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Using Spheroids to build 3D Bioprinted Tumor Microenvironment
this great potential of PDX models within an aspect of be quiescent or hypoxic due to the limited supply of
precision medicine, the outcomes were compromised oxygen and nutrient delivery . On the other hand, the
[14]
by notably the insufficient relevant tissue-specific oxygen-depleted cells anaerobically convert pyruvate to
microenvironment support . Often after engraftment, the lactic acid, in an effort to produce an acidic core within
[3]
stromal components in tumors undergo remodeling with spheroids. Above-mentioned observations reflect in vivo
embedded stromal cells which are gradually replaced by features of avascular tumors, in terms of cell morphology,
host stroma. The use of immunodeficient mice also leads growing kinetics, hypoxia, metabolism, nutrient gradient,
to incompetent PDX models in immunotherapy-relevant and gene expression, which represent a promising
studies which currently is a widespread concern . Other platform for a better understanding of cancer biology and
[4]
problems, such as low engraftment rate , have also been drug discovery ex vivo.
[5]
frequently raised as a part of the key challenges. In the past few decades, 3D bioprinting has
On the other hand, in vitro models are speculated as garnered extensive attention [15-17] . 3D bioprinting
promising platforms to interrogatively extrapolate in vivo possesses superior flexibility and controllability on the
conditions. 2D culture models lack cell-to-cell and cell- spatial arrangement of biomaterials and cells, which
to-extracellular matrix (ECM) interactions rendered in 2D has been expansively applied to tumor-related studies
culture platforms, which are incompetent in recapitulating including TME mimicking, tumor angiogenesis, tumor
the heterogeneous features characteristically shown in the metastasis, and antitumor drug screening using individual
tumor microenvironment (TME). Substantial evidence cells and miscellaneous biomaterials [18-21] . Nevertheless,
has revealed that 3D culture is more physiologically individually dispersed cells within the hydrogel matrix
relevant in comparison to planar culture [6,7] . The essential are insufficient in faithfully recapitulating specific disease
[22]
differences between cell behaviors, gene and protein states either indicating fibrosis or tumor propagation .
expressions, and drug responses in 2D versus 3D cell In contrast, spheroids could be a perfect alternative and
culture systems are driving communal adoption of 3D implementable approach. Despite the high potential in
culture toward more faithful and sophisticated tumor building tissue constructs by combining 3D bioprinting
models. Thereafter, a series of 3D in vitro tumor models and spheroidal assembly, 3D printing or positioning
with diverse configurations and various complexities have spheroids with high precision remains challenging.
been investigated for cancer research, drug discovery and Herein, we review state-of-the-art status of using
have become a promising complimentary tool in bridging spheroids for mimicking tumor tissue microenvironment
the in vitro, in vivo, and clinical investigations [8,9] . and their potential as building blocks in 3D bioprinting
Spheroids have been recognized as classic 3D technology. We first concisely describe the context
culture models for pathophysiological studies, which of the TME, followed by an introduction of various
mimics the aggregation of one or multiple types of tumor methodologies for spheroid formation, including the
and tumor tissue microenvironment relevant cells grown comparison of their merits and drawbacks. We then
in suspension or in a 3D matrix. Spheroids are formed compile contemporary literature sources, providing a
by boosting the cell-to-cell interaction while minimizing compelling overview of recent progress of using spheroids
the cell-to-matrix adhesion . Cells initially aggregate as building blocks for 3D printed tissue modeling, with a
[10]
to form loose bonds by integrin-mediated attachment to particular emphasis on tumor models. Finally, we discuss
ECM, which substantiates the upregulation of cadherin. the future potential and challenges on spheroid formation,
This accumulation of cadherin on the cell membrane 3D bioprinting and their combination thereof utilized for
facilitates the compact spheroid formation , as opposed advancing cancer research.
[11]
to individual cells, spheroids possess an non-apical cell 2. TME
morphology with stronger cell-to-cell, and cell-to-ECM
interactions. Spheroids with increased cell survival rates, Tumorigenesis is a dynamically complicated process
higher levels of ECM proteins secretion, and a more involving its initiation, progression, and metastasis. It
stable morphology have been reported in comparison to is governed by not only malignant tumor cells but also
2D culture . Diffusion limit (~250 µm) enables ordered the constantly interacting, surrounding stroma, which
[12]
gradient proliferation rates observed in a large size of is referred to as TME . During tumorigenesis, the
[23]
spheroids over 500 µm , which exhibit different zones interplay between tumor cells and associated TME,
[13]
with varied cell conditions delineated by the proliferation reciprocally remodeling the ECM and their subsequent
zone in the outer layer, quiescent zone in the middle layer, competition, determines whether tumorigenesis
and necrotic zone in the center core . Cells presenting proceeds . The TME is a highly heterogeneous,
[24]
[11]
in the outer layer receive abundant oxygen and culture stage- and localization- dependent, and individually
medium, thus displaying much higher proliferation specific to its origination . Only a small fraction of
[25]
rate and viability. In contrast, cells in the core tend to the tumor is comprised of tumor cells, while the larger,
2 International Journal of Bioprinting (2021)–Volume 7, Issue 4