Molecular Alterations in Pancreatic Cancer: Transfer to the Clinic

Gil, Yolanda Rodríguez; Sánchez, Paula Jiménez; Velasco, Raúl Muñoz; García, Ana García; Lobo, Víctor J. Sánchez-Arévalo

doi:10.3390/ijms22042077

Cited by 6 publications

(5 citation statements)

References 102 publications

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“…If this is the case, then PanINs with squamous metaplasia and intraductal lesions with squamous epithelium would fit into the PanIN pathway conceptually. This might be tested experimentally by genetic analyses to determine if some of the same oncogenes found in PDACs and PanINs 9,10 are also present in areas of squamous metaplasia in the pancreatic ducts. We are aware of 1 report that 13 microdissected lesions with squamous metaplasia were negative for codon 12 K-ras mutations, whereas intraductal papillary hyperplasia lesions had codon 12 K-ras mutations in 27 of 44 lesions.…”

Section: Discussionmentioning

confidence: 99%

Incidence of Pancreatic Intraepithelial Neoplasia in an Autopsy Series

Longnecker

Suriawinata

2022

Pancreas

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ObjectivesPancreatic intraepithelial neoplasia (PanIN) is the currently preferred designation for putative preneoplastic changes in the pancreas. There are few data for the incidence of PanIN in the general population. Our goal was to determine the incidence of PanIN in a large group of pancreases obtained at autopsy.MethodsSlides stained with hematoxylin and eosin were scanned to count PanIN.ResultsWe found multiple PanINs in most pancreases and at least 1 in 86.4% of 154 pancreases when multiple slides (8–12) from each were examined. The average age at autopsy was 62 years, and 90% of the patients were 40 years or older. Several questions were raised by our observations. Should a minimum size be defined for classification as PanIN? Do PanINs occur in lesions that apparently arise from acinar to ductal metaplasia? Does squamous metaplasia in PanIN have any special significance, and do purely squamous lesions have preneoplastic significance?ConclusionsWe conclude that the incidence of PanIN is higher than previously reported.

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Section: Discussionmentioning

confidence: 99%

Incidence of Pancreatic Intraepithelial Neoplasia in an Autopsy Series

Longnecker

Suriawinata

2022

Pancreas

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“…У результаті дослідження не виявили абсолютної зворотної кореляції між маркером і агресивністю ПАПЗ. Це може підтверджувати факт високоінвазивної, агресивної поведінки клітин ПАПЗ при збереженні диференційованого фенотипу [7,8]. Ця невідповідність може підтверджувати також гіпотезу про те, що ЕМТ є багатоступеневим процесом, який передбачає кілька фенотипових змін і є проявом часткового фенотипу ЕМТ [6,7,8].…”

Section: обговоренняunclassified

“…У первинних пухлинах виявляють низьку кількість ракових клітин, що проходять ЕМТ, а більшість клітин, що циркулюють, експресують і епітеліальні, й мезенхімальні маркери. Тому, за результатами наукових досліджень, інфільтрація й дисемінація можуть відбуватися під час ЕМТ, що підтверджує роль ЕМТ в прогресуванні злоякісного процесу [6,7,8]. Втім, окремі автори піддають сумніву думку про те, чи є ЕМТ передумовою метастазування, особливо колонізації [9].…”

Section: Introductionunclassified

Immunohistochemical characteristics of epithelial-mesenchymal transition in pancreatic ductal adenocarcinoma

Shyshkin,

Kabachenko

2024

Zaporozhye Medical Journal

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The epithelial-mesenchymal transition (EMT) plays a crucial role in the development of pancreatic ductal adenocarcinoma (PDAC). There are insufficient and contradictory data in the scientific literature on the peculiarities of epithelial and mesenchymal marker expression in PDAC ducts and EMT zone, which requires further research on the role of EMT in the development and progression of PDAC. Aim: to conduct a comprehensive assessment of epithelial and mesenchymal markers of EMT in the PDAC ducts and EMT zone at different degrees of differentiation. Materials and methods. A comprehensive pathomorphological and immunohistochemical examination including 49 cases of surgical material from patients with PDAC, divided into groups of moderate (G2) and low degree of tumor differentiation (G3). Results. PDAC was characterized by low levels of E-cadherin expression in both ducts and EMT – Me = 22.58 % [12.81; 36.23] and Me = 25.17 % [19.04; 35.37], respectively (p > 0.05). Only membrane expression of the marker was detected in the ducts and membrane-cytoplasmic one – in the EMT zone without significant differences in the groups. There was a significant decrease in the ductal β-catenin expression (p < 0.05) in G2 with membrane-cytoplasmic staining (Me = 15.58 % [10.42; 26.24]), in G3 – with membrane (Me = 4.42 % [2.35; 5.93]); in the EMT zone, only membrane-cytoplasmic expression was observed in both groups without significant difference (p > 0.05). Membrane expression of CK7 was positive in 100 % of PDAC, significantly lower at G2 (Me = 19.51 % [10.70; 27.24]; Me = 26.19 % [20.93; 30.05], p < 0.05), and CK18 (Me = 21.34 % [9.68; 29.96] – in G2, in G3 – Me = 22.50 % [8.24; 40.08], p > 0.05). Expression of α-SMA and Vim was seen in spindle-shaped stromal cells, around tubular and trabecular structures with membrane-cytoplasmic staining. There was no significant difference between α-SMA in G2 and G3, the level of vimentin was significantly lower in G3 (p < 0.05). Conclusions. The features of PDAC E-cadherin, β-catenin, CK7 and CK18 marker expression indicate a greater EMT process at the periphery of the tumor and its severity increases with tumor progression. The optimal markers to determine the mesenchymal phenotype of PDAC cells are α-SMA and vimentin.

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“…Pancreatic cancer is a highly aggressive and poorly prognostic disease with an overall five-year survival rate of 12.5%[ 1 , 2 ]. Many molecular alternations have been identified and evaluated for their potential as a therapeutic target in pancreatic cancer[ 3 ]. Nevertheless, there is still an urgent need to develop an effective treatment for pancreatic cancer.…”

Section: Introductionmentioning

confidence: 99%

Erlotinib combination with a mitochondria-targeted ubiquinone effectively suppresses pancreatic cancer cell survival

Leung,

Chen,

Sari

et al. 2024

World J Gastroenterol

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BACKGROUND Pancreatic cancer is a leading cause of cancer-related deaths. Increased activity of the epidermal growth factor receptor (EGFR) is often observed in pancreatic cancer, and the small molecule EGFR inhibitor erlotinib has been approved for pancreatic cancer therapy by the food and drug administration. Nevertheless, erlotinib alone is ineffective and should be combined with other drugs to improve therapeutic outcomes. We previously showed that certain receptor tyrosine kinase inhibitors can increase mitochondrial membrane potential (Δψm), facilitate tumor cell uptake of Δψm-sensitive agents, disrupt mitochondrial homeostasis, and subsequently trigger tumor cell death. Erlotinib has not been tested for this effect. AIM To determine whether erlotinib can elevate Δψm and increase tumor cell uptake of Δψm-sensitive agents, subsequently triggering tumor cell death. METHODS Δψm-sensitive fluorescent dye was used to determine how erlotinib affects Δψm in pancreatic adenocarcinoma (PDAC) cell lines. The viability of conventional and patient-derived primary PDAC cell lines in 2D- and 3D cultures was measured after treating cells sequentially with erlotinib and mitochondria-targeted ubiquinone (MitoQ), a Δψm-sensitive MitoQ. The synergy between erlotinib and MitoQ was then analyzed using SynergyFinder 2.0. The preclinical efficacy of the two-drug combination was determined using immune-compromised nude mice bearing PDAC cell line xenografts. RESULTS Erlotinib elevated Δψm in PDAC cells, facilitating tumor cell uptake and mitochondrial enrichment of Δψm-sensitive agents. MitoQ triggered caspase-dependent apoptosis in PDAC cells in culture if used at high doses, while erlotinib pretreatment potentiated low doses of MitoQ. SynergyFinder suggested that these drugs synergistically induced tumor cell lethality. Consistent with in vitro data, erlotinib and MitoQ combination suppressed human PDAC cell line xenografts in mice more effectively than single treatments of each agent. CONCLUSION Our findings suggest that a combination of erlotinib and MitoQ has the potential to suppress pancreatic tumor cell viability effectively.

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Molecular Alterations in Pancreatic Cancer: Transfer to the Clinic

Cited by 6 publications

References 102 publications

Incidence of Pancreatic Intraepithelial Neoplasia in an Autopsy Series

Incidence of Pancreatic Intraepithelial Neoplasia in an Autopsy Series

Immunohistochemical characteristics of epithelial-mesenchymal transition in pancreatic ductal adenocarcinoma

Erlotinib combination with a mitochondria-targeted ubiquinone effectively suppresses pancreatic cancer cell survival

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