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Metastatic behaviour of primary human tumours in a zebrafish xenotransplantation model.

ABSTRACT: BACKGROUND: Aberrant regulation of cell migration drives progression of many diseases, including cancer cell invasion and metastasis formation. Analysis of tumour invasion and metastasis in living organisms to date is cumbersome and involves difficult and time consuming investigative techniques. For primary human tumours we establish here a simple, fast, sensitive and cost-effective in vivo model to analyse tumour invasion and metastatic behaviour. METHODS: We fluorescently labelled small explants from gastrointestinal human tumours and investigated their metastatic behaviour after transplantation into zebrafish embryos and larvae. The transparency of the zebrafish embryos allows to follow invasion, migration and micrometastasis formation in real-time. High resolution imaging was achieved through laser scanning confocal microscopy of live zebrafish. RESULTS: In the transparent zebrafish embryos invasion, circulation of tumour cells in blood vessels, migration and micrometastasis formation can be followed in real-time. Xenografts of primary human tumours showed invasiveness and micrometastasis formation within 24 hours after transplantation, which was absent when non-tumour tissue was implanted. Furthermore, primary human tumour cells, when organotopically implanted in the zebrafish liver, demonstrated invasiveness and metastatic behaviour, whereas primary control cells remained in the liver. Pancreatic tumour cells showed no metastatic behaviour when injected into cloche mutant embryos, which lack a functional vasculature. CONCLUSION: Our results show that the zebrafish is a useful in vivo animal model for rapid analysis of invasion and metastatic behaviour of primary human tumour specimen.

SUBMITTER: Marques IJ

PROVIDER: S-EPMC2697170 | biostudies-literature | 2009

REPOSITORIES: biostudies-literature

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Metastatic behaviour of primary human tumours in a zebrafish xenotransplantation model.

Marques Ines J IJ Weiss Frank Ulrich FU Vlecken Danielle H DH Nitsche Claudia C Bakkers Jeroen J Lagendijk Anne K AK Partecke Lars Ivo LI Heidecke Claus-Dieter CD Lerch Markus M MM Bagowski Christoph P CP

BMC cancer 20090428

<h4>Background</h4>Aberrant regulation of cell migration drives progression of many diseases, including cancer cell invasion and metastasis formation. Analysis of tumour invasion and metastasis in living organisms to date is cumbersome and involves difficult and time consuming investigative techniques. For primary human tumours we establish here a simple, fast, sensitive and cost-effective in vivo model to analyse tumour invasion and metastatic behaviour.<h4>Methods</h4>We fluorescently labelled ...[more]

PMID: 19400945

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Project description:BackgroundThe response to chemotherapy treatment of patients with pancreatic ductal adenocarcinoma (PDAC) is difficult to predict and the identification of patients who most likely will benefit from aggressive chemotherapy approaches is crucial. The concept of personalized medicine has emerged in the last years with the objective to tailor the medical treatment to the individual characteristics of each patient, and particularly to the tumor biology of each patient. The need for in-vivo xenotransplantation models for cancer patients has increased exponentially, and for this reason zebrafish avatars have gained popularity. Preliminary studies were conducted also with PDAC tissue.AimTo develop a simple, not expensive, diffusible zebrafish embryo model as avatar for patients affected by PDAC.MethodsTumor tissue was taken from the surgical specimen by the histopathologist. After its fragmentation into small pieces, they are stained with CM-Dil. Small pieces of stained tissue were transplanted into the yolk of wt AB zebrafish embryos with a glass capillary needle. Embryos were incubated at 35 °C in E3 medium supplemented with 1% Pen/Strep in the presence or absence of drugs for the following days in respect of the treatment plan (Gemcitabine; Gemcitabine and Oxaliplatin; Gemcitabine and nab-Paclitaxel; 5-Fluorouracil and Folinic acid and Oxaliplatin and Irinotecan). The response of zebrafish xenografts to the chemotherapy options has been analyzed by monitoring the fluorescent stained area at 2 h post injection (hpi), 1 d and 2 d post injection (dpi). In each time point, the mean size of the stained area was measured by ImageJ and it was normalized with respect to the 1 dpi time point mean relative tumor area (RTA). We evaluated the effect of the chemotherapy exposition comparing the mean RTA of each treated subgroup and the control group and evaluating the percentage reduction of the mean RTA by comparing each treated subgroup with the control group.ResultsBetween July 2018 and October 2019, a total of 15 patients with pancreatic cancer were prospectively enrolled. In all cases, it was possible to take a fragment of the tumor from the surgical specimen for the xenotransplantation in the zebrafish embryos. The histological examination confirmed the presence of a PDAC in all cases. In absence of chemotherapy (control group), over time the Dil-stained area showed a statistically significant increase in all cases. A statistically significant reduction of the mean RTA in the treated subgroups for at least one chemotherapy scheme was reported in 6/15 (40%) cases. The analysis of the percentage reduction of the RTA in treated subgroups in comparison to the control group revealed the presence of a linear relationship in each subgroup between the percentage reduction of the RTA and the number of cases reporting each percentage threshold considered for the analysis.ConclusionOur model seems to be effective for the xenotransplantation of PDAC tissue and evaluation of the effect of each chemotherapy scheme on the xenotransplanted tumor tissue.

Dataset Information

Metastatic behaviour of primary human tumours in a zebrafish xenotransplantation model.

Publications

Metastatic behaviour of primary human tumours in a zebrafish xenotransplantation model.

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