Contents lists available at ScienceDirect Pharmacology and Therapeutics journal homepage: www.elsevier.com/locate/pharmthera Emerging tumor spheroids technologies for 3D in vitro cancer modeling ☆ Tânia Rodrigues a,b,1 , Banani Kundu a,b,1 , Joana Silva-Correia a,b , S.C. Kundu a,b , Joaquim M. Oliveira a,b,c , Rui L. Reis a,b,c , Vitor M. Correlo a,b,c, ⁎ a 3B's Research Group – Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Zona Industrial da Gandra, 4805-017 Barco, Guimarães, Portugal b ICVS/3B’s - PT Government Associate Laboratory, Braga/Guimarães, Portugal c The Discoveries Centre for Regenerative and Precision Medicine, Headquarters at University of Minho, Avepark, 4805-017 Barco, Guimarães, Portugal ARTICLE INFO Keywords: Metastasis 3D tumor models Multicellular tumor spheroids Bioprinting Biomaterials ABSTRACT Cancer is a leading cause of mortality and morbidity worldwide. Around 90% of deaths are caused by metastasis and just 10% by primary tumor. The advancement of treatment approaches is not at the same rhythm of the disease; making cancer a focal target of biomedical research. To enhance the understanding and prompts the therapeutic delivery; concepts of tissue engineering are applied in the development of in vitro models that can bridge between 2D cell culture and animal models, mimicking tissue microenvironment. Tumor spheroid re- presents highly suitable 3D organoid-like framework elucidating the intra and inter cellular signaling of cancer, like that formed in physiological niche. However, spheroids are of limited value in studying critical biological phenomenon such as tumor-stroma interactions involving extra cellular matrix or immune system. Therefore, a compelling need of tailoring spheroid technologies with physiologically relevant biomaterials or in silico models, is ever emerging. The diagnostic and prognostic role of spheroids rearrangements within biomaterials or mi- crofluidic channel is indicative of patient management; particularly for the decision of targeted therapy. Fragmented information on available in vitro spheroid models and lack of critical analysis on transformation aspects of these strategies; pushes the urge to comprehensively overview the recent technological advancements (e.g. bioprinting, micro-fluidic technologies or use of biomaterials to attain the third dimension) in the shed of translationable cancer research. In present article, relationships between current models and their possible ex- ploitation in clinical success is explored with the highlight of existing challenges in defining therapeutic targets and screening of drug efficacy. 1. Biological fundaments of metastasis progression The alterations in oncogenes and tumor suppressors underlie the autonomous defects in cells; the characteristics of cancer initiation within a healthy non-transformed cellular microenvironment. But tu- mors are not simply autonomous neoplastic cells; instead the cross-talk among tumorous or malignant and non-malignant cells, signals and secretory proteins (such as cytokines) influences cancer development, metastasis formation and dissemination (Barcellos-Hoff, Lyden, & Wang, 2013; Bremnes et al., 2011). Metastasis is “the spread of cancer cells from primary tumor to secondary locations within the body” (Barcellos-Hoff et al., 2013). The cascade events of metastasis start with the growth of primary tumor cells, which needs the supply of blood to support their metabolism — the phenomenon known as angiogenesis. The proliferating tumor cells commandees available vasculature or stimulate neovessel generation for continuous supply of oxygen, nu- trients and growth factors. The rapid proliferation soon exhausts the supply of nutrient and oxygen; becomes hypoxic (Thoma, Zimmermann, Agarkova, Kelm, & Krek, 2014). The newly formed blood vessel offers the escape route to tumor cells, that then enter into cir- culatory system (such as blood or lymphatic system) — the process known as intravation. Migratory tumor cells surviving within the cir- culation, extravasate into a near or far guest-tissue/organ and start formation of a secondary tumor mass as depicted in Fig. 1. Despite of https://doi.org/10.1016/j.pharmthera.2017.10.018 ☆ Associate editor: B. Teicher ⁎ Corresponding author. 3B's Research Group – Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Zona Industrial da Gandra, 4805-017 Barco, Guimarães, Portugal. 1 Contributed equally. E-mail address: vitorcorrelo@dep.uminho.pt (V.M. Correlo). Abbreviations: DTCs, dormat tumour cells; TGF-β, transforming growth factor-β; ECM, extracellular matrix; 2D, two dimensional; 3D, three dimensional; PDTX, patient derived tumor xenografts; MCTS, multi-cellular tumor spheroid; Me-GG, methacrylate - Gellan gum Pharmacology and Therapeutics xxx (xxxx) xxx–xxx 0163-7258/ © 2017 Elsevier Inc. All rights reserved. Please cite this article as: Rodrigues, T., Pharmacology and Therapeutics (2017), http://dx.doi.org/10.1016/j.pharmthera.2017.10.018