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3D Modeling of Epithelial Tumors
The current statistics on cancer show that 90% of all human cancers originate from epithelial cells. Breast and prostate cancer are examples of common tumors of epithelial origin that would benefit from improved drug treatment strategies. About 90% of preclinically approved drugs fail in clinical trials, partially due to the use of too simplified in vitro models and a lack of mimicking the tumor microenvironment in drug efficacy testing. This entry focuses on the epithelial cancers, followed by experimental models designed to recapitulate the epithelial tumor structure and microenvironment. A specific focus is to put on novel technologies for cell culture of spheroids, organoids, and 3D-printed tissue-like models, utilizing biomaterials of natural or synthetic origins, and how the models could be utilized for nanotechnology-based drug delivery in the future.
2. In vitro 3D Experimental Models in Cancer Research
In vitro cancer models are the simplified versions in comparison to in vivo models, when studying cancer mechanisms, and the effect of anticancer moieties on tumor growth and progression. Standard 2D cell culture models fail to recapitulate the cellular mechanisms involved in tumor progression such as cell-cell adhesion, polarization, epithelial differentiation, mechanotransduction, invasion and proper signaling of cells within the tumor tissues. Recent developments have shown that 3D in vitro models have tremendous potential in cancer research due to their most promising characteristic of very closely mimicking the in vivo model systems. An ideal in vitro tumor model should be able to recapitulate the 3D in vivo environment along with reproducing the interaction between tumor and stromal cells, thus regulating the cellular functions. Depending upon the method of cell seeding, the 3D in vitro models could be categorized as scaffold-based and scaffold free models. The scaffold-based models utilize the prefabricated ECMs prepared from different materials such as natural or synthetic materials, or decellularized ECM. While in scaffold-free models, cells proliferate as non-adherent floaters without any support material and 3D constructs are formed due to cellular self-assembly .
Non-adherent 3D spheroids can to some degree mimic the solid tumor architecture and it is comprised of different cell layers. The core is composed of necrotic cells while the middle layer has mostly senescent cells. The necrotic or senescent cells of the inner layer is dedicated to the absence or deprivation of nutrients and hypoxic environment, which results in the accumulation of lactate in the spheroids same as that of in vivo solid tumors. The outer layer is formed of cells with high proliferating rates due to convenient access to oxygen and nutrients .
Tumor cells can also be cultured embedded in ECM, where they spontaneously form 3D structures of organotypic nature, which can be called spheroids if they are round or tumoroids if they have an invasive appearance. Here, single cells that are embedded into ECM grow into multicellular, organotypic structures. Each of the functional structures are of clonal nature, but often has characteristic phenotypes that correspond to different tumor stages. Normal epithelial cells or non-aggressive cancer cells can form well differentiated, polarized, round spheroids with functional basement membranes. In contrast, tumoroids formed by aggressive cells mainly result in undifferentiated clusters of cells, or massive invasive structures. In epithelial cancers, invasion through the ECM is typically of the collective type, and ameoeboid invasion is less frequently observed . Tumor cells can also be embedded together with stromal cells and be co-cultured in the ECM. Incorporation of stromal cells such as CAFs will promote genuine, functional interactions between the different cell types, which can be observed in vivo . 3D organotypic cell cultures can therefore act as a bridge between traditional 2D cell culture and costly animal models.
Organoids are more advanced 3D in vitro multicellular structures that mimic the corresponding architecture of in vivo organs. The term organoid is mostly used to describe structures obtained in 3D culture derived from stem cells that are isolated from primary patient samples. The complexity of an organoid is regulated by the developmental potential of the starting stem cells . The organoids can like the spheroids be cultured in non-adherent conditions or embedded in ECM. Organoids are mostly used for translational epithelial research, patient specific treatment planning and disease modelling due to close resemblance to the native tissue composition. However, the 3D organoid culture is advantageous over 3D spheroids due to enhanced physiological and clinical functions. The 3D organoid models of various tumor types have provided concrete evidence to validate the use of these models . Thus, in the future, with continuous development, they can provide substantial information in cancer research.
3. 3D Bioprinting Technologies
3.1. Types of 3D Printing Technologies
4. Biomaterials for Organotypic 3D Cancer Models
The entry is from 10.3390/ijms22126225
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