Lessons from patient-derived xenografts for better in vitro modeling of human cancer

Choi, Si‐Sun; Lin, Dong; Gout, Peter W.; Collins, Colin C.; Xu, Yong; Wang, Yuzhuo

doi:10.1016/j.addr.2014.09.009

Cited by 157 publications

(146 citation statements)

References 316 publications

(352 reference statements)

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“…Histologically, these PDX models show a similar architecture and stroma as the original tumour. 10,17,18 The intratumour heterogeneity is preserved, such as chromosomal copy numbers, single-nucleotide polymorphisms and gene expression profiles. The orthotopic implantation may better mimic the human environment in which tumours originated and progressed.…”

Section: Limitations Of Mouse Tumour Modelsmentioning

confidence: 99%

Tumour and normal tissue radiobiology in mouse models: how close are mice to mini-humans?

Koontz¹,

Verhaegen²,

Ruysscher³

2017

BJR

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Animal modelling is essential to the study of radiobiology and the advancement of clinical radiation oncology by providing preclinical data. Mouse models in particular have been highly utilized in the study of both tumour and normal tissue radiobiology because of their cost effectiveness and versatility. Technology has significantly advanced in preclinical radiation techniques to allow highly conformal image-guided irradiation of small animals in an effort to mimic human treatment capabilities. However, the biological and physical limitations of animal modelling should be recognized and considered when interpreting preclinical radiotherapy (RT) studies. Murine tumour and normal tissue radioresponse has been shown to vary from human cellular and molecular pathways. Small animal irradiation techniques utilize different anatomical boundaries and may have different physical properties than human RT. This review addresses the difference between the human condition and mouse models and discusses possible strategies for future refinement of murine models of cancer and radiation for the benefit of both basic radiobiology and clinical translation.

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Section: Limitations Of Mouse Tumour Modelsmentioning

confidence: 99%

Tumour and normal tissue radiobiology in mouse models: how close are mice to mini-humans?

Koontz¹,

Verhaegen²,

Ruysscher³

2017

BJR

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“…In addition, aberrant utilization of glutamine, also leading to elevated lactic acid production, has been observed to be highly common for cancers (13). These metabolic energy pathways lead to increased lactic acid secretion by the cancer cells into their microenvironment, facilitating multiple oncogenic, lactate-stimulated processes, including tissue invasion/metastasis, neoangiogenesis and responses to hypoxia (14)(15)(16)(17); furthermore, lactic acid-induced acidification of the cancer cell microenvironment (to pH 6.0-6.5) can lead to the suppression of local host anticancer immunity (14,18). The phenomenon of enhanced glucose metabolism by cancers is most commonly exploited clinically by 18 F-fluorodeoxyglucose PET (FDG-PET).…”

Section: Introductionmentioning

confidence: 99%

TheMCT4Gene: A Novel, Potential Target for Therapy of Advanced Prostate Cancer

Choi

Xue

et al. 2016

Clinical Cancer Research

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Purpose: The management of castration-resistant prostate cancer (CRPC) is a major challenge in the clinic. Androgen receptor signaling–directed strategies are not curative in CRPC therapy, and new strategies targeting alternative, key cancer properties are needed. Using reprogrammed glucose metabolism (aerobic glycolysis), cancer cells typically secrete excessive amounts of lactic acid into their microenvironment, promoting cancer development, survival, and progression. Cellular lactic acid secretion is thought to be predominantly mediated by MCT4, a plasma membrane transporter protein. As such, the MCT4 gene provides a unique, potential therapeutic target for cancer. Experimental Design: A tissue microarray of various Gleason grade human prostate cancers was stained for MCT4 protein. Specific, MCT4-targeting antisense oligonucleotides (MCT4 ASO) were designed and candidate MCT4 ASOs checked for effects on (i) MCT4 expression, lactic acid secretion/content, glucose consumption, glycolytic gene expression, and proliferation of human CRPC cells and (ii) growth of PC-3 tumors in nude mice. Results: Elevated MCT4 expression was associated with human CRPC and an earlier time to relapse. The treatment of PC-3, DU145, and C4-2 CRPC cultures with candidate MCT4 ASOs led to marked inhibition of MCT4 expression, lactic acid secretion, to increased intracellular lactic acid levels, and markedly reduced aerobic glycolysis and cell proliferation. Treatment of PC-3 tumor-bearing nude mice with the MCT4 ASOs markedly inhibited tumor growth without inducing major host toxicity. Conclusions: MCT4-targeting ASOs that inhibit lactic acid secretion may be useful for therapy of CRPC and other cancers, as they can interfere with reprogrammed energy metabolism of cancers, an emerging hallmark of cancer. Clin Cancer Res; 22(11); 2721–33. ©2016 AACR.

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“…Most recently, Hidalgo and collaborators used "avatar" models as an in vivo platform to test treatment strategies suggested by parallel whole-exome sequencing analysis of 25 patients with advanced solid tumors, including seven PDAC patients 22 . However, the use of primary xenografts has still several inherent limitations and deficiencies 26 . The major challenge is the lack of a fully functional human immune system, which could only be reproduced via co-grafting of tumor tissue along with bone marrow stem cells of the same patient, developing extremely complex "humanized mice" 27 .…”

Section: Discussionmentioning

confidence: 99%

Development of bioluminescent chick chorioallantoic membrane (CAM) models from primary pancreatic cancer cells: A platform for drug testing

León

Rovithi

Avan³

et al. 2017

Pancreatology

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The aim of the present study was to develop chick-embryo chorioallantoic membrane (CAM) bioluminescent tumor models employing low passage cell cultures obtained from primary pancreatic ductal adenocarcinoma (PDAC) cells. Primary PDAC cells transduced with lentivirus expressingFirefly-luciferase (Fluc) were established and inoculated onto the CAM membrane, with >80% engraftment. Fluc signal reliably correlated with tumor growth. Tumor features were evaluated by immunohistochemistry and genetic analyses, including analysis of mutations and mRNA expression of PDAC pivotal genes, as well as microRNA (miRNA) profiling. These studies showed that CAM tumors had histopathological and genetic characteristic comparable to the original tumors. We subsequently tested the modulation of key miRNAs and the activity of gemcitabine and crizotinib on CAM tumors, showing that combination treatment resulted in 63% inhibition of tumor growth as compared to control (p < 0.01). These results were associated with reduced expression of miR-21 and increased expression of miR-155. Our study provides the first evidence that transduced primary PDAC cells can form tumors on the CAM, retaining several histopathological and (epi)genetic characteristics of original tumors. Moreover, our results support the use of these models for drug testing, providing insights on molecular mechanisms underlying antitumor activity of new drugs/combinations.With less than 7% of patients alive five years after diagnosis, pancreatic ductal adenocarcinoma (PDAC) exhibits one of the poorest prognoses of all solid tumors. Despite extensive clinical efforts, the outcome of this malignancy has not improved in the last decade, and PDAC is expected to become the second deadliest cancer, after lung cancer, by 2030 1,2 .Gaining more insight into the mechanisms that delineate tumor progression in PDAC could ultimately provide more successful therapeutic approaches. To this end, genetically engineered mouse models (GEMMs) have provided a powerful tool, developing tumors that recapitulate both the underlying biology and the dense desmoplastic reaction of PDACs. This stromal reaction has been considered for years as one of the mediators of resistance to chemotherapy 3 . However, experimental and clinical evidence demonstrated that anti-stromal approaches may favour PDAC aggressiveness, reinforcing the need to critically revisit the complexity of cancer-stroma interactions for translational and pharmacological implications 4 . Recent studies suggested that early passages of primary PDAC cells and "avatar" mice can mimic the genetic diversity that characterizes the human disease and might be better predictors of drug activity, including the standard treatment with gemcitabine 5,6 .Despite several studies used such in vivo models in order to promote drug development and selection, their costs and complexity impaired the translation of these results in the clinical setting. Novel, cost-effective models that similarly mimic tumor biology and provide faster information on the activ...

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Lessons from patient-derived xenografts for better in vitro modeling of human cancer

Cited by 157 publications

References 316 publications

Tumour and normal tissue radiobiology in mouse models: how close are mice to mini-humans?

Tumour and normal tissue radiobiology in mouse models: how close are mice to mini-humans?

TheMCT4Gene: A Novel, Potential Target for Therapy of Advanced Prostate Cancer

Development of bioluminescent chick chorioallantoic membrane (CAM) models from primary pancreatic cancer cells: A platform for drug testing

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