3D Bioprinted Cancer Models Advantages, Roles & Applications In Drug Development

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3D Bioprinted Cancer Models: Advantages,
Roles & Applications In Drug Development

Currently, efforts invested in developing new drugs often fail to translate into meaningful
clinical benefits for cancer patients. Therefore, developing more effective anticancer
therapies and accurately predicting their clinical value remains an urgent medical need.
Because solid cancers have complex and heterogeneous structures composed of
different cell types and extracellular matrices, three-dimensional (3D) cancer models
have great potential to advance our understanding of cancer
biology.

Advanced 3D bioprinted cancer models have the potential to revolutionize the way we
discover therapeutic targets, develop new drugs, and personalize anticancer treatments in
an accurate, reproducible, clinically transferable and robust manner. Therefore, it is
critical to gain insight into the differences in tumorigenesis between 2D, 3D, and tumor
animal models, and this emerging field will contribute to current cancer research as well
as clinical translation of new therapies.

Advantages of 3D Bioprinted Cancer Models

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An ideal 3D bioprinted cancer model can precisely reproduce the in vivo
environment of a specific tumor, including its perfusion vessels. This enables
multiple biochemical assessments of tumor cell behavior that mimic the in vivo
environment. Indeed, gene expression analysis showed that compared with 2D cultures,
3D bioprinted cancer models could show immunoglobulin production, expression of
proinflammatory molecules, activation of cytokines and/or chemokines, upregulation of
cell-cell adhesion pathways, and reduction of proteins associated with cell division and
DNA replication. These differences provide insights into how the 3D environment affects
cancer cell growth, migration, invasion, stem cells, and gene expression.

In addition, the elasticity, plasticity, and mechanical properties of the original tumor ECM
can be modeled by using specific matrix materials. For example, hepatogenic
decellularized ECM and mammary decellularized ECM have retained microstructures and

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ultrastructures that, together with growth factors bound and sequestered in the matrix,
control cell location and orientation. The decellularized ECM scaffolds printed by digital
light processing (DLP) technology enable accurate spatial cell deposition, thereby
preserving these tissue-specific growth factors. DLP-based models have also been used
to study the initial stages of pancreatic ductal adenocarcinoma development.

Blood vessels play a crucial role in tumor proliferation, oxygen diffusion, angiogenesis,
endovascular and extravasation. Therefore, the realization of functional vascular networks
in biomimetic tumor models is essential to maintain cell viability and reveal the close
relationship between tumor and blood vessels. This dynamic environment can be studied
by 3D bioprinted cancer models containing vasculature, including how circulating cancer
cells interact with stromal cells and infiltrating immune cells, the exchange of secreted
factors between different cell types, the response to external stimuli, and the behavioral
adaptation of cancer cells to the metastatic microenvironment.

Each cancer has a unique TME that includes various healthy functional cell types, such as
stromal cells, vascular cells, and immune cells. However, non-bioprinted 3D cancer
models, which are implemented by means of structures such as hydrogel constructs,
polymer scaffolds, microcarrier beads, and hanging droplets, do not allow spatiotemporal
control of tissue formation and do not allow long-term observation of dynamic changes.
3D bioprinted models can overcome these limitations by reconstructing the entire TME,
including its functional and structural hierarchies, thus faithfully mimicking the complex in
vivo tumor tissue structure at high resolution and maintaining the viability and function of
patient-derived tissue.

The Important Role of 3D Bioprinted Cancer
Models

Simulating a Metastatic Niche

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An important challenge in cancer research is to construct in vitro models that can
reproduce natural metastatic niches. In addition to differences in ECM properties between
metastatic sites, the interaction between invading cancer cells and the TME within the
metastatic niche is critical in mediating the metastatic cascade.

In a 3D bioprinted model simulating the bone metastatic niche, MDA-MB-231 breast
cancer cells were co-cultured with osteoblasts and human bone marrow mesenchymal
stem cells (MSCs) to mimic the bone TME. The proliferation rate of MSCs and osteoblasts
decreased within 5 days after the addition of cancer cells, suggesting that breast cancer
cells induce osteolysis in tumor bone. In addition, breast cancer cells in this model
showed increased secretion of the proangiogenic factor VEGF and decreased alkaline
phosphatase activity, which are markers of new bone formation.

Simulating tumor blood vessel

Improved understanding of tumor cell-endothelial cell interactions could reveal important
mechanisms of tumor metastasis and angiogenesis. By 3D bioprinting, breast cancer
microspheres were generated, which encapsulated microfibers containing human
umbilical vein endothelial cells (HUVEC). When co-cultured with breast cancer cells,
HUVEC elongates toward cancer cells outside the fibers, which remain exclusively within
the fibers and form vascular-like cavities within the fibers. This finding shows the potential
of co-cultured 3D bioprinted cancer models to reshape the interaction between cancer
cells and endothelial cells.

Anti-tumor immunity

Bringing immune cells from the TME and periphery into 3D bioprinted models can provide
a reproducible platform to study human anticancer immune responses, thereby
generating tumor models suitable for understanding tumor biology and drug testing. For
example, in a 3D bioprinted model consisting of bladder cancer cells, fibroblasts, HUVEC,

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and monocytes, treatment with Bacille Calmette-Guerin (BCG) resulted in increased
monocyte proinflammatory cytokine secretion and decreased cancer cell growth.

Currently, several 3D bioprinted models have been developed to rapidly and reliably
evaluate the efficacy of immune modulators and cell-based cancer immunotherapies. For
example, 3D bioprinted models have been used to evaluate chimeric antigen receptor
(CAR) T-cell therapy for neuroblastoma.

Brain malignancies face considerable therapeutic challenges, in part because of their
unique brain TMEs that promote tumor progression. A DLP-based 3D bioprinted
glioblastoma model has been developed that mimics the brain TME and contains glioma
stem cells, astrocytes, neural precursor cells, and macrophages. The model is also
capable of analyzing macrophage phenotypes and detecting multiple transcriptional
changes that occur as a result of cancer cells interacting with the TME. In this model,
macrophages recruited by cancer cells acquire a glioma-associated phenotype that
promotes tumorigenesis.

By combining different technologies and tuning the desired tissue-like properties and
cellular components, 3D bioprinted models can serve as valuable tools for studying TME
and cancer immunology.

Drug Development Applications of 3D
Bioprinted Cancer Models

3D bioprinting enables the assembly of cells and ECMs to form 3D constructs that
demonstrate the complexity of cancer tissues and serve as a robust and reproducible
platform for the discovery of new therapeutic targets, preclinical testing of anticancer
drugs, and the development of personalized cancer therapies.

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Drug Efficacy Evaluation

3D-printed biological cancer models have been used in the screening and discovery of a
variety of drugs. ECM properties, such as density and composition, influence drug spread
and tumor penetration, and some 3D bioprinted tumor models take these factors into
account. In an iterative 3D bioprinting approach using GP-118 patient-derived gastric
adenocarcinoma cells suspended in a gelatin-alginate-matrix biomaterial, this 3D
bioprinted gastric adenocarcinoma model is chemo-resistant to Docetaxel, 5-fluorouracil,
and cisplatin and can be used to assess resistance to developing drugs.

3D bioprinted models have also been used to evaluate the therapeutic effects of
monoclonal antibodies. For example, metuzumab, an anti-CD174 antibody used to treat a
variety of cancers, researchers used heat-sensitive biomaterials to 3D bioprint
microfluidics composed of SMMC-7721 liver cancer cells and HUVECs. Higher doses of
metuzumab were required to inhibit cancer cell migration and proliferation in 3D models

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compared with 2D cultures. Additionally, the incorporation of human peripheral blood
mononuclear cells into the 3D bioprinted model allowed the investigators to assess
metuzumab-induced ADCC cytotoxicity, an important aspect of therapeutic antibodies.

Drug screening platform

In addition to evaluating tumor response to drugs, 3D bioprinting platforms can help
high-throughput screening of compounds and approval of drugs for different diseases or
indications. Whole exome sequencing (WES) can identify the mutation profiles of patient
cancer samples and predict drug sensitivity by associating these profiles with specific
drugs that target mutations.

Target Discovery

The addition of perfusable vascular systems to multicellular 3D bioprinted models may
further improve drug screening platforms. For example, a 3D bioprinted microengineered
glioblastoma model is being developed that contains perfusable capillaries lined with
endothelial and pericytes and connected to a peripheral blood pump. This 3D model can
reflect the heterogeneity of glioblastoma samples, and the tumor cells in this 3D model are
transcriptionally more similar to in vivo glioblastoma tumor cells than 2D cultures derived
from the same cells. Notably, this model shows upregulation of P-selectin, whereas
glioblastoma cells grown in 2D medium do not express P-selectin and are not affected by
P-selectin inhibitors, suggesting that the use of 3D bioprinted cancer models may reveal
therapeutic targets that cannot be detected by conventional 2D culture.

In conclusion, 3D bioprinted cancer models have been shown to better reflect tumor
heterogeneity, TME complexity, cancer cell behavior, gene expression signatures, and
drug response than traditional 2D culture methods. These models also provide a platform
for studying parameters of cancer therapeutic approaches that cannot be adequately
studied using conventional 2D culture methods or simple 3D models.

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Clinical Trials

Various ongoing clinical trials are evaluating the predictive power of 3D cancer models for
drug screening, target discovery, and personalized therapy. For example, an ongoing
clinical trial is evaluating 3D bioprinted liver cancer models to predict the response of
chemotherapy to colorectal cancer as well as liver metastases from colorectal cancer
(NCT04755907). Another trial uses 3D bioprinting of hyaluronic acid-gelatin biomaterials
to create organ-like models of myeloma (NCT03890614) and aims to create
patient-specific bioimprinted models to study myeloma biology and chemotherapy
sensitivity. These clinical studies provide proof of concept for the feasibility of using 3D
bioprinted cancer models to accurately model patient tumors and their dynamic
microenvironment and predict treatment outcomes.

Conclusion

3D bioprinted cancer models have the potential to transform the way we study, diagnose,
prevent and treat cancer. The commercialization of these models, especially in drug
development and testing, is expected to yield substantial economic benefits. In addition,
advanced 3D bioprinting technologies, combined with machine learning and AI-based
omics approaches, may uncover fundamental mechanisms of cancer biology, reveal
novel biomarkers and drug targets, and advance the development of effective
personalized cancer treatments. develop.

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used to crosslink into degradable PEG hydrogels.

Reference:
[1]. 3D bioprinted cancer models: from basic biology to drug development. Nat Rev
Cancer.2022 Oct 24.

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