In Vitro Modeling of Tissue-Specific 3D Microenvironments and Possibile Application to Pediatric Cancer Research

Abstract

A large body of evidence indicates that three dimensional (3D) cancer models are superior to two-dimensional (2D) ones in better representing the in vivo phenomena. Indeed, 3D models allow recapitulating in vitro the in vivo features observed in solid tumors (e.g. cell polarity, cell-cell/cell-matrix interactions, biochemical/metabolic gradients, anchorage-independent growth and hypoxia). Moreover, it is well established that the microenvironment plays a fundamental role in regulating tumor development and behavior, including drug resistance. Thus, innovative models able to mimic this complexity represent attractive tools in cancer research. In this review article, we provide a comprehensive review of the application of 3D culture systems in pediatrics' cancer research. In particular, 3D in vitro/ex vivo models of the most common pediatric tumors, such as leukemias, lymphomas and malignancies of the nervous system, will be considered.

The extracellular matrix of hematopoietic stem cell niches

“…This matrix is rich in basement membrane components, mainly collagen type IV, laminins (mainly LM-111), perlecan, nidogen and trophic factors. It allows 3D culture of many different cell types, however, it has limitations including batch-to-batch variability in quality, inability to mimic the mechanical properties of the basement membrane and inappropriateness to recapitulate other matrices of connective tissues due to the not-corresponding composition [525] . To overcome these limitations, more and more biomaterials are synthesized and applied which allow controlling their mechanical properties, the 3D architecture and biochemical composition.…”

“…via adhesion [521] , [522] . Amongst the natural polymers, proteins such as collagen/gelatin or serum albumins as well as carbohydrates including chitosan, alginate, dextran, hyaluronic acid or heparin are applied [474] , [499] , [510] , [522] , [525] , [526] . More complex ECM mimics are provided by working with decellularized ECMs, derived either directly from bone or BM or from cell culture [522] , [527] , [528] , [529] , [530] .…”

“…More complex ECM mimics are provided by working with decellularized ECMs, derived either directly from bone or BM or from cell culture [522] , [527] , [528] , [529] , [530] . While they can preserve the natural composition and 3D architecture of the ECM, their composition is hardly ever exactly known, hampering the interpretation of results in terms of connecting observed cellular responses to a single ECM derived stimulus [525] . Besides, also inorganic compounds of bone including tricalciumphosphate or hydroxyapatite were applied [531] .…”

“…All in all, it appears that 3D culture and adhesion of leukemic cells to a stromal niche enhance their survival rates during drug treatment, possibly by induction of a phenomenon called cell adhesion mediated drug resistance (CAM-DR), by promoting leukemic cells to enter a quiescent state in which they are protected from drugs that act on quickly proliferating cells and by increasing hypoxic regions that might also contribute to chemoresistance [525] . Thus, not only the malignant cells themselves but also their tumor microenvironments including the ECM therein are potential targets for molecular therapies.…”

Fibroblasts Enhance Migration of Human Lung Cancer Cells in a Paper‐Based Coculture System

“…[27][28][29] Mono-cultures, additionally, do not exhibit in vivo physiological behavior of cancer cells properly. [30] To provide an improved mimic of natural tumors, VXN2 and TF cells were grown as co-cultures in multi-layered paper stacks with different configurations.…”