Cell Line Derived Xenograft Mouse Models Are a Suitable in vivo Model for Studying Tumor Budding in Colorectal Cancer

Georges, Laurent M. C.; Wever, Olivier De; Galván, José A.; Dawson, Heather; Lugli, Alessandro; Demetter, Pieter; Zlobec, Inti

doi:10.3389/fmed.2019.00139

Cited by 27 publications

(17 citation statements)

References 20 publications

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“…Although many GEMMs are available, researchers frequently face the problem that induced intestinal neoplasms of mice lack the invasive features characteristic for late-stage CRC, e.g., tumor budding. There are orthotopic mouse xenograft models which show tumor budding that are morphologically and immunohistochemically close to what is seen in human CRC; however, these models often have an immunocompromised background and thus are limited in their relevance to the human situation [ 28 , 29 ]. Moreover, the very limited availability of in vivo budding models to date is another drawback [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

Bridging the Species Gap: Morphological and Molecular Comparison of Feline and Human Intestinal Carcinomas

Groll

Schopf

Denk

et al. 2021

Cancers

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Limited availability of in vivo experimental models for invasive colorectal cancer (CRC) including metastasis and high tumor budding activity is a major problem in colorectal cancer research. In order to compare feline and human intestinal carcinomas, tumors of 49 cats were histologically subtyped, graded and further characterized according to the human WHO classification. Subsequently, feline tumors were compared to a cohort of 1004 human CRC cases. Feline intestinal tumors closely resembled the human phenotype on a histomorphological level. In both species, adenocarcinoma not otherwise specified (ANOS) was the most common WHO subtype. In cats, the second most common subtype of the colon (36.4%), serrated adenocarcinoma (SAC), was overrepresented compared to human CRC (8.7%). Mucinous adenocarcinoma (MAC) was the second most common subtype of the small intestine (12.5%). Intriguingly, feline carcinomas, particularly small intestinal, were generally of high tumor budding (Bd) status (Bd3), which is designated an independent prognostic key factor in human CRC. We also investigated the relevance of feline CTNNB1 exon 2 alterations by Sanger sequencing. In four cases of feline colonic malignancies (3 ANOS, 1 SAC), somatic missense mutations of feline CTNNB1 (p.D32G, p.D32N, p.G34R, and p.S37F) were detected, indicating that mutational alterations of the WNT/β-catenin signaling pathway potentially play an essential role in feline intestinal tumorigenesis comparable to humans and dogs. These results indicate that spontaneous intestinal tumors of cats constitute a useful but so far underutilized model for human CRC. Our study provides a solid foundation for advanced comparative oncology studies and emphasizes the need for further (molecular) characterization of feline intestinal carcinomas.

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Section: Discussionmentioning

confidence: 99%

Bridging the Species Gap: Morphological and Molecular Comparison of Feline and Human Intestinal Carcinomas

Groll

Schopf

Denk

et al. 2021

Cancers

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“…Pu et al ( 21 ) demonstrated that patient-derived immune cells coexist in the first and second passages with a survival rate of 290 days in the mouse. Recently, tumor budding has also been demonstrated in both center and the invasion front in CRC cell-line xenografts ( 22 ). These findings strongly suggest that early passages of PDXs preserve the distinctive cross talk between cancer cells and the immune microenvironment and determine the suitability of this preclinical platform as a model of tumor budding in CRC.…”

Section: Discussionmentioning

confidence: 99%

Association of Tumor Budding With Immune Evasion Pathways in Primary Colorectal Cancer and Patient-Derived Xenografts

et al. 2020

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Tumor budding has been found to be of prognostic significance for several cancers, including colorectal cancer (CRC). Additionally, the molecular classification of CRC has led to the identification of different immune microenvironments linked to distinct prognosis and therapeutic response. However, the association between tumor budding and the different molecular subtypes of CRC and distinct immune profiles have not been fully elucidated. This study focused, firstly, on the validation of derived xenograft models (PDXs) for the evaluation of tumor budding and their human counterparts and, secondly, on the association between tumor budding and the immune tumor microenvironment by the analysis of gene expression signatures of immune checkpoints, Toll-like receptors (TLRs), and chemokine families. Clinical CRC samples with different grades of tumor budding and their corresponding PDXs were included in this study. Tumor budding grade was reliably reproduced in early passages of PDXs, and high-grade tumor budding was intimately related with a poor-prognosis CMS4 mesenchymal subtype. In addition, an upregulation of negative regulatory immune checkpoints (PDL1, TIM-3, NOX2, and IDO1), TLRs (TLR1, TLR3, TLR4, and TLR6), and chemokine receptors and ligands (CXCR2, CXCR4, CXCL1, CXCL2, CXCL6, and CXCL9) was detected in high-grade tumor budding in both human samples and their corresponding xenografts. Our data support a close link between high-grade tumor budding in CRC and a distinctive immune-suppressive microenvironment promoting tumor invasion, which may have a determinant role in the poor prognosis of the CMS4 mesenchymal subtype. In addition, our study demonstrates that PDX models may constitute a robust preclinical platform for the development of novel therapies directed against tumor budding in CRC.

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“…More recently, primary cells have been established as organoid models that more accurately mimic threedimensional tumour development [13]. Alternatively, cancer cell lines or patient-derived tumors can also be engrafted into immunocompromised mice to generate so-called cell line-derived xenografts (CDX) or patientderived xenografts (PDX), respectively [20][21][22]. These xenograft models are thought to more accurately recapitulate human tumor specimens, due to the presence of matrix components and stromal cells (i.e.…”

Section: Clinical Sample Preparation Methodsmentioning

confidence: 99%

Recent advances in mass spectrometry based clinical proteomics: applications to cancer research

2020

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Cancer biomarkers have transformed current practices in the oncology clinic. Continued discovery and validation are crucial for improving early diagnosis, risk stratification, and monitoring patient response to treatment. Profiling of the tumour genome and transcriptome are now established tools for the discovery of novel biomarkers, but alterations in proteome expression are more likely to reflect changes in tumour pathophysiology. In the past, clinical diagnostics have strongly relied on antibody-based detection strategies, but these methods carry certain limitations. Mass spectrometry (MS) is a powerful method that enables increasingly comprehensive insights into changes of the proteome to advance personalized medicine. In this review, recent improvements in MS-based clinical proteomics are highlighted with a focus on oncology. We will provide a detailed overview of clinically relevant samples types, as well as, consideration for sample preparation methods, protein quantitation strategies, MS configurations, and data analysis pipelines currently available to researchers. Critical consideration of each step is necessary to address the pressing clinical questions that advance cancer patient diagnosis and prognosis. While the majority of studies focus on the discovery of clinically-relevant biomarkers, there is a growing demand for rigorous biomarker validation. These studies focus on high-throughput targeted MS assays and multi-centre studies with standardized protocols. Additionally, improvements in MS sensitivity are opening the door to new classes of tumour-specific proteoforms including posttranslational modifications and variants originating from genomic aberrations. Overlaying proteomic data to complement genomic and transcriptomic datasets forges the growing field of proteogenomics, which shows great potential to improve our understanding of cancer biology. Overall, these advancements not only solidify MS-based clinical proteomics' integral position in cancer research, but also accelerate the shift towards becoming a regular component of routine analysis and clinical practice.

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Cell Line Derived Xenograft Mouse Models Are a Suitable in vivo Model for Studying Tumor Budding in Colorectal Cancer

Cited by 27 publications

References 20 publications

Bridging the Species Gap: Morphological and Molecular Comparison of Feline and Human Intestinal Carcinomas

Bridging the Species Gap: Morphological and Molecular Comparison of Feline and Human Intestinal Carcinomas

Association of Tumor Budding With Immune Evasion Pathways in Primary Colorectal Cancer and Patient-Derived Xenografts

Recent advances in mass spectrometry based clinical proteomics: applications to cancer research

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