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Biomaterial-Assisted 3D In Vitro Tumor Models: From Organoid towards Cancer...
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Biomaterial-Assisted 3D In Vitro Tumor Models: From Organoid towards Cancer Tissue Engineering Approaches

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (1 March 2022) | Viewed by 62199

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Dr. Serena Danti

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Guest Editor
Department of Civil and Industrial Engineering, University of Pisa, Largo L. Lazzarino 2, 56122 Pisa, Italy
Interests: electrospinning; biomaterials; biomedical polymers; piezoelectric materials; smart materials; tissue engineering; advanced in vitro models
Special Issues, Collections and Topics in MDPI journals
Dr. Nicola Contessi Negrini

E-Mail Website
Guest Editor
Department of Bioengineering, Imperial College London, South Kensington, SW7 2AZ, London, United Kingdom
Prof. Alessandro Franchi

E-Mail Website
Guest Editor
Department of Translational Research and of New Technologies in Medicine and Surgery, University of Pisa, via Savi 2, 56126 Pisa, Italy
Interests: sinonasal cancer; synovial chondrosarcoma;ameloblastic fibrosarcoma; clinical pathology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The structural and biological complexity of tumors represents a great challenge for the development of effective therapies and drugs. Traditional in vitro cultures are inherently bi-dimensional (2D), whereas in vivo animal models are inherently nonhuman and therefore affected by drawbacks that slow down and limit advancements in cancer research. In this scenario, biomaterial-assisted 3D in vitro models are currently catalyzing high interest, as they can provide more reliable answers toward a better understanding of tumor biology and personalized screening of existing and new therapies. By using biomaterials to generate 3D structures, such as hydrogels and porous scaffolds, 3D in vitro models can overcome the oversimplification of traditional cell cultures by offering a physiological-like microenvironment for cancer cell growth and interaction with diverse cell types. Moreover, these models are not affected by the variability and ethical issues related to in vivo animal models, thus representing a powerful tool in cancer research.

The potential of biomaterial-assisted approaches, including organoids and tissue engineering, for the development of in vitro cancer models, has opened up exciting frontiers and associated new challenges to be tackled in order to obtain cellular constructs that correctly resemble the tumor/pathological microenvironment. These challenges regard the choice of the biomaterial, the set-up of appropriate fabrication technologies able to control physical, mechanical, and biological cues so as to resemble in vitro the complexity of the pathological tissue, the understanding of the cancer cell/biomaterial interaction, the obtainment of multicell type constructs, and their standardized use for new drug/therapeutic discovery, as well as the study of cancer development, progression, and metastasis within such 3D microenvironments.

This Special Issue covers current research (by original research papers, review articles, and short communications) that focuses on the development and study of innovative biomaterial-assisted strategies to recapitulate in vitro, within a 3D microenvironment, the formation of cancer, the spread of metastasis, and all the related aspects aimed to provide an advancement in the study of tumor pathology for oncologic research to be also implemented for drug screening.

Dr. Serena Danti
Dr. Nicola Contessi Negrini
Dr. Alessandro Franchi
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • in vitro tumor model
  • 3D cell culture
  • cancer model
  • scaffold
  • biomaterial
  • organoid

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Published Papers (14 papers)

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Editorial

Jump to: Research, Review, Other

3 pages, 195 KiB  
Editorial
Biomaterial-Assisted 3D In Vitro Tumor Models: From Organoid towards Cancer Tissue Engineering Approaches
by Nicola Contessi Negrini, Alessandro Franchi and Serena Danti
Cancers 2023, 15(4), 1201; https://doi.org/10.3390/cancers15041201 - 14 Feb 2023
Cited by 3 | Viewed by 1602
Abstract
Cancers are a leading cause of death around the world, accounting for nearly 10 million deaths yearly [...] Full article
(This article belongs to the Special Issue Biomaterial-Assisted 3D In Vitro Tumor Models: From Organoid towards Cancer Tissue Engineering Approaches)

Research

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24 pages, 7426 KiB  
Article
3D Disease Modelling of Hard and Soft Cancer Using PHA-Based Scaffolds
by Akanksha Tomar, Pinar Uysal-Onganer, Pooja Basnett, Uttam Pati and Ipsita Roy
Cancers 2022, 14(14), 3549; https://doi.org/10.3390/cancers14143549 - 21 Jul 2022
Cited by 5 | Viewed by 2824
Abstract
Tumour cells are shown to change shape and lose polarity when they are cultured in 3D, a feature typically associated with tumour progression in vivo, thus making it significant to study cancer cells in an environment that mimics the in vivo milieu. In [...] Read more.
Tumour cells are shown to change shape and lose polarity when they are cultured in 3D, a feature typically associated with tumour progression in vivo, thus making it significant to study cancer cells in an environment that mimics the in vivo milieu. In this study we established hard (MCF7 and MDA-MB-231, breast cancer) and soft (HCT116, colon cancer) 3D cancer tumour models utilizing a blend of P(3HO-co-3HD) and P(3HB). P(3HO-co-3HD) and P(3HB) belong to a group of natural biodegradable polyesters, PHAs, that are synthesised by microorganisms. The 3D PHA scaffolds produced, with a pore size of 30 to 300 µm, allow for nutrients to diffuse within the scaffold and provide the cells with the flexibility to distribute evenly within the scaffold and grow within the pores. Interestingly, by Day 5, MDA-MB-231 showed dispersed growth in clusters, and MCF7 cells formed an evenly dispersed dense layer, while HCT116 formed large colonies within the pockets of the 3D PHA scaffolds. Our results show Epithelial Mesenchymal Transition (EMT) marker gene expression profiles in the hard tumour cancer models. In the 3D-based PHA scaffolds, MDA-MB-231 cells expressed higher levels of Wnt-11 and mesenchymal markers, such as Snail and its downstream gene Vim mRNAs, while MCF7 cells exhibited no change in their expression. On the other hand, MCF7 cells exhibited a significantly increased E-Cadherin expression as compared to MDA-MB-231 cells. The expression levels of EMT markers were comparative to their expression reported in the tumour samples, making them good representative of cancer models. In future these models will be helpful in mimicking hypoxic tumours, in studying gene expression, cellular signalling, angiogenesis and drug response more accurately than 2D and perhaps other 3D models. Full article
(This article belongs to the Special Issue Biomaterial-Assisted 3D In Vitro Tumor Models: From Organoid towards Cancer Tissue Engineering Approaches)
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20 pages, 5516 KiB  
Article
An Osteosarcoma Model by 3D Printed Polyurethane Scaffold and In Vitro Generated Bone Extracellular Matrix
by Nicola Contessi Negrini, Claudio Ricci, Federica Bongiorni, Luisa Trombi, Delfo D’Alessandro, Serena Danti and Silvia Farè
Cancers 2022, 14(8), 2003; https://doi.org/10.3390/cancers14082003 - 15 Apr 2022
Cited by 20 | Viewed by 3288
Abstract
Osteosarcoma is a primary bone tumor characterized by a dismal prognosis, especially in the case of recurrent disease or metastases. Therefore, tools to understand in-depth osteosarcoma progression and ultimately develop new therapeutics are urgently required. 3D in vitro models can provide an optimal [...] Read more.
Osteosarcoma is a primary bone tumor characterized by a dismal prognosis, especially in the case of recurrent disease or metastases. Therefore, tools to understand in-depth osteosarcoma progression and ultimately develop new therapeutics are urgently required. 3D in vitro models can provide an optimal option, as they are highly reproducible, yet sufficiently complex, thus reliable alternatives to 2D in vitro and in vivo models. Here, we describe 3D in vitro osteosarcoma models prepared by printing polyurethane (PU) by fused deposition modeling, further enriched with human mesenchymal stromal cell (hMSC)-secreted biomolecules. We printed scaffolds with different morphologies by changing their design (i.e., the distance between printed filaments and printed patterns) to obtain different pore geometry, size, and distribution. The printed PU scaffolds were stable during in vitro cultures, showed adequate porosity (55–67%) and tunable mechanical properties (Young’s modulus ranging in 0.5–4.0 MPa), and resulted in cytocompatible. We developed the in vitro model by seeding SAOS-2 cells on the optimal PU scaffold (i.e., 0.7 mm inter-filament distance, 60° pattern), by testing different pre-conditioning factors: none, undifferentiated hMSC-secreted, and osteo-differentiated hMSC-secreted extracellular matrix (ECM), which were obtained by cell lysis before SAOS-2 seeding. Scaffolds pre-cultured with osteo-differentiated hMSCs, subsequently lysed, and seeded with SAOS-2 cells showed optimal colonization, thus disclosing a suitable biomimetic microenvironment for osteosarcoma cells, which can be useful both in tumor biology study and, possibly, treatment. Full article
(This article belongs to the Special Issue Biomaterial-Assisted 3D In Vitro Tumor Models: From Organoid towards Cancer Tissue Engineering Approaches)
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23 pages, 7390 KiB  
Article
A Systematic Comparative Assessment of the Response of Ovarian Cancer Cells to the Chemotherapeutic Cisplatin in 3D Models of Various Structural and Biochemical Configurations—Does One Model Type Fit All?
by Priyanka Gupta, Aline Miller, Adedamola Olayanju, Thumuluru Kavitha Madhuri and Eirini Velliou
Cancers 2022, 14(5), 1274; https://doi.org/10.3390/cancers14051274 - 1 Mar 2022
Cited by 9 | Viewed by 3826
Abstract
Epithelial Ovarian Cancer (EOC) is a silent, deadly and aggressive gynaecological disease with a relatively low survival rate. This has been attributed, to some extent, to EOC’s high recurrence rate and resistance to currently available platinum-based chemotherapeutic treatment methods. Multiple groups have studied [...] Read more.
Epithelial Ovarian Cancer (EOC) is a silent, deadly and aggressive gynaecological disease with a relatively low survival rate. This has been attributed, to some extent, to EOC’s high recurrence rate and resistance to currently available platinum-based chemotherapeutic treatment methods. Multiple groups have studied and reported the effect of chemotherapeutic agents on various EOC 3D in vitro models. However, there are very few studies wherein a direct comparative study has been carried out between the different in vitro 3D models of EOC and the effect of chemotherapy within them. Herein, we report, for the first time, a direct comprehensive systematic comparative study of three different 3D in vitro platforms, namely (i) spheroids, (ii) synthetic PeptiGels/hydrogels of various chemical configurations and (iii) polymeric scaffolds with coatings of various extracellular matrices (ECMs) on the cell growth and response to the chemotherapeutic (Cisplatin) for ovary-derived (A2780) and metastatic (SK-OV-3) EOC cell lines. We report that all three 3D models are able to support the growth of EOC, but for different time periods (varying from 7 days to 4 weeks). We have also reported that chemoresistance to Cisplatin, in vitro, observed especially for metastatic EOC cells, is platform-dependent, in terms of both the structural and biochemical composition of the model/platform. Our study highlights the importance of selecting an appropriate 3D platform for in vitro tumour model development. We have demonstrated that the selection of the best platform for producing in vitro tumour models depends on the cancer/cell type, the experimental time period and the application for which the model is intended. Full article
(This article belongs to the Special Issue Biomaterial-Assisted 3D In Vitro Tumor Models: From Organoid towards Cancer Tissue Engineering Approaches)
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19 pages, 82686 KiB  
Article
Longitudinal Monitoring of Intra-Tumoural Heterogeneity Using Optical Barcoding of Patient-Derived Colorectal Tumour Models
by Carolyn Shembrey, Jai Smith, Mélodie Grandin, Nathalia Williams, Hyun-Jung Cho, Christina Mølck, Corina Behrenbruch, Benjamin NJ. Thomson, Alexander G. Heriot, Delphine Merino and Frédéric Hollande
Cancers 2022, 14(3), 581; https://doi.org/10.3390/cancers14030581 - 24 Jan 2022
Cited by 5 | Viewed by 4182
Abstract
Geno- and phenotypic heterogeneity amongst cancer cell subpopulations are established drivers of treatment resistance and tumour recurrence. However, due to the technical difficulty associated with studying such intra-tumoural heterogeneity, this phenomenon is seldom interrogated in conventional cell culture models. Here, we employ a [...] Read more.
Geno- and phenotypic heterogeneity amongst cancer cell subpopulations are established drivers of treatment resistance and tumour recurrence. However, due to the technical difficulty associated with studying such intra-tumoural heterogeneity, this phenomenon is seldom interrogated in conventional cell culture models. Here, we employ a fluorescent lineage technique termed “optical barcoding” (OBC) to perform simultaneous longitudinal tracking of spatio-temporal fate in 64 patient-derived colorectal cancer subclones. To do so, patient-derived cancer cell lines and organoids were labelled with discrete combinations of reporter constructs, stably integrated into the genome and thus passed on from the founder cell to all its clonal descendants. This strategy enables the longitudinal monitoring of individual cell lineages based upon their unique optical barcodes. By designing a novel panel of six fluorescent proteins, the maximum theoretical subpopulation resolution of 64 discriminable subpopulations was achieved, greatly improving throughput compared with previous studies. We demonstrate that all subpopulations can be purified from complex clonal mixtures via flow cytometry, permitting the downstream isolation and analysis of any lineages of interest. Moreover, we outline an optimized imaging protocol that can be used to image optical barcodes in real-time, allowing for clonal dynamics to be resolved in live cells. In contrast with the limited intra-tumour heterogeneity observed in conventional 2D cell lines, the OBC technique was successfully used to quantify dynamic clonal expansions and contractions in 3D patient-derived organoids, which were previously demonstrated to better recapitulate the heterogeneity of their parental tumour material. In summary, we present OBC as a user-friendly, inexpensive, and high-throughput technique for monitoring intra-tumoural heterogeneity in in vitro cell culture models. Full article
(This article belongs to the Special Issue Biomaterial-Assisted 3D In Vitro Tumor Models: From Organoid towards Cancer Tissue Engineering Approaches)
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18 pages, 5773 KiB  
Article
On the Evaluation of a Novel Hypoxic 3D Pancreatic Cancer Model as a Tool for Radiotherapy Treatment Screening
by Gabrielle Wishart, Priyanka Gupta, Andrew Nisbet, Giuseppe Schettino and Eirini Velliou
Cancers 2021, 13(23), 6080; https://doi.org/10.3390/cancers13236080 - 2 Dec 2021
Cited by 15 | Viewed by 3799
Abstract
Tissue engineering is evolving to mimic intricate ecosystems of tumour microenvironments (TME) to more readily map realistic in vivo niches of cancerous tissues. Such advanced cancer tissue models enable more accurate preclinical assessment of treatment strategies. Pancreatic cancer is a dangerous disease with [...] Read more.
Tissue engineering is evolving to mimic intricate ecosystems of tumour microenvironments (TME) to more readily map realistic in vivo niches of cancerous tissues. Such advanced cancer tissue models enable more accurate preclinical assessment of treatment strategies. Pancreatic cancer is a dangerous disease with high treatment resistance that is directly associated with a highly complex TME. More specifically, the pancreatic cancer TME includes (i) complex structure and complex extracellular matrix (ECM) protein composition; (ii) diverse cell populations (e.g., stellate cells), cancer associated fibroblasts, endothelial cells, which interact with the cancer cells and promote resistance to treatment and metastasis; (iii) accumulation of high amounts of (ECM), which leads to the creation of a fibrotic/desmoplastic reaction around the tumour; and (iv) heterogeneous environmental gradients such as hypoxia, which result from vessel collapse and stiffness increase in the fibrotic/desmoplastic area of the TME. These unique hallmarks are not effectively recapitulated in traditional preclinical research despite radiotherapeutic resistance being largely connected to them. Herein, we investigate, for the first time, the impact of in vitro hypoxia (5% O2) on the radiotherapy treatment response of pancreatic cancer cells (PANC-1) in a novel polymer (polyurethane) based highly macroporous scaffold that was surface modified with proteins (fibronectin) for ECM mimicry. More specifically, PANC-1 cells were seeded in fibronectin coated macroporous scaffolds and were cultured for four weeks in in vitro normoxia (21% O2), followed by a two day exposure to either in vitro hypoxia (5% O2) or maintenance in in vitro normoxia. Thereafter, in situ post-radiation monitoring (one day, three days, seven days post-irradiation) of the 3D cell cultures took place via quantification of (i) live/dead and apoptotic profiles and (ii) ECM (collagen-I) and HIF-1a secretion by the cancer cells. Our results showed increased post-radiation viability, reduced apoptosis, and increased collagen-I and HIF-1a secretion in in vitro hypoxia compared to normoxic cultures, revealing hypoxia-induced radioprotection. Overall, this study employed a low cost, animal free model enabling (i) the possibility of long-term in vitro hypoxic 3D cell culture for pancreatic cancer, and (ii) in vitro hypoxia associated PDAC radio-protection development. Our novel platform for radiation treatment screening can be used for long-term in vitro post-treatment observations as well as for fractionated radiotherapy treatment. Full article
(This article belongs to the Special Issue Biomaterial-Assisted 3D In Vitro Tumor Models: From Organoid towards Cancer Tissue Engineering Approaches)
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26 pages, 8073 KiB  
Article
Brain and Breast Cancer Cells with PTEN Loss of Function Reveal Enhanced Durotaxis and RHOB Dependent Amoeboid Migration Utilizing 3D Scaffolds and Aligned Microfiber Tracts
by Annalena Wieland, Pamela L. Strissel, Hannah Schorle, Ezgi Bakirci, Dieter Janzen, Matthias W. Beckmann, Markus Eckstein, Paul D. Dalton and Reiner Strick
Cancers 2021, 13(20), 5144; https://doi.org/10.3390/cancers13205144 - 14 Oct 2021
Cited by 7 | Viewed by 3931
Abstract
Background: Glioblastoma multiforme (GBM) and metastatic triple-negative breast cancer (TNBC) with PTEN mutations often lead to brain dissemination with poor patient outcome, thus new therapeutic targets are needed. To understand signaling, controlling the dynamics and mechanics of brain tumor cell migration, we implemented [...] Read more.
Background: Glioblastoma multiforme (GBM) and metastatic triple-negative breast cancer (TNBC) with PTEN mutations often lead to brain dissemination with poor patient outcome, thus new therapeutic targets are needed. To understand signaling, controlling the dynamics and mechanics of brain tumor cell migration, we implemented GBM and TNBC cell lines and designed 3D aligned microfibers and scaffolds mimicking brain structures. Methods: 3D microfibers and scaffolds were printed using melt electrowriting. GBM and TNBC cell lines with opposing PTEN genotypes were analyzed with RHO-ROCK-PTEN inhibitors and PTEN rescue using live-cell imaging. RNA-sequencing and qPCR of tumor cells in 3D with microfibers were performed, while scanning electron microscopy and confocal microscopy addressed cell morphology. Results: In contrast to the PTEN wildtype, GBM and TNBC cells with PTEN loss of function yielded enhanced durotaxis, topotaxis, adhesion, amoeboid migration on 3D microfibers and significant high RHOB expression. Functional studies concerning RHOB-ROCK-PTEN signaling confirmed the essential role for the above cellular processes. Conclusions: This study demonstrates a significant role of the PTEN genotype and RHOB expression for durotaxis, adhesion and migration dependent on 3D. GBM and TNBC cells with PTEN loss of function have an affinity for stiff brain structures promoting metastasis. 3D microfibers represent an important tool to model brain metastasizing tumor cells, where RHO-inhibitors could play an essential role for improved therapy. Full article
(This article belongs to the Special Issue Biomaterial-Assisted 3D In Vitro Tumor Models: From Organoid towards Cancer Tissue Engineering Approaches)
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Graphical abstract

20 pages, 10482 KiB  
Article
Erlotinib Promotes Ligand-Induced EGFR Degradation in 3D but Not 2D Cultures of Pancreatic Ductal Adenocarcinoma Cells
by Nausika Betriu, Anna Andreeva and Carlos E. Semino
Cancers 2021, 13(18), 4504; https://doi.org/10.3390/cancers13184504 - 7 Sep 2021
Cited by 10 | Viewed by 3792
Abstract
The epithelial growth factor receptor (EGFR) is a tyrosine kinase receptor that participates in many biological processes such as cell proliferation. In addition, EGFR is overexpressed in many epithelial cancers and therefore is a target for cancer therapy. Moreover, EGFR responds to lots [...] Read more.
The epithelial growth factor receptor (EGFR) is a tyrosine kinase receptor that participates in many biological processes such as cell proliferation. In addition, EGFR is overexpressed in many epithelial cancers and therefore is a target for cancer therapy. Moreover, EGFR responds to lots of stimuli by internalizing into endosomes from where it can be recycled to the membrane or further sorted into lysosomes where it undergoes degradation. Two-dimensional cell cultures have been classically used to study EGFR trafficking mechanisms in cancer cells. However, it has been widely demonstrated that in 2D cultures cells are exposed to a non-physiological environment as compared to 3D cultures that provide the normal cellular conformation, matrix dimensionality and stiffness, as well as molecular gradients. Therefore, the microenvironment of solid tumors is better recreated in 3D culture models, and this is why they are becoming a more physiological alternative to study cancer physiology. Here, we develop a new model of EGFR internalization and degradation upon erlotinib treatment in pancreatic ductal adenocarcinoma (PDAC) cells cultured in a 3D self-assembling peptide scaffold. In this work, we show that treatment with the tyrosine kinase inhibitor erlotinib promotes EGFR degradation in 3D cultures of PDAC cell lines but not in 2D cultures. We also show that this receptor degradation does not occur in normal fibroblast cells, regardless of culture dimensionality. In conclusion, we demonstrate not only that erlotinib has a distinct effect on tumor and normal cells but also that pancreatic ductal adenocarcinoma cells respond differently to drug treatment when cultured in a 3D microenvironment. This study highlights the importance of culture systems that can more accurately mimic the in vivo tumor physiology. Full article
(This article belongs to the Special Issue Biomaterial-Assisted 3D In Vitro Tumor Models: From Organoid towards Cancer Tissue Engineering Approaches)
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Graphical abstract

Review

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29 pages, 5088 KiB  
Review
Tumor Microenvironment and Hydrogel-Based 3D Cancer Models for In Vitro Testing Immunotherapies
by Chiara Vitale, Monica Marzagalli, Silvia Scaglione, Alessandra Dondero, Cristina Bottino and Roberta Castriconi
Cancers 2022, 14(4), 1013; https://doi.org/10.3390/cancers14041013 - 17 Feb 2022
Cited by 26 | Viewed by 5617
Abstract
In recent years, immunotherapy has emerged as a promising novel therapeutic strategy for cancer treatment. In a relevant percentage of patients, however, clinical benefits are lower than expected, pushing researchers to deeply analyze the immune responses against tumors and find more reliable and [...] Read more.
In recent years, immunotherapy has emerged as a promising novel therapeutic strategy for cancer treatment. In a relevant percentage of patients, however, clinical benefits are lower than expected, pushing researchers to deeply analyze the immune responses against tumors and find more reliable and efficient tools to predict the individual response to therapy. Novel tissue engineering strategies can be adopted to realize in vitro fully humanized matrix-based models, as a compromise between standard two-dimensional (2D) cell cultures and animal tests, which are costly and hardly usable in personalized medicine. In this review, we describe the main mechanisms allowing cancer cells to escape the immune surveillance, which may play a significant role in the failure of immunotherapies. In particular, we discuss the role of the tumor microenvironment (TME) in the establishment of a milieu that greatly favors cancer malignant progression and impact on the interactions with immune cells. Then, we present an overview of the recent in vitro engineered preclinical three-dimensional (3D) models that have been adopted to resemble the interplays between cancer and immune cells and for testing current therapies and immunotherapeutic approaches. Specifically, we focus on 3D hydrogel-based tools based on different types of polymers, discussing the suitability of each of them in reproducing the TME key features based on their intrinsic or tunable characteristics. Finally, we introduce the possibility to combine the 3D models with technological fluid dynamics platforms, reproducing the dynamic complex interactions between tumor cells and immune effectors migrated in situ via the systemic circulation, pointing out the challenges that still have to be overcome for setting more predictive preclinical assays. Full article
(This article belongs to the Special Issue Biomaterial-Assisted 3D In Vitro Tumor Models: From Organoid towards Cancer Tissue Engineering Approaches)
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24 pages, 2214 KiB  
Review
3D Printing and Bioprinting to Model Bone Cancer: The Role of Materials and Nanoscale Cues in Directing Cell Behavior
by Tiziana Fischetti, Gemma Di Pompo, Nicola Baldini, Sofia Avnet and Gabriela Graziani
Cancers 2021, 13(16), 4065; https://doi.org/10.3390/cancers13164065 - 12 Aug 2021
Cited by 25 | Viewed by 5246
Abstract
Bone cancer, both primary and metastatic, is characterized by a low survival rate. Currently, available models lack in mimicking the complexity of bone, of cancer, and of their microenvironment, leading to poor predictivity. Three-dimensional technologies can help address this need, by developing predictive [...] Read more.
Bone cancer, both primary and metastatic, is characterized by a low survival rate. Currently, available models lack in mimicking the complexity of bone, of cancer, and of their microenvironment, leading to poor predictivity. Three-dimensional technologies can help address this need, by developing predictive models that can recapitulate the conditions for cancer development and progression. Among the existing tools to obtain suitable 3D models of bone cancer, 3D printing and bioprinting appear very promising, as they enable combining cells, biomolecules, and biomaterials into organized and complex structures that can reproduce the main characteristic of bone. The challenge is to recapitulate a bone-like microenvironment for analysis of stromal–cancer cell interactions and biological mechanics leading to tumor progression. In this review, existing approaches to obtain in vitro 3D-printed and -bioprinted bone models are discussed, with a focus on the role of biomaterials selection in determining the behavior of the models and its degree of customization. To obtain a reliable 3D bone model, the evaluation of different polymeric matrices and the inclusion of ceramic fillers is of paramount importance, as they help reproduce the behavior of both normal and cancer cells in the bone microenvironment. Open challenges and future perspectives are discussed to solve existing shortcomings and to pave the way for potential development strategies. Full article
(This article belongs to the Special Issue Biomaterial-Assisted 3D In Vitro Tumor Models: From Organoid towards Cancer Tissue Engineering Approaches)
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Graphical abstract

28 pages, 1631 KiB  
Review
Printing the Pathway Forward in Bone Metastatic Cancer Research: Applications of 3D Engineered Models and Bioprinted Scaffolds to Recapitulate the Bone–Tumor Niche
by Anne M. Hughes, Alexus D. Kolb, Alison B. Shupp, Kristy M. Shine and Karen M. Bussard
Cancers 2021, 13(3), 507; https://doi.org/10.3390/cancers13030507 - 29 Jan 2021
Cited by 21 | Viewed by 5253
Abstract
Breast cancer commonly metastasizes to bone, resulting in osteolytic lesions and poor patient quality of life. The bone extracellular matrix (ECM) plays a critical role in cancer cell metastasis by means of the physical and biochemical cues it provides to support cellular crosstalk. [...] Read more.
Breast cancer commonly metastasizes to bone, resulting in osteolytic lesions and poor patient quality of life. The bone extracellular matrix (ECM) plays a critical role in cancer cell metastasis by means of the physical and biochemical cues it provides to support cellular crosstalk. Current two-dimensional in-vitro models lack the spatial and biochemical complexities of the native ECM and do not fully recapitulate crosstalk that occurs between the tumor and endogenous stromal cells. Engineered models such as bone-on-a-chip, extramedullary bone, and bioreactors are presently used to model cellular crosstalk and bone–tumor cell interactions, but fall short of providing a bone-biomimetic microenvironment. Three-dimensional bioprinting allows for the deposition of biocompatible materials and living cells in complex architectures, as well as provides a means to better replicate biological tissue niches in-vitro. In cancer research specifically, 3D constructs have been instrumental in seminal work modeling cancer cell dissemination to bone and bone–tumor cell crosstalk in the skeleton. Furthermore, the use of biocompatible materials, such as hydroxyapatite, allows for printing of bone-like microenvironments with the ability to be implanted and studied in in-vivo animal models. Moreover, the use of bioprinted models could drive the development of novel cancer therapies and drug delivery vehicles. Full article
(This article belongs to the Special Issue Biomaterial-Assisted 3D In Vitro Tumor Models: From Organoid towards Cancer Tissue Engineering Approaches)
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24 pages, 1276 KiB  
Review
Three-Dimensional Culture System of Cancer Cells Combined with Biomaterials for Drug Screening
by Teruki Nii, Kimiko Makino and Yasuhiko Tabata
Cancers 2020, 12(10), 2754; https://doi.org/10.3390/cancers12102754 - 24 Sep 2020
Cited by 118 | Viewed by 11929
Abstract
Anticancer drug screening is one of the most important research and development processes to develop new drugs for cancer treatment. However, there is a problem resulting in gaps between the in vitro drug screening and preclinical or clinical study. This is mainly because [...] Read more.
Anticancer drug screening is one of the most important research and development processes to develop new drugs for cancer treatment. However, there is a problem resulting in gaps between the in vitro drug screening and preclinical or clinical study. This is mainly because the condition of cancer cell culture is quite different from that in vivo. As a trial to mimic the in vivo cancer environment, there has been some research on a three-dimensional (3D) culture system by making use of biomaterials. The 3D culture technologies enable us to give cancer cells an in vitro environment close to the in vivo condition. Cancer cells modified to replicate the in vivo cancer environment will promote the biological research or drug discovery of cancers. This review introduces the in vitro research of 3D cell culture systems with biomaterials in addition to a brief summary of the cancer environment. Full article
(This article belongs to the Special Issue Biomaterial-Assisted 3D In Vitro Tumor Models: From Organoid towards Cancer Tissue Engineering Approaches)
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Other

24 pages, 1211 KiB  
Systematic Review
The Development of a Three-Dimensional Platform for Patient-Derived Ovarian Cancer Tissue Models: A Systematic Literature Review
by Lusine Sevinyan, Priyanka Gupta, Eirini Velliou and Thumuluru Kavitha Madhuri
Cancers 2022, 14(22), 5628; https://doi.org/10.3390/cancers14225628 - 16 Nov 2022
Cited by 1 | Viewed by 1882
Abstract
There is an unmet biomedical need for ex vivo tumour models that would predict drug responses and in turn help determine treatment regimens and potentially predict resistance before clinical studies. Research has shown that three dimensional models of ovarian cancer (OvCa) are more [...] Read more.
There is an unmet biomedical need for ex vivo tumour models that would predict drug responses and in turn help determine treatment regimens and potentially predict resistance before clinical studies. Research has shown that three dimensional models of ovarian cancer (OvCa) are more realistic than two dimensional in vitro systems as they are able to capture patient in vivo conditions in more accurate manner. The vast majority of studies aiming to recapitulate the ovarian tumour morphology, behaviors, and study chemotherapy responses have been using ovarian cancer cell lines. However, despite the advantages of utilising cancer cell lines to set up a platform, they are not as informative as systems applying patient derived cells, as cell lines are not able to recapitulate differences between each individual patient characteristics. In this review we discussed the most recent advances in the creation of 3D ovarian cancer models that have used patient derived material, the challenges to overcome and future applications. Full article
(This article belongs to the Special Issue Biomaterial-Assisted 3D In Vitro Tumor Models: From Organoid towards Cancer Tissue Engineering Approaches)
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Commentary
Combined Application of Patient-Derived Cells and Biomaterials as 3D In Vitro Tumor Models
by Asbiel Hasbum, Ozan Karabulut, Ruben Edgar Reyes, Claudio Ricci, Alessandro Franchi, Serena Danti and Sue Anne Chew
Cancers 2022, 14(10), 2503; https://doi.org/10.3390/cancers14102503 - 19 May 2022
Cited by 8 | Viewed by 2209
Abstract
Although advances have been made in cancer therapy, cancer remains the second leading cause of death in the U.S. and Europe, and thus efforts to continue to study and discover better treatment methods are ongoing. Three-dimensional (3D) tumor models have shown advantages over [...] Read more.
Although advances have been made in cancer therapy, cancer remains the second leading cause of death in the U.S. and Europe, and thus efforts to continue to study and discover better treatment methods are ongoing. Three-dimensional (3D) tumor models have shown advantages over bi-dimensional (2D) cultures in evaluating the efficacy of chemotherapy. This commentary aims to highlight the potential of combined application of biomaterials with patient-derived cancer cells as a 3D in vitro model for the study and treatment of cancer patients. Five studies were discussed which demonstrate and provided early evidence to create 3D models with accurate microenvironments that are comparable to in vivo tumors. To date, the use of patient-derived cells for a more personalized approach to healthcare in combination with biomaterials to create a 3D tumor is still relatively new and uncommon for application in clinics. Although highly promising, it is important to acknowledge the current limitations and challenges of developing these innovative in vitro models, including the need for biologists and laboratory technicians to become familiar with biomaterial scaffolds, and the effort for bioengineers to create easy-to-handle scaffolds for routine assessment. Full article
(This article belongs to the Special Issue Biomaterial-Assisted 3D In Vitro Tumor Models: From Organoid towards Cancer Tissue Engineering Approaches)
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