ◽

Tumor Tissue ◽

Cultured Cells ◽

Ductal Adenocarcinoma ◽

Nuclear Staining ◽

Cell Nuclei ◽

Primary Tumor Cell

Abstract Purpose HMGA2 has frequently been found in benign as well as malignant tumors and a significant association between HMGA2 overexpression and poor survival in different malignancies was described. In pancreatic ductal adenocarcinoma (PDAC), nuclear HMGA2 expression is associated with tumor dedifferentiation and presence of lymph node metastasis. Nevertheless, the impact of HMGA2 occurrence in other cell compartments is unknown. Methods Intracellular distribution of HMGA2 was analyzed in PDAC (n = 106) and peritumoral, non-malignant ducts (n = 28) by immunohistochemistry. Findings were correlated with clinico-pathological data. Additionally, intracellular HMGA2 presence was studied by Western blotting of cytoplasmic and nuclear fractions of cultured cells. Results HMGA2 was found in the cytoplasm and in the nucleus of cultured cells. In human tumor tissue, HMGA2 was also frequently found in the cytoplasm and the nucleus of tumor cells, however, nuclear staining was generally stronger. Direct comparison from tumor tissue with corresponding non-neoplastic peritumoral tissue revealed significantly stronger expression in tumors (p = 0.003). Of note, the nuclear staining was significantly stronger in lymph node metastatic cell nuclei compared to primary tumor cell nuclei (p = 0.049). Interestingly, cytoplasmic staining positively correlated with lymph vessel (p = 0.004) and venous invasion (p = 0.046). Conclusion HMGA2 is a prognostic marker in PDAC. Firstly, we found a positive correlation for cytoplasmic HMGA2 expression with lympho-vascular invasion and, secondly, we found a significantly stronger nuclear expression of HMGA2 in cancer-positive lymph node nuclei compared to primary tumor cell nuclei. So far, the role of cytoplasmic HMGA2 is nearly unknown, however, our data lend support to the hypothesis that cytoplasmic HMGA2 expression is involved in nodal spread.

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