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1
Division of Gastroenterology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada; Michael Smith Genome Sciences Center, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; Laboratoire d'Oncobiologie, Hôpital René Huguenin, Institut Curie, St Cloud, France; Université Paris Descartes, Faculté de Pharmacie de Paris, Sorbonne Paris Cité, Paris, France. Electronic address: [email protected].
2
Laboratoire d'Oncobiologie, Hôpital René Huguenin, Institut Curie, St Cloud, France; Université Paris Descartes, Faculté des Sciences Pharmaceutiques et Biologiques, UMR 8151 CNRS-U1022 Inserm, Sorbonne Paris Cité, Paris, France.
3
Université Paris Descartes, Faculté de Pharmacie de Paris, Sorbonne Paris Cité, Paris, France; Département de Recherche Translationnelle, Research Center, Institut Curie, Paris, France. Electronic address: [email protected].
1
Division of Gastroenterology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada; Michael Smith Genome Sciences Center, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; Laboratoire d'Oncobiologie, Hôpital René Huguenin, Institut Curie, St Cloud, France; Université Paris Descartes, Faculté de Pharmacie de Paris, Sorbonne Paris Cité, Paris, France. Electronic address: [email protected].
2
Laboratoire d'Oncobiologie, Hôpital René Huguenin, Institut Curie, St Cloud, France; Université Paris Descartes, Faculté des Sciences Pharmaceutiques et Biologiques, UMR 8151 CNRS-U1022 Inserm, Sorbonne Paris Cité, Paris, France.
3
Université Paris Descartes, Faculté de Pharmacie de Paris, Sorbonne Paris Cité, Paris, France; Département de Recherche Translationnelle, Research Center, Institut Curie, Paris, France. Electronic address: [email protected].
Three-dimensional (3D) in vitro models have been used in cancer research as an intermediate model between in vitro cancer cell line cultures and in vivo tumor. Spherical cancer models represent major 3D in vitro models that have been described over the past 4 decades. These models have gained popularity in cancer stem cell research using tumorospheres. Thus, it is crucial to define and clarify the different spherical cancer models thus far described. Here, we focus on in vitro multicellular spheres used in cancer research. All these spherelike structures are characterized by their well-rounded shape, the presence of cancer cells, and their capacity to be maintained as free-floating cultures. We propose a rational classification of the four most commonly used spherical cancer models in cancer research based on culture methods for obtaining them and on subsequent differences in sphere biology: the multicellular tumor spheroid model, first described in the early 70s and obtained by culture of cancer cell lines under nonadherent conditions; tumorospheres, a model of cancer stem cell expansion established in a serum-free medium supplemented with growth factors; tissue-derived tumor spheres and organotypic multicellular spheroids, obtained by tumor tissue mechanical dissociation and cutting. In addition, we describe their applications to and interest in cancer research; in particular, we describe their contribution to chemoresistance, radioresistance, tumorigenicity, and invasion and migration studies. Although these models share a common 3D conformation, each displays its own intrinsic properties. Therefore, the most relevant spherical cancer model must be carefully selected, as a function of the study aim and cancer type.
Steps for formation of spherical cancer models. (A) Multicellular tumor spheroids are obtained after aggregation and compaction of cell suspension cultured in nonadherent conditions. (B) Tumorospheres are formed by clonal proliferation in low-adherent conditions and with stem cell medium. (C) Tissue-derived tumor spheres are generated through partial dissociation of tumor tissue and compaction/remodeling. (D) Organotypic multicellular spheroids are formed from cutting tumor tissue in nonadherent conditions that rounded up during the culture.
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