Intramuscular Transplantation Improves Engraftment Rates for Esophageal Patient-Derived Tumor Xenografts

Read, Matthew; Liu, David Shi Hao; Duong, Cuong; Cullinane, Carleen; Murray, William K.; Fennell, Christina M.; Shortt, Jake; Westerman, David; Burton, Paul R.; Clemons, Nicholas J.; Phillips, Wayne A.

doi:10.1245/s10434-015-4425-3

Cited by 24 publications

(25 citation statements)

References 22 publications

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“…Notably, B-LPLs in PDX apparently occur across a broad range of solid tumor entities. 15,[17][18][19][20][21] In summary, we demonstrate that CRC and PDAC PDX are frequently affected by EBV-associated B-LPLs in highly immunodeficient NSG mice, and that B-lymhoproliferations can develop from rare B-lymphocytes present in almost all PDX immediately after xenotransplantation, or in delay during serial transplantations. LPLs may remain undetected by solely relying on the assessment of the initial status of serially transplanted PDX or on patient identity instead of cell type identity.…”

Section: Discussionmentioning

confidence: 68%

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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: 68%

“…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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“…For cell line xenografts, 5 million cells suspended in 100 μl of 1:1 PBS and Matrigel (BD Bioscience) were subcutaneously injected into the flank of 6 weeks old, female nude or NOD-SCID IL-2Rγ KO (NSG) mice. Patient-derived xenografts (PDX) were established as previously described and implanted subcutaneously on the dorsum of NSG mice44. The collection and use of human tissue was approved by the Human Research Ethics Committee at PMCC.…”

Section: Methodsmentioning

confidence: 99%

Inhibiting the system xC−/glutathione axis selectively targets cancers with mutant-p53 accumulation

et al. 2017

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TP53, a critical tumour suppressor gene, is mutated in over half of all cancers resulting in mutant-p53 protein accumulation and poor patient survival. Therapeutic strategies to target mutant-p53 cancers are urgently needed. We show that accumulated mutant-p53 protein suppresses the expression of SLC7A11, a component of the cystine/glutamate antiporter, system xC−, through binding to the master antioxidant transcription factor NRF2. This diminishes glutathione synthesis, rendering mutant-p53 tumours susceptible to oxidative damage. System xC− inhibitors specifically exploit this vulnerability to preferentially kill cancer cells with stabilized mutant-p53 protein. Moreover, we demonstrate that SLC7A11 expression is a novel and robust predictive biomarker for APR-246, a first-in-class mutant-p53 reactivator that also binds and depletes glutathione in tumours, triggering lipid peroxidative cell death. Importantly, system xC− antagonism strongly synergizes with APR-246 to induce apoptosis in mutant-p53 tumours. We propose a new paradigm for targeting cancers that accumulate mutant-p53 protein by inhibiting the SLC7A11–glutathione axis.

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“…For CLX, 5 million Eso26, OE19 or FLO-1 cells suspended in 100 µL of 1:1 phosphate-buffered saline and Matrigel (BD Bioscience) were subcutaneously injected into the right flank of 6-week-old female nude (Eso26 and OE19) or NOD-SCID IL-2Rγ KO mice (FLO-1). PDXs were developed as previously described and summarised in online supplementary methods 27. The collection and use of human tissue for this study was approved by the Human Research Ethics Committee at PMCC.…”

Section: Methodsmentioning

confidence: 99%

APR-246 potently inhibits tumour growth and overcomes chemoresistance in preclinical models of oesophageal adenocarcinoma

Liu

Read

Cullinane

et al. 2015

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Intramuscular Transplantation Improves Engraftment Rates for Esophageal Patient-Derived Tumor Xenografts

Abstract: We achieved a much higher engraftment rate of PDTXs using our novel intramuscular transplant technique than has been reported in other published studies. It is hoped that this advancement will help expedite the development and testing of new therapies for esophageal cancer.

Cited by 24 publications

References 22 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

Inhibiting the system xC−/glutathione axis selectively targets cancers with mutant-p53 accumulation

APR-246 potently inhibits tumour growth and overcomes chemoresistance in preclinical models of oesophageal adenocarcinoma

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