Luca PersaniIstituto Auxologico Italiano, IRCCS, Laboratorio Sperimentale di Ricerche Endocrino-Metaboliche, Milan, Italy Department of Clinical Sciences and Community Health (DISCCO), University of Milan, Milan, Italy
Giovanni VitaleIstituto Auxologico Italiano, IRCCS, Laboratorio Sperimentale di Ricerche di Neuroendocrinologia Geriatrica ed Oncologica, Milan, Italy Department of Clinical Sciences and Community Health (DISCCO), University of Milan, Milan, Italy
Neuroendocrine tumors (NETs) are a class of rare and heterogeneous neoplasms that originate from the neuroendocrine system. In several cases, these neoplasms can release bioactive hormones leading to characteristic clinical syndromes and hormonal dysregulations with detrimental impact on the quality of life and survival of these patients. Only few animal models are currently available to investigate pathogenesis, progression and functional syndromes in NETs and to identify new therapeutic strategies. The tropical teleost zebrafish (Danio rerio) is a popular vertebrate model system that offers unique advantages for the study of several biological processes, ranging from embryonic development to human diseases such as cancer. In this review, we summarize recent advances on zebrafish models for NET preclinical research that take advantage of modern genetic and transplantable technologies. In the future, these tools may have a role in the treatment decision-making and tertiary prevention of NETs.
Chiara Alessandra CellaDivision of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy Department of Molecular and Translational Medicine, Division of Biology and Genetics, University of Brescia, Brescia, Italy
Riccardo CazzoliDepartment of Experimental Oncology, European Institute of Oncology, IEO, IRCCS, Milan, Italy Metal Targeted Therapy & Immunology lab, Childrens’ cancer institute, Sydney, NSW, Australia
Giovanni VitaleLaboratory of Geriatric and Oncologic Neuroendocrinology Research, IRCCS, Istituto Auxologico Italiano, Milan, Italy Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
Neuroendocrine tumors (NETs) are highly vascularized malignancies in which angiogenesis may entail cell proliferation and survival. Among the emerging compounds with antivascular properties, cabozantinib (CAB) appeared promising. We analyzed the antitumor activity of CAB against NETs utilizing in vitro and in vivo models. For cell cultures, we used BON-1, NCI-H727 and NCI-H720 cell lines. Cell viability was assessed by manual count coupled with quantification of cell death, performed through fluorescence-activated cell sorting analysis as propidium iodide exclusion assay. In addition, we investigated the modulation of the antiapoptotic myeloid cell leukemia 1 protein under CAB exposure, as a putative adaptive pro-survival mechanism, and compared the responses with sunitinib. The activity of CAB was also tested in mouse and zebrafish xenograft tumor models. Cabozantinib showed a dose-dependent and time-dependent effect on cell viability and proliferation in human NET cultures, besides a halting of cell cycle progression for endoduplication, never reported for other tyrosine kinase inhibitors. In a transplantable zebrafish model, CAB drastically inhibited NET-induced angiogenesis and migration of implanted cells through the embryo body. CAB showed encouraging activity in NETs, both in vitro and in vivo models. On this basis, we envisage future research to further investigate along these promising lines.