Generation of orthotopic and heterotopic human pancreatic cancer xenografts in immunodeficient mice

Kim, Michael P.; Evans, Douglas B.; Wang, Huamin; Abbruzzese, James L.; Fleming, Jason B.; Gallick, Gary E.

doi:10.1038/nprot.2009.171

Cited by 340 publications

(322 citation statements)

References 28 publications

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“…Male BALB/c (nu/nu) nude mice were purchased from CREA Japan (Tokyo, Japan). The transplantation of tumour cells into mouse livers was performed using previously reported methods 57,58 . Briefly, 2×10 6 control or miR122-silenced PLC/PRF5 cells were suspended in 30 µl of PBS containing 1% Matrigel (Becton Dickinson).…”

Section: Gtp-binding Rhoa and Rac1 Immunoprecipitation Assaymentioning

confidence: 99%

MicroRNA122 is a key regulator of α-fetoprotein expression and influences the aggressiveness of hepatocellular carcinoma

et al. 2011

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α-fetoprotein (AFP) is not only a widely used biomarker in hepatocellular carcinoma (HCC) surveillance, but is also clinically recognized as linked with aggressive tumour behaviour. Here we show that deregulation of microRnA122, a liver-specific microRnA, is a cause of both AFP elevation and a more biologically aggressive phenotype in HCC. We identify CuX1, a direct target of microRnA122, as a common central mediator of these two effects. using liver tissues from transgenic mice in which microRnA122 is functionally silenced, an orthotopic xenograft tumour model, and human clinical samples, we further demonstrate that a microRnA122/ CuX1/microRnA214/ZBTB20 pathway regulates AFP expression. We also show that the microRnA122/CuX1/RhoA pathway regulates the aggressive characteristics of tumours. We conclude that microRnA122 and associated signalling proteins may represent viable therapeutic targets, and that serum AFP levels in HCC patients may be a surrogate marker for deregulated intracellular microRnA122 signalling pathways in HCC tissues.

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Section: Gtp-binding Rhoa and Rac1 Immunoprecipitation Assaymentioning

confidence: 99%

MicroRNA122 is a key regulator of α-fetoprotein expression and influences the aggressiveness of hepatocellular carcinoma

et al. 2011

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“…All animals were used in accordance with the guidelines of the Institutional Animal Care and Use Committee of the Institute of Nutritional Sciences. Orthotopic xenograft transplantation was performed as previously described 49 . Briefly, mice were anesthetized by intraperitoneal injection of ketamine (100 mg kg À 1 ) and xylazine (20 mg kg À 1 ).…”

Section: Methodsmentioning

confidence: 99%

Loss of polarity protein AF6 promotes pancreatic cancer metastasis by inducing Snail expression

Chang

Peng

et al. 2015

Nat Commun

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Pancreatic cancer (PC) is a particularly lethal form of cancer with high potential for metastasis to distant organs. Disruption of cell polarity is a hallmark of advanced epithelial tumours. Here we show that the polarity protein AF6 (afadin and MLLT4) is expressed at low levels in PC. We demonstrate that depletion of AF6 markedly promotes proliferation and metastasis of PC cells through upregulation of the expression of Snail protein, and this requires the nuclear localization of AF6. Furthermore, AF6 deficiency in PC cells leads to increased formation of a Dishevelled 2 (Dvl2)-FOXE1 complex on the promoter region of Snail gene, and activation of Snail expression. Altogether, our data established AF6 as a potential inhibitor of metastasis in PC cells. Targeting the Dvl2-FOXE1-Snail signalling axis may thus represent a promising therapeutic strategy.

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“…The PDX with enhanced YAP nuclear expression was implanted in NOD/ SCID-immunodeficient mice (n ϭ 10) as reported previously (32,33). Similarly, PDX with no YAP nuclear expression was implanted in NOD/SCID mice (n ϭ 12).…”

Section: Pcr Primersmentioning

confidence: 99%

A Hippo and Fibroblast Growth Factor Receptor Autocrine Pathway in Cholangiocarcinoma

Rizvi

Yamada

Hirsova

et al. 2016

Journal of Biological Chemistry

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Cholangiocarcinomas are highly lethal hepatobiliary cancers with features of cholangiocyte differentiation (1). Although the incidence of CCA 4 is increasing in Western countries (2), therapeutic options for advanced disease not amenable to surgical extirpation remain limited, and overall survival rates are less than 10% (3). Treatment options for advanced CCA are limited, in part, because of the genetic heterogeneity of this malignancy and an incomplete understanding of CCA signaling pathways and biology. There is a critical need to elucidate the molecular mechanisms underlying CCA pathogenesis so that targeted, individualized therapies coupled with biomarkers may be developed (4). Hippo, a highly conserved growth control pathway, is deregulated in several human malignancies (5-7) including human CCA (8, 9). Recently, we reported that direct transfection of the biliary tree with a constitutively active mediator of the Hippo pathway, YAPS127A, along with mouse myr-Akt as a permissive factor, induces CCA in mice (10). This observation directly implicates oncogenic Hippo pathway signaling in CCA biology. The core machinery of the Hippo pathway consists of a kinase relay module and a transcriptional module (11). When the kinase module is "on" it inactivates the transcriptional module, and when it is "off" the transcriptional module becomes active (11). The core components of the kinase module consist of the serine/threonine kinases MST1 and MST2, large tumor suppressor 1 (LATS1), and LATS2 (6). The downstream kinases LATS1 and LATS2 directly phosphorylate the mediators of the transcriptional module, the co-transcriptional activators YAP, and its paralog TAZ, resulting in their inactivation (12). Indeed, the phosphorylation of YAP and TAZ results in their nuclear export, cytoplasmic retention, and/or degradation by the proteasome (6). Although YAP and TAZ have functional redundancy, they also have distinct functions, and accordingly YAP, but not TAZ, has been more strongly implicated in cancer biology to date. The Hippo pathway has been implicated in CCA biology based mainly on nuclear localization of YAP by immunohistochemistry (8), a finding suggesting disruption of the kinase module by yet undefined mechanisms. The Hippo pathway is unique in that it does not have an extracellular ligand or a dedicated plasma membrane receptor and therefore must be activated by cross-talk mechanisms.Fibroblast growth factor receptors (FGFR) are also deregulated in a myriad of malignancies (13). Recently, we and others have described FGFR2 gene fusions in solid organ malignancies including CCA (10 -15% prevalence in CCA) (4, 14 -17). * This work was supported by National Institutes of Health Grants DK59427(to G. J. G.), T32DK007198 (to S. R.), DK84567 (Optical Microscopy Core for the Mayo Center for Cell Signaling in Gastroenterology), and ES020715 (to E. T.) and by the Mayo Foundation. The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the auth...

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Generation of orthotopic and heterotopic human pancreatic cancer xenografts in immunodeficient mice

Cited by 340 publications

References 28 publications

MicroRNA122 is a key regulator of α-fetoprotein expression and influences the aggressiveness of hepatocellular carcinoma

MicroRNA122 is a key regulator of α-fetoprotein expression and influences the aggressiveness of hepatocellular carcinoma

Loss of polarity protein AF6 promotes pancreatic cancer metastasis by inducing Snail expression

A Hippo and Fibroblast Growth Factor Receptor Autocrine Pathway in Cholangiocarcinoma

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