Establishment and characterisation of patient-derived xenografts as paraclinical models for gastric cancer

Choi, Yoon Young; Lee, Jae Eun; Kim, Hyunki; Sim, Moon Hee; Kim, Ka Kyung; Lee, Gun-Ho; Kim, Wook; An, Ji Yeong; Hyung, Woo Jin; Kim, Choong Bai; Noh, Sung Hoon; Kim, Sang Woo; Cheong, Jae‐Ho

doi:10.1038/srep22172

Cited by 93 publications

(107 citation statements)

References 59 publications

(79 reference statements)

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“…A recent study hypothesizes that the development of B‐LPLs might be related to the host's degree of immunodeficiency since no lymphomas formed after xenotransplantations of primary gastric carcinomas into nude mice, while five EBV‐associated lymphomas developed in nine PDX in more efficiently immunocompromised NOD.Cg‐ Prkdc scid II2rg tm Sug /Jic (NOG) mice . Still, generalizability of these data is limited due to the relatively small sample size.…”

Section: Discussionmentioning

confidence: 99%

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Patient-derived xenografts of gastrointestinal cancers are susceptible to rapid and delayed B-lymphoproliferation

et al. 2017

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Patient-derived cancer xenografts (PDX) are widely used to identify and evaluate novel therapeutic targets, and to test therapeutic approaches in preclinical mouse avatar trials. Despite their widespread use, potential caveats of PDX models remain considerably underappreciated. Here, we demonstrate that EBV-associated B-lymphoproliferations frequently develop following xenotransplantation of human colorectal and pancreatic carcinomas in highly immunodeficient NOD.Cg-Prkdc Il2rg /SzJ (NSG) mice (18/47 and 4/37 mice, respectively), and in derived cell cultures in vitro. Strikingly, even PDX with carcinoma histology can host scarce EBV-infected B-lymphocytes that can fully overgrow carcinoma cells during serial passaging in vitro and in vivo. As serial xenografting is crucial to expand primary tumor tissue for biobanks and cohorts for preclinical mouse avatar trials, the emerging dominance of B-lymphoproliferations in serial PDX represents a serious confounding factor in these models. Consequently, repeated phenotypic assessments of serial PDX are mandatory at each expansion step to verify "bona fide" carcinoma xenografts.

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Section: Discussionmentioning

confidence: 99%

“…found only 1 lymphoma in 43 CRC PDX (2%) in NOD/SCID mice, which is significantly lower than 38.3% of CRC PDX developing B‐LPLs in our cohort of PDX in more severely immunocompromised NSG mice. Notably, B‐LPLs in PDX apparently occur across a broad range of solid tumor entities …”

Section: Discussionmentioning

confidence: 99%

Patient-derived xenografts of gastrointestinal cancers are susceptible to rapid and delayed B-lymphoproliferation

et al. 2017

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“…Establishing PDX models for DGC has posed a significant challenge for us and others in the field (25,26). To overcome the difficulty in obtaining primary tumors of sufficient tumor cellularity from DGC tissues, we collected peritoneal ascites fluid from DGC patients (Supplementary Table S1) and depleted GlyA þ red blood cells and CD45 þ hematopoietic cells.…”

Section: Development and Validation Of Robust Dgc Pdx Modelsmentioning

confidence: 99%

Acquired Resistance to FGFR Inhibitor in Diffuse-Type Gastric Cancer through an AKT-Independent PKC-Mediated Phosphorylation of GSK3β

Lau

Teng

Huang

et al. 2018

Molecular Cancer Therapeutics

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Preclinical models of diffuse-type gastric cancer (DGC) that reliably predict clinical activity of novel compounds are lacking. To overcome the problem of poor tumor cellularity in DGC, we used cells from malignant ascites to establish DGC patientderived xenograft (PDX) models that recapitulate the primary cancer. Cells in PDX model GAGA6 with FGFR2 amplification were sensitive to AZD4547, a potent FGFR inhibitor that is being clinically evaluated for FGFR-aberrant cancer types. Intermittent in vivo treatment of GAGA6 tumors with AZD4547 gave rise to PDX tumors with acquired resistance to AZD4547, GAGA6-R. Surprisingly, there were no mutations in the FGFR2 gene in GAGA6-R, negating gatekeeper mutations as a mechanism of drug resistance. Phosphorylation of FGFR2 and downstream signaling molecules AKT/PKB and MAPK/ERK remained inhibited by AZD4547. Further analysis of signaling pathways identified AKT-independent phosphorylation and inhibition of GSK3b as a mechanism of drug resistance in GAGA6-R cells. Treatment of GAGA6-R cells with protein kinase C (PKC) inhibitor H7 in combination with AZD4547 led to dephosphorylation and activation of GSK3b with concomitant downregulation of MCL-1 and BCL-XL. Combined treatment with AZD4547 and H7 in vitro synergistically enhanced cell death in GAGA6-R but not GAGA6 cells. Furthermore, midostaurin, a multikinase inhibitor with PKC-inhibiting activity, in part reversed resistance of GAGA6-R tumor to AZD4547 in vivo. Our results suggest that upon challenge with FGFR inhibitors, FGFR2-amplified tumors that are highly dependent on FGFR2 signaling for survival rapidly develop resistance by switching to a PKC-mediated inhibition of GSK3b to gain a survival advantage.

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“…Inducing ER stress may be a promising gastric cancer treatment strategy in combination with strategies for decreasing GPR177 levels, regardless of the gastric cancer subtype . From a clinical perspective, using patient‐derived xenograft models and patient‐specific molecular information, we can stratify gastric cancer patients according to tumor ER stress resistance and predict therapeutic outcomes of ER stress inducer treatments …”

Section: Discussionmentioning

confidence: 99%

GPR177 promotes gastric cancer proliferation by suppressing endoplasmic reticulum stress‐induced cell death

Seo

Lee

Park

et al. 2018

J of Cellular Biochemistry

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Gastric cancer is the fourth most common cancer worldwide. Despite the high incidence of gastric cancer, efficient chemotherapy treatments still need to be developed. In this study, we examined the anticancer effects of endoplasmic reticulum (ER) stress inducer tunicamycin in gastric cancer. Previously, we found that overexpression of WLS1/GPR177 correlated with poor prognosis in patients with gastric cancer. Furthermore, tunicamycin treatment downregulated GPR177 expression in a dose-dependent manner. GPR177 transports WNT ligand from ER to the plasma membrane, mediating its secretion to the extracellular matrix. In gastric cancer cells, GPR177 preferentially localizes to the ER. Small interfering RNA-mediated knockdown of GPR177 leads to sensitization to ER stress and induces apoptosis of cancer cells along with tunicamycin treatment. GPR177 suppression promoted the ER stress-mediated proapoptotic pathway, such as PERK-CHOP cascade. Furthermore, fluorouracil treatment combined with tunicamycin dramatically reduced cancer cell proliferation. Efficacy of tunicamycin chemotherapy treatments depended on GPR177 expression in gastric cancer cell lines. Together, our results indicate that ER stress can potentiate anticancer effects and suggest GPR177 as a potential gastric cancer therapeutic target.

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Establishment and characterisation of patient-derived xenografts as paraclinical models for gastric cancer

Cited by 93 publications

References 59 publications

Patient-derived xenografts of gastrointestinal cancers are susceptible to rapid and delayed B-lymphoproliferation

Patient-derived xenografts of gastrointestinal cancers are susceptible to rapid and delayed B-lymphoproliferation

Acquired Resistance to FGFR Inhibitor in Diffuse-Type Gastric Cancer through an AKT-Independent PKC-Mediated Phosphorylation of GSK3β

GPR177 promotes gastric cancer proliferation by suppressing endoplasmic reticulum stress‐induced cell death

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