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International Journal of Bioprinting Biomimetic 3D printed glioma model

transformation to neuron-like cells may reduce the Ca signaling pathway may be a new strategy for glioma
2+
proliferative capacity of glioma cells to significantly treatment .
[65]
inhibit tumor growth , and prolong the survival time of Our results support the idea that the interactions
[35]
patients . Thus, the effects of neurons on glioma cells are between neurons and glioma cells are complex and
[36]
complex and should be further explored by in vivo and in bidirectional . Ideally, new antiglioma therapies should
[37]
vitro experiments. take advantages of the cell–cell interactions in glioma
Neurons cultured in the bioprinted glioma in vitro 3D tissues to minimize the damage and improve the efficacy .
[66]
model showed a higher survival rate, more neurites and For example, in clinical and research settings, noninvasive
longer axons. After 1 day of culture, the reason for the low brain stimulation (NiBS) involves applying magnetic or
survival rate of neurons in both models may be attributed electrical fields to modify neuronal activity in order to
[67]
to the fact that neurons may be damaged in the process of modulate the behaviors of glioma cells, so as to influence
isolation and did not adapt to the 3D matrix materials in the development of glioma. However, the mechanism of
the initial stage. After 3 days of culture, with the adaptation this treatment is still unclear and its efficacy is difficult to
of neurons to 3D culture environment, the survival rate of predict. The studies about the complex interactions between
neurons in both models increased significantly (27.36% in glioma cells and their surrounding neurons are urgently
G/N and 17.47% in N), and the neurons showed a good needed to improve the understanding and therapies.
spreading and presented a large number of neurites. After 5 Herein, the bioprinted glioma in vitro 3D model provides
days of culture, neurons become apoptotic, resulting in the a novel model to understand and utilize the complex
decline of survival rate . During the 5 days of culturing, the interactions between glioma cells and their surrounding
[37]
significantly higher survival rate, more neurites and longer neurons, and a two-way promotion relationship between
axons of neurons in G/N than in G indicates that glioma glioma cells and neurons around them in the early stage of
cells may trigger synaptic differentiation and neuronal glioma is shown, which will promote the development of
process growth [38,39] and increase the hyperexcitability of new glioma treatment methods, such as NiBS.
neural circuits [40-43] .
The complex microenvironment of glioma includes
Ca is closely related to cell proliferation, neuronal multiple cells and biochemical factors, which matters in
2+
plasticity, and intracellular signal transduction [44-49] . Ca the progression of glioma . In this study, we only included
2+
[5]
can regulate cell behaviors of glioma cells, including cell neurons and glioma cells, which results in an inconspicuous
proliferation, migration, invasion and apoptosis [50-54] . Our glioma invasion. Besides, cells like astrocytes and
results indicated that neurons may promote the expression microglia support the survival and function of neurons ,
[68]
of Ca in glioma cells, which is possibly related to the and the lack of these cells leads to the imbalance of the
2+
extracellular K during neuronal activity , but needs to be microenvironment of the model; therefore, the survival
+
[17]
verified by further experiments. During the development time of the model is short and then, the neuron death
of glioma, Ca activates ERK/MAPKs and PKA occurs. However, since 3D printing can produce complex
2+
[55]
[56]
pathways of glioma cells and promotes glioma cells to structures containing multiple materials, it is promising to
produce synaptic plasticity required for migration and integrate other cells and biochemical factors in this model
invasion , so as to promote glioma progression , which to make it closer to natural glioma tissue to solve existing
[57]
[44]
may further explain that GL261 cells around neurons in problems and provide more accurate pathological and
our study have experienced neuron-like transformation pharmacological models for glioma in the future.
and increased in number when their intercellular Ca
2+
concentration increased. On the other hand, the increase of 5. Conclusion
Ca in glioma cells may stimulate glioma cells to produce
2+
glutamate and release it to surrounding cells [58-60] , leading In this study, a bioprinted glioma in vitro 3D model was
to the excitotoxicity and the enhancement of synaptic constructed using a step-by-step bioprinting method to
plasticity of surrounding neurons, which can further reproducibly and better control the spatial relationship
explain that neurons near GL261 cells in our study show between glioma cells and neurons in natural human glioma
more neurites and longer axons. In addition, the increase tissue. Our findings indicated that the proposed bioprinted
of glutamate caused by the increase of Ca can further glioma in vitro 3D model is better suited to mimic the
2+
stimulate the growth of adjacent glioma cells [61,62] . All these state of glioma encapsulated by neurons found in vivo.
evidences, combined with our results, indicate that one of In the bioprinted glioma in vitro 3D model, the glioma
the ways that neurons promote glioma progression is to cells around neurons showed larger number, neuron-like
promote the expression of Ca in glioma cells , leading morphology, and higher intracellular Ca concentration.
2+
2+
[63]
to the deterioration of glioma . Therefore, targeting An appropriate amount of glioma cells was found to
[64]
Volume 9 Issue 4 (2023) 11 https://doi.org/10.18063/ijb.715