FIGURE 1
Timeline of cell biology and experimental cancer models-From complexity. . .to simplicity. . .and complexity again. The three research areas-in vitro cell-and tissue-culturing, organoid technology and 3D bioprinting-are developing, and their co-evolution with cancer research supports the establishment of new cancer models. A detailed explanation can be found in the text.
Source publication
Growing evidence propagates those alternative technologies (relevant human cell-based—e.g., organ-on-chips or biofabricated models—or artificial intelligence-combined technologies) that could help in vitro test and predict human response and toxicity in medical research more accurately. In vitro disease model developments have great efforts to crea...
Contexts in source publication
Context 1
... in 1858, Virchow defined the cell as the fundamental unit of life, and he also created a pathogenic concept-accordingly, diseases are the results of changes in normal cells ("cells with bad behaviour") (14). In addition, he was the one who laid the base of cellular pathology in 1863 (15) (Figure 1). ...
Similar publications
The basic idea behind the use of 3-dimensional (3D) tools in biomedical research is the assumption that the structures under study will perform at the best in vitro if cultivated in an environment that is as similar as possible to their natural in vivo embedding. Tissue slicing fulfills this premise optimally: it is an accessible, unexpensive, imag...
Human embryonic stem cells (hESCs)- and induced pluripotent stem cells (hiPSCs)-derived retinal organoids (ROs) are three-dimensional laminar structures that recapitulate the developmental trajectory of the human retina. The ROs provide a fascinating tool for basic science research, eye disease modeling, treatment development, and biobanking for ti...
Purpose of Review
Kidney organoids are heterocellular structures grown in vitro that resemble nephrons. Organoids contain diverse cell types, including podocytes, proximal tubules, and distal tubules in contiguous segments, patterned along a proximal-to-distal axis. Human organoids are being explored for their potential as regenerative grafts, as a...
Kidney organoids possess the potential to revolutionize the treatment of renal diseases. However, their growth and maturation are impeded by insufficient growth of blood vessels. Through a PubMed search, we have identified 34 studies that attempted to address this challenge. Researchers are exploring various approaches including animal transplantat...
![Figure 1: The process flow for chrome mask [(a)-(d)] and silicon mold...](publication/371499499/figure/fig1/AS:11431281167101186@1686576428958/The-process-flow-for-chrome-mask-a-d-and-silicon-mold-preparations-e-g_Q320.jpg)
We report the fabrication of very thin microfluidic active and passive devices on rigid and flexible substrates for sample-space-restricted applications. Thin glass coverslips are commonly used substrates, but these being fragile often crack during experiments, leading to device failure. Here, we used PET as a flexible substrate to fabricate robust...
Citations
... However, a substantial percentage of clinical trial failures result from the frequent difficulty of these models in appropriately estimating the efficacy of drugs and their toxicity in vivo [63]. In contrast, 3D bioprinted tumor models provide a more physiologically appropriate platform for evaluating novel candidates for therapeutic purposes [63][64][65][66][67]. Researchers can measure medication responses more accurately by embedding tumor cells in a 3D matrix that replicates the natural tumor microenvironment. ...
... In contrast, 3D bioprinted tumor models provide a more comprehensive understanding of tumor biology by enabling researchers to examine the complex interactions between tumor cells, stromal components, and the extracellular matrix. By analyzing these intricate relationships, scientists can find new therapeutic targets and create more potent treatment plans to halt the spread of cancer and overcome drug resistance [67,81]. ...
Cancer vasculogenesis is a pivotal focus of cancer research and treatment given its critical role in tumor development, metastasis, and the formation of vasculogenic microenvironments. Traditional approaches to investigating cancer vasculogenesis face significant challenges in accurately modeling intricate microenvironments. Recent advancements in three-dimensional (3D) bioprinting technology present promising solutions to these challenges. This review provides an overview of cancer vasculogenesis and underscores the importance of precise modeling. It juxtaposes traditional techniques with 3D bioprinting technologies, elucidating the advantages of the latter in developing cancer vasculogenesis models. Furthermore, it explores applications in pathological investigations, preclinical medication screening for personalized treatment and cancer diagnostics, and envisages future prospects for 3D bioprinted cancer vasculogenesis models. Despite notable advancements, current 3D bioprinting techniques for cancer vasculogenesis modeling have several limitations. Nonetheless, by overcoming these challenges and with technological advances, 3D bioprinting exhibits immense potential for revolutionizing the understanding of cancer vasculogenesis and augmenting treatment modalities.
... Cells were plated in 96-well plates (Sarstedt; Germany; 3000 cell/well) or into T25 flasks (Sarstedt; 2.5 ×10 4 cells per flask) and after 24 h, the following treatments were added in refreshed media for 72 h: tacrolimus (TAC; 10 and 50 ng/mL; Merck; USA (NJ)), rapamycin (RAPA; 10 and 50 ng/mL; Merck) and PP242 (1 μM; Tocris; UK). The applied concentrations were selected based on the recommended IS serum levels [34,35] and our previous studies [36][37][38]. Long-term TAC treatment (10 ng/mL; 21-day) was also applied in all cell lines. ...
Background
Kidney transplant recipients (KTRs) face an increased risk of renal cell carcinoma (RCC), in which the immunosuppressive regimen plays an important role. This study aimed to identify intracellular signalling alterations associated with post-transplant (post-tx) tumour formation.
Methods
Expression of mTOR-related proteins were analysed in kidneys obtained from end-stage renal disease (ESRD) patients and RCCs developed in KTRs or non-transplant patients. The effects of tacrolimus (TAC) and rapamycin (RAPA) on mTOR activity, proliferation, and tumour growth were investigated through different in vitro and in vivo experiments.
Results
Elevated mTORC1/C2 activity was observed in post-tx RCCs and in kidneys of TAC-treated ESRD patients. In vitro experiments demonstrated that TAC increases mTOR activity in a normal tubular epithelial cell line and in the investigated RCC cell lines, moreover, promotes the proliferation of some RCC cell line. In vivo, TAC elevated mTORC1/C2 activity in ischaemic kidneys of mice and enhanced tumour growth in xenograft model.
Conclusions
We observed significantly increased mTOR activity in ischaemic kidneys and post-tx RCCs, which highlights involvement of mTOR pathway both in the healing or fibrotic processes of kidney and in tumorigenesis. TAC-treatment further augmented the already elevated mTOR activity of injured kidney, potentially contributing to tumorigenesis during immunosuppression.
... In cancer research, these models can accurately replicate a patient's cancer cells and cultivate threedimensional tumor models, providing a more realistic experimental platform for studying the mechanisms of cancer development and evaluating the effectiveness of drugs [35]. On the other hand, cancer modeling utilizes 3D printing technology to create precise tumor models that surpass the limitations of traditional two-dimensional cell cultures [36]. These models incorporate features such as cell interactions, cell-matrix interactions, and vascular systems, facilitating in-depth studies on tumor growth, metastasis, drug responses, and the development of new treatment strategies. ...
3D printing technology is an increasing approach consisting of material manufacturing through the selective incremental delamination of materials to form a 3D structure to produce products. This technology has different advantages, including low cost, short time, diversification, and high precision. Widely adopted additive manufacturing technologies enable the creation of diagnostic tools and expand treatment options. Coupled with its rapid deployment, 3D printing is endowed with high customizability that enables users to build prototypes in shorts amounts of time which translates into faster adoption in the medical field. This review mainly summarizes the application of 3D printing technology in the diagnosis and treatment of cancer, including the challenges and the prospects combined with other technologies applied to the medical field.
... An overview of recent studies using 3D bioprinting to create preclinical models for different cancer types can be seen in Figure 3. Breast cancer is among the most prevalent cancer types worldwide and has an abnormally high risk of death after diagnosis for many more years compared to other cancer types [160]. As such, breast cancer is the most commonly researched cancer type among experimental papers [161]. Laser-based 3D bioprinting techniques have been previously used to produce breast cancer spheroids with high spatial control. ...
Simple Summary
Traditional preclinical testing, including 2D cell culture and animal models, often fails to accurately predict drug efficacy in humans, especially for oncology drugs, where drug candidates that enter clinical trials have very high failure rates. Advancements in biology and tissue engineering techniques allow researchers to evaluate drug candidates before human trials using 3D cell culture models that more closely resemble human tissues than 2D culture methods. These techniques can better mimic the patterns of drug diffusion, cell–cell signalling, and the presence of vasculature in tumours in vivo. Furthermore, the FDA Modernization Act 2.0 promotes the use of higher complexity in vitro models such as 3D cell cultures. By offering more accurate representations of human tissue, 3D culture platforms have the potential to enhance preclinical drug development and lead to safer and more effective cancer treatments.
Abstract
Prior to clinical trials, preclinical testing of oncology drug candidates is performed by evaluating drug candidates with in vitro and in vivo platforms. For in vivo testing, animal models are used to evaluate the toxicity and efficacy of drug candidates. However, animal models often display poor translational results as many drugs that pass preclinical testing fail when tested with humans, with oncology drugs exhibiting especially poor acceptance rates. The FDA Modernization Act 2.0 promotes alternative preclinical testing techniques, presenting the opportunity to use higher complexity in vitro models as an alternative to in vivo testing, including three-dimensional (3D) cell culture models. Three-dimensional tissue cultures address many of the shortcomings of 2D cultures by more closely replicating the tumour microenvironment through a combination of physiologically relevant drug diffusion, paracrine signalling, cellular phenotype, and vascularization that can better mimic native human tissue. This review will discuss the common forms of 3D cell culture, including cell spheroids, organoids, organs-on-a-chip, and 3D bioprinted tissues. Their advantages and limitations will be presented, aiming to discuss the use of these 3D models to accurately represent human tissue and as an alternative to animal testing. The use of 3D culture platforms for preclinical drug development is expected to accelerate as these platforms continue to improve in complexity, reliability, and translational predictivity.
... An overview of recent studies using 3D bioprinting to create preclinical models for different cancer types can be seen in Figure 3. Breast cancer is among the most prevalent cancer types worldwide and has an abnormally high risk of death after diagnosis for many more years compared to other cancer types [157]. As such, breast cancer is the most commonly researched cancer type among experimental papers [158]. Laserbased 3D bioprinting techniques have been previously used to produce breast cancer spheroids with high spatial control. ...
Prior to clinical trials, preclinical testing of oncology drug candidates is performed by evaluating drug candidates with in vitro and in vivo platforms. For in vivo testing, animal models are used to evaluate the toxicity and efficacy of drug candidates. However, animal models often display poor translational results as many drugs that pass preclinical testing fail when tested in humans, with oncology drugs exhibiting especially poor acceptance rates. The FDA Modernization Act 2.0 promotes alternative preclinical testing techniques, presenting the opportunity to use higher complexity in vitro models as an alternative to in vivo testing, including 3D cell culture models. 3D tissue cultures address many of the shortcomings of 2D cultures by more closely replicating the tumour microenvironment through a combination of realistic drug diffusion, paracrine signaling, cellular phenotype, and vascularization that can better mimic native human tissue. This review will discuss the common forms of 3D cell culture, including cell spheroids, organoids, organs-on-a-chip, and 3D bioprinted tissues. Their advantages and limitations will be presented, aiming to discuss the use of these 3D models to accurately represent human tissue and as an alternative to animal testing. The use of 3D culture platforms for preclinical drug development is expected to accelerate as these platforms continue to improve in complexity, reliability, and translational predictivity.
... Several reviews already discussed the advantages and disadvantages of using 3D versus 2D cultures in cancer research. They listed different 3D culture models, including spheroids grown on ultra-low attachment plates or in spinner flasks, synthetic or natural hydrogel models and 3D-printed scaffolds, microfluidic organ-on-a-chip models, and cell line or patient-derived xenografts, and discussed their applications and limitations [351][352][353][354][355][356][357][358][359][360]. The ability of 3D models to mimic the architecture and microenvironment of tumors enables the maintenance of undifferentiated states and cancer stem-cell-like properties, providing insight into the role of CSC in cancer initiation, progression, and resistance to treatment. ...
Breast cancer (BC) and ovarian cancer (OC) are among the most common and deadly cancers affecting women worldwide. Both are complex diseases with marked heterogeneity. Despite the induction of screening programs that increase the frequency of earlier diagnosis of BC, at a stage when the cancer is more likely to respond to therapy, which does not exist for OC, more than 50% of both cancers are diagnosed at an advanced stage. Initial therapy can put the cancer into remission. However, recurrences occur frequently in both BC and OC, which are highly cancer-subtype dependent. Therapy resistance is mainly attributed to a rare subpopulation of cells, named cancer stem cells (CSC) or tumor-initiating cells, as they are capable of self-renewal, tumor initiation, and regrowth of tumor bulk. In this review, we will discuss the distinctive markers and signaling pathways that characterize CSC, their interactions with the tumor microenvironment, and the strategies they employ to evade immune surveillance. Our focus will be on identifying the common features of breast cancer stem cells (BCSC) and ovarian cancer stem cells (OCSC) and suggesting potential therapeutic approaches.
... Along with the development of increasingly effective technologies for recreating in vitro tissues using 3D bioprinting, various models of both healthy and tumor tissues have been developed [158][159][160]. The major limitation of the other tumor models lies in replicating exact tumor physiological conditions, including the TME composition in terms of matrix and cells composition. ...
Cancer is intrinsically complex, comprising both heterogeneous cellular composition and extracellular matrix. In vitro cancer research models have been widely used in the past to model and study cancer. Although two-dimensional (2D) cell culture models have traditionally been used for cancer research, they have many limitations, such as the disturbance of interactions between cellular and extracellular environments and changes in cell morphology, polarity, division mechanism, differentiation and cell motion. Moreover, 2D cell models are usually monotypic. This implies that 2D tumor models are ineffective at accurately recapitulating complex aspects of tumor cell growth, as well as their radiation responses. Over the past decade there has been significant uptake of three-dimensional (3D) in vitro models by cancer researchers, highlighting a complementary model for studies of radiation effects on tumors, especially in conjunction with chemotherapy. The introduction of 3D cell culture approaches aims to model in vivo tissue interactions with radiation by positioning itself halfway between 2D cell and animal models, and thus opening up new possibilities in the study of radiation response mechanisms of healthy and tumor tissues.
... In recent years, three-dimensional (3D) bioprinting has been widely utilized as a novel manufacturing technique by more and more tissue engineering researchers to construct various organ or tissue substitutes with complex architectures and geometries [1][2][3]. Moreover, 3D bioprinting, integrating regenerative medicine, 3D printing, biomaterials, and tissue engineering can construct tissue or organ substitutes by accurately bioprinting various bioinks layer by layer via a computer-controlled dispensing system [4][5][6]. In the field of tissue engineering and regenerative medicine, 3D bioprinting technology utilizes hydrogels as bioinks to load various cells to fabricate tissue substitutes [7]. ...
In recent years, three-dimensional (3D) bioprinting has been widely utilized as a novel manufacturing technique by more and more researchers to construct various tissue substitutes with complex architectures and geometries. Different biomaterials, including natural and synthetic materials, have been manufactured into bioinks for tissue regeneration using 3D bioprinting. Among the natural biomaterials derived from various natural tissues or organs, the decellularized extracellular matrix (dECM) has a complex internal structure and a variety of bioactive factors that provide mechanistic, biophysical, and biochemical signals for tissue regeneration and remodeling. In recent years, more and more researchers have been developing the dECM as a novel bioink for the construction of tissue substitutes. Compared with other bioinks, the various ECM components in dECM-based bioink can regulate cellular functions, modulate the tissue regeneration process, and adjust tissue remodeling. Therefore, we conducted this review to discuss the current status of and perspectives on dECM-based bioinks for bioprinting in tissue engineering. In addition, the various bioprinting techniques and decellularization methods were also discussed in this study.
Drug resistance that affects patients universally is a major challenge in cancer therapy. The development of drug resistance in cancer cells is a multifactor event, and its process involves numerous mechanisms that allow these cells to evade the effect of treatments. As a result, the need to understand the molecular mechanisms underlying cancer drug sensitivity is imperative. Traditional 2D cell culture systems have been utilized to study drug resistance, but they often fail to mimic the 3D milieu and the architecture of real tissues and cell-cell interactions. As a result of this, 3D cell culture systems are now considered a comprehensive model to study drug resistance in vitro . Cancer cells exhibit an in vivo behavior when grown in a three-dimensional environment and react to therapy more physiologically. In this review, we discuss the relevance of main 3D culture systems in the study of potential approaches to overcome drug resistance and in the identification of personalized drug targets with the aim of developing patient-specific treatment strategies that can be put in place when resistance emerges.
