c‑Met affects gemcitabine resistance during carcinogenesis in a mouse model of pancreatic cancer

Noguchi, Kozo; Konno, Masamitsu; Eguchi, Hidetoshi; Kikuchi, Kôichi; Mukai, Ryouta; Nishida, Naohiro; Koseki, Junichi; Wada, Hiroshi; Akita, Hirofumi; Satoh, Taroh; Marubashi, Shigeru; Nagano, Hiroaki; Doki, Yuichiro; Mori, Masaki; Ishii, Hideshi

doi:10.3892/ol.2018.8793

Cited by 14 publications

(17 citation statements)

References 22 publications

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“…Furthermore, gemcitabine-resistant cancer cells acquire the hallmarks of EMT in association with an increment of MET phosphorylation and the expression of the stem cell marker CD (cluster of differentiation) [113]. In vivo, knock-out of the MET gene in a mouse model of spontaneous pancreatic neoplasia resulted in a reduction of neoplastic cell proliferation, a predictive marker for chemotherapeutic responses and clinical prognosis [114]. Finally, the inhibition of the tumor–stroma interaction by MET/HGF interception induces stroma remodeling, which results in increased drug delivery and restoration of the response to gemcitabine [106,115].…”

Section: Met/hgf Signaling In Pancreatic Cancermentioning

confidence: 99%

MET/HGF Co-Targeting in Pancreatic Cancer: A Tool to Provide Insight into the Tumor/Stroma Crosstalk

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et al. 2018

IJMS

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The ‘onco-receptor’ MET (Hepatocyte Growth Factor Receptor) is involved in the activation of the invasive growth program that is essential during embryonic development and critical for wound healing and organ regeneration during adult life. When aberrantly activated, MET and its stroma-secreted ligand HGF (Hepatocyte Growth Factor) concur to tumor onset, progression, and metastasis in solid tumors, thus representing a relevant target for cancer precision medicine. In the vast majority of tumors, wild-type MET behaves as a ‘stress-response’ gene, and relies on ligand stimulation to sustain cancer cell ‘scattering’, invasion, and protection form apoptosis. Moreover, the MET/HGF axis is involved in the crosstalk between cancer cells and the surrounding microenvironment. Pancreatic cancer (namely, pancreatic ductal adenocarcinoma, PDAC) is an aggressive malignancy characterized by an abundant stromal compartment that is associated with early metastases and resistance to conventional and targeted therapies. Here, we discuss the role of the MET/HGF axis in tumor progression and dissemination considering as a model pancreatic cancer, and provide a proof of concept for the application of dual MET/HGF inhibition as an adjuvant therapy in pancreatic cancer patients.

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Section: Met/hgf Signaling In Pancreatic Cancermentioning

confidence: 99%

MET/HGF Co-Targeting in Pancreatic Cancer: A Tool to Provide Insight into the Tumor/Stroma Crosstalk

Modica

Tortarolo

Comoglio

et al. 2018

IJMS

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“…The MET/HGF axis have been associated with poor overall survival of pancreatic cancer patients [58]. MET gene is also involved in 1 3 resistance to palliative chemotherapy in PDAC patients, possibly due to the downstream pathway of MET/HGF axis in the maintenance of pancreatic progenitor cells and stem cells [59]. Therefore, MET/HGF pathway is a promising target for therapies.…”

Section: Discussionmentioning

confidence: 99%

PDAC-ANN: an artificial neural network to predict Pancreatic Ductal Adenocarcinoma based on gene expression

Almeida

Cardoso

Freitas

2019

Preprint

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Background: Although the pancreatic ductal adenocarcinoma (PDAC) presents high mortality and metastatic potential, there is a lack of effective therapies and a low survival rate for this disease. This PDAC scenario urges new strategies for diagnosis, drug targets, and treatment. Methods:We performed a gene expression microarray meta-analysis of the tumor against healthy tissues in order to identify differentially expressed genes shared among all datasets, named core-genes (CG). We confirmed the pancreatic expressed proteins of the CG through The Human Protein Atlas. The five most expressed proteins in the tumor group were selected to train an artificial neural network to classify samples. 2 Results: This microarray included 110 tumor and 77 healthy samples. We identified a CG composed of 60 genes, 58 upregulated and two downregulated. The upregulated CG included proteins and extracellular matrix receptors linked to actin cytoskeleton reorganization. With the Human Protein Atlas, we verified that thirteen genes of the CG are translated, with high or medium expression in most of the pancreatic tumor samples. To train our artificial neural network, we used the five most expressed genes (KRT19, LAMC2, MELK, MET, TOP2A). The artificial neural network model (PDAC-ANN) classified the train samples with sensitivity of 0.95, specificity of 0.9, and f1-score of 0.93. The PDAC-ANN could classify the test samples with a sensitivity of 0.97, specificity of 0.88, and f1-score 0.94. Conclusion:The gene expression meta-analysis and confirmation of the protein expression allow us to select five genes highly expressed PDAC samples. We could build a python script to classify the samples based on mRNA expression. This software can be useful in the PDAC diagnosis.1 5 migration, and metastasis. The PDAC-ANN trained using gene expression information could classify the samples in normal and PDAC with an f1-score of 0.94 and sensitivity = 0.97. The PDAC-ANN tool can only be used when the gene expression information from KRT19, LAMC2, MELK, MET, and TOP2A are available, in addition to min-max gene expression values rescaling. The PDAC-ANN is a free tool (Additional file 4) that can support in the pancreatic ductal adenocarcinoma diagnosis.

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“…Mice were maintained under specific-pathogen-free conditions and given free access to water and chow, under the ethical agreement of animal study in Osaka University (approved by professor Y. Kaneda as the approval number 24-122-022), of which experimental procedure had been performed as descried previously [14]. Briefly, Kras LSL-G12D strain carries a loxP-stop-loxP sequence followed by constitutive active form of Kras G12D .…”

Section: Methodsmentioning

confidence: 99%

“…We have introduced Kras G12D mutation in pancreas specific manner, by crossing Kras LSL-G12D/+ mice with Pdx-1-Cre +/- mice. Kras LSL-G12D mice were crossbred to c-Met Fx to obtain mixed background (C57Bl/6/129/Sv) Kras LSL-G12D/+ ;c-Met Fx/Fx (for spontaneous tumors) or Kras +/+ ,c-Met +/+ (control recipients) mice [14, 15]. We have generated mutation of Kras in pancreas specific manner in mice, which was compared with pancreas specific deletion of c-Met, as described [15].…”

Section: Methodsmentioning

confidence: 99%

“…Kras G12D point mutation allele is commonly associate with human cancer and leads to a constitutive active form of Kras. On the other hand, c-Met is involved in the chemotherapy resistant phonotype of pancreatic cancer [13, 14]. Therefore, we have generated mutation of Kras in pancreas specific manner in mice, which was compared with pancreas specific deletion of c-Met, as described [14].…”

Section: Introductionmentioning

confidence: 99%

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Application of C. elegans cancer screening test for the detection of pancreatic tumor in genetically engineered mice

et al. 2019

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Pancreatic ductal adenocarcinoma (PDAC) exhibits a very early onset of metastasis. Thus, early detection and treatment are pivotal to successful eradication of pancreatic cancers. Economical and non-invasive cancer screening systems is indispensable for this purpose. Previously our group developed a novel method to detect various kinds of human cancer using nematode Caenorhabditis elegans (C. elegans) that respond to cancer odor in urine; however, whether this method is useful for non-human species remains to be understood. In this study, we examined its effectiveness in the detection of murine pancreatic tumor spontaneously generated in genetically-engineered mice. We generated pancreas-specific KrasG12D and/or c-Met deletion mutant mice and measured the probability of spontaneous tumor generation in these mice. The chemotactic indexes of C. elegans to the urine samples of these mutant mice were measured. As previously described, oncogenic KrasG12D was necessary to induce pancreatic intraepithelial neoplasia in this mouse model, while c-Met mutation did not show further effect. The chemotactic analysis indicated that C. elegans avoids urine of healthy recipient mice, while they tended to be attracted to urine of mice with KrasG12D. Our study demonstrated that C. elegans can recognize the odor of pancreatic cancer in urine of KrasG12D model mouse, suggesting the similarity of cancer odor between species. Our result facilitates further studies on mechanism of cancer detection by C. elegans.

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c‑Met affects gemcitabine resistance during carcinogenesis in a mouse model of pancreatic cancer

Cited by 14 publications

References 22 publications

MET/HGF Co-Targeting in Pancreatic Cancer: A Tool to Provide Insight into the Tumor/Stroma Crosstalk

MET/HGF Co-Targeting in Pancreatic Cancer: A Tool to Provide Insight into the Tumor/Stroma Crosstalk

PDAC-ANN: an artificial neural network to predict Pancreatic Ductal Adenocarcinoma based on gene expression

Application of C. elegans cancer screening test for the detection of pancreatic tumor in genetically engineered mice

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