Heralding a new paradigm in 3D tumor modeling

Abstract

Numerous studies to date have contributed to a paradigm shift in modeling cancer, moving from the traditional two-dimensional culture system to three-dimensional (3D) culture systems for cancer cell culture. This led to the inception of tumor engineering, which has undergone rapid advances over the years. In line with the recognition that tumors are not merely masses of proliferating cancer cells but rather, highly complex tissues consisting of a dynamic extracellular matrix together with stromal, immune and endothelial cells, significant efforts have been made to better recapitulate the tumor microenvironment in 3D. These approaches include the development of engineered matrices and co-cultures to replicate the complexity of tumor-stroma interactions in vitro. However, the tumor engineering and cancer biology fields have traditionally relied heavily on the use of cancer cell lines as a cell source in tumor modeling. While cancer cell lines have contributed to a wealth of knowledge in cancer biology, the use of this cell source is increasingly perceived as a major contributing factor to the dismal failure rate of oncology drugs in drug development. Backing this notion is the increasing evidence that tumors possess intrinsic heterogeneity, which predominantly homogeneous cancer cell lines poorly reflect. Tumor heterogeneity contributes to therapeutic resistance in patients. To overcome this limitation, cancer cell lines are beginning to be replaced by primary tumor cell sources, in the form of patient-derived xenografts and organoids cultures. Moving forward, we propose that further advances in tumor engineering would require that tumor heterogeneity (tumor variants) be taken into consideration together with tumor complexity (tumor-stroma interactions). In this review, we provide a comprehensive overview of what has been achieved in recapitulating tumor complexity, and discuss the importance of incorporating tumor heterogeneity into 3D in vitro tumor models. This work carves out the roadmap for 3D tumor engineering and highlights some of the challenges that need to be addressed as we move forward into the next chapter.

Perivascular signals alter global gene expression profile of glioblastoma and response to temozolomide in a gelatin hydrogel

“…Transwell ®), as well as immunofluorescent or immunohistochemical staining and imaging [4,19,20]. However, the inability of 2D culture to accurately predict therapeutic response and the complexity of animal models has paved the way for the development of 3D in vitro models, which utilize materials such as hydrogels to recapitulate elements of the tumor microenvironment [21][22][23]. To date, 3D in vitro models for GBM primarily incorporate only tumor cells, despite the demonstrated contributions of additional cell types to in vivo GBM behavior [6,[24][25][26][27][28][29][30].…”

Spheroids of HER2-Positive Breast Adenocarcinoma for Studying Anticancer Immunotoxins In Vitro

“…The phenomenon of greater resistance shown by tumors in vivo to therapeutic agents compared to corresponding cancer cells in culture is well known [23, 24]. We have previously shown the toxic effect of the 4D5scFv-PE40 immunotoxin at picomolar concentrations on the HER2-overexpressing human ovarian adenocarcinoma cells SKOV-kat in culture, while its in vivo activity against SKOV-kat xenograft tumors becomes evident under its administration at nanomolar concentration [25].…”

Mesenchymal Stem Cells Relevance in Multicellular Bioengineered 3D In Vitro Tumor Models

“…This correlation, resulting from the incorporation of diverse cell lines, is also observed in scaffold‐based models that provide an ECM‐mimicking environment without requiring previous cell mediated ECM deposition . The advantages and disadvantages of various 3D models production methodologies have been extensively discussed in several reviews . These different formulation technologies are addressed herein mainly in the context of heterotypic cancer‐MSCs 3D in vitro models establishment.…”

“…3D models production methodologies extend over a gamut of techniques which can be grouped into: i) scaffold‐free; ii) scaffold‐based; and iii) combinatorial methodologies. Regardless of the production methodology, all these platforms have as a unifying element: the establishment of 3D multicellular structures, or microtissues, comprised of one or more cell types, either derived from immortalized cancer cells cultures or from patient's primary cells . 3D cell culture methods, range from monotypic cell line cellular spheroids (single cell type), for instance cultured in non‐adherent substrates or through hanging‐drop techniques, up to complex co‐culture systems comprising heterotypic cell lines (e.g., tumor stroma cells including fibroblasts) in a complex tumor ECM‐like supporting matrix, or even associated with microfluidic systems for dynamic nutrient perfusion …”

“…Irrespectively of 3D disease models production methodology, heterotypic cell co‐cultures comprising cancer‐stromal cells provide a better reproduction of the complex tumor microenvironment when compared to monotypic 3D models (comprised by cancer cells alone) . Different bi‐ or tri‐co‐culture systems combining cancer cells and stromal cells have thus far been employed for the study of cancer‐TME specific interactions and drug screenings …”