Page 248 - IJB-10-3

International Journal of Bioprinting Increased ECM stiffness enhances chemoresistance

ability, and provided a solid foundation for later-stage stiffness of 3D tumor models may promote malignant
pharmacodynamic research on antitumor drugs. In phenotypes such as tumor stemness and tumor progression.
addition to extrusion-based bioprinting, other 3D culture In pharmacodynamic research, it is widely accepted
methods, such as organoids and patient-derived xenografts that pharmacodynamic results obtained from 3D culture
(PDXs), are gaining attention. Despite the utilization conditions are more reliable than those obtained from
of organoids in studying various diseases, including 2D planar cultures. Our findings demonstrate that cell
cancer, the cost factor and a lack of standardization in proliferation in 3D model (6%-3DP) was higher than that
terms of establishment and quality control are still a in 2D model. Furthermore, the IC values obtained using
matter of concern. On the other hand, PDXs belong to 3D model (6%-3DP) were more closely aligned with the
53
50
a type of tumor tissue that is extracted from biopsies or clinically effective blood concentrations. Additionally, the
surgical excisions and propagated in mice via implants
and explants. To some extent, the propagation of this responses of the two tumor models with different matrix
54
tissue via culturing method can still accurately retain the stiffness to antitumor drugs also varied, with the IC values
50
genomic and transcriptomic characteristics of the parental of the three tested drugs in 8%-3DP model being notably
tumor tissue, and the resultant cultures can be used for higher than those in 6%-3DP model. The expression of
measuring tumor response to treatment; however, it has several common drug resistance genes, such as MDR1 and
several shortcomings, such as the time-consuming and MRP1, except for ABCA1, was upregulated in rigid model,
costly culturing process, and the likelihood of intratumoral partly accounting for the distinct responses of the two tumor
heterogeneity and genome evolution. Additionally, the models to the three tested chemotherapy drugs. Hence, 3D
existing PDX models, which are constructed with tissues models offer a superior platform for preclinical drug testing,
acquired from immunodeficient mice, are not feasible and matrix stiffness plays a critical role in modulating the
for use in immuno-oncology research. Therefore, the sensitivity of tumor cells to chemotherapy drugs.
55
development of new 3D tumor models for preclinical We also identified unique transcriptomic
studies is imperative. characteristics in the stiffer 3D-bioprinted ovarian cancer
Before the construction of 3D tumor models, we first model. Specifically, 3D models with different levels of
performed rheological analysis for both concentrations stiffness were found to manifest varied transcriptional
of GelMA hydrogels. Temperature sweep oscillatory tests expression profiles. In comparison to the 6%-3DP model,
indicated that the temperature at which 6% GelMA and the 8%-3DP model showed elevated expression of 145
8% GelMA reached the intersection of G′ and G″ was genes and attenuated expression of 72 genes. Notably,
about 18.8°C and 20.7°C, respectively. Therefore, in the among these DEGs, we discovered several significant
subsequent experiments, we set the printing temperature ones associated with enhanced chemotherapy resistance,
at 21.5°C to avoid extrusion needle clogging, to reduce including FOS, CRYAB, G6PD, and DUSP1. According
the damage of shear stress on tumor cells during the to Javellana et al., FOS was particularly upregulated in
printing process and ensure good formability of printed chemotherapy-resistant specimens obtained from a cohort
structure. Furthermore, the results of semi-quantification of patients with advanced stage IIIC or IV high-grade
40
of printability showed that the Pr values of 6% GelMA serous ovarian cancer. Another research confirmed
and 8% GelMA were both close to 1. As a result, smooth that CRYAB overexpression was associated with acquired
41
and uniform filaments could be continuously extruded, drug tolerance and poor patient prognosis. Through a
resulting in a standard grid structure with obvious layering. correlation analysis between chemoresistance data and
gene expression profiles of ovarian cancer patient-derived
When examining the biological behavior of tumor cells spheroids, Yamawaki et al. proved that cisplatin resistance
in 3D tumor models, we observed that 8%-3DP model was significantly related with increased expression levels
exhibited a lower rate of cell proliferation than 6%-3DP of G6PD. In addition, Kang et al. demonstrated that
42
model. However, we also noted a higher expression level DUSP1 overexpression impaired chemotherapy response
of p53, an ovarian cancer cell marker, in 8%-3DP model. in ovarian cancer, whereas silencing the gene in vivo
Additionally, increasing the stiffness of the tumor model significantly enhanced sensitivity to paclitaxel and
resulted in a significant increase in the expression levels increased apoptosis. Consistent with these findings,
43
of the tumor stemness markers like ALDH1 and CD44, our study revealed that an increase in ECM stiffness can
57
56
whereas the level of CD133 remained unchanged. promote the expression of related genes, which collectively
58
Notably, the rigid model also showed higher expression contributes to enhanced chemoresistance.
levels of IL-6, a factor associated with poor prognosis and
chemotherapy resistance in patients with ovarian cancer. However, several limitations of this study need to
59
These findings suggest that appropriately increasing the be addressed. The TME is composed of various cellular
Volume 10 Issue 3 (2024) 240 doi: 10.36922/ijb.1673