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Cancers
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3D Cell Culture Cancer Models: Development and Applications 2.0
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3D Cell Culture Cancer Models: Development and Applications 2.0

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Methods and Technologies Development".

Deadline for manuscript submissions: closed (20 June 2023) | Viewed by 19016

Special Issue Editors

Dr. Loretta L. del Mercato

E-Mail Website
Guest Editor
CNR-Institute of Nanotechnology, c/o Campus Ecotekne, Via Monteroni, 73100 Lecce, Italy
Interests: optical pH and oxygen sensors; 3D in vitro tumor models; tumor microenvironment; cell metabolism; cell–cell interactions; fluorescence live cell imaging; scientific computing and data processing
Special Issues, Collections and Topics in MDPI journals
Dr. Enza Lonardo

E-Mail Website
Guest Editor
Institute of Genetics and Biophysics ‘Adriano Buzzati-Traverso’ (IGB), CNR, Via Pietro Castellino 111, 80131 Naples, Italy
Interests: 3D cancer models; pancreatic cancer; colorectal cancer; tumor microenvironment; TGFb
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is the second edition of the previous one, "3D Cell Culture Cancer Models: Development and Applications" (https://www.mdpi.com/journal/cancers/special_issues/3D_Cell_Culture_Cancer_Models).

Despite the advances in treatment, cancer is still among the top 10 causes of death worldwide. Therefore, the need for new patient-derived cancer models to improve personalized therapy is critical. Due to their ability to recapitulate the structural and functional aspects of their matched organs, 3D cell culture cancer models have received huge attention from a variety of specialized fields, including cell biology, molecular biology, chemistry, physics, engineering and nanotechnology This Special Issue aims to bring together scientists and physicians to discuss the state-of-the-art in in vitro cancer modeling. The goal is to highlight those approaches that will drive future research in the study of 3D cell culture cancer models for personalized drug sensitivity testing or to study tumor cell physiology.

Reviews, articles and protocols that explore advanced materials and methods to generate 3D in vitro tumor models that mimic the native heterogeneity and the three-dimensionality of their in vivo counterparts are welcome.

Dr. Loretta L. del Mercato
Dr. Enza Lonardo
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

  • cancer modeling
  • preclinical cancer models
  • patient-derived 3D cancer models
  • organoids
  • spheroids
  • biomaterials (hydrogels, scaffolds, bioreactors, 3D printing technology, organ-on-chips)
  • conditionally reprogrammed cells
  • drug response and resistance
  • personalized therapy
  • live-cell analyses of 3D cancer models
  • gene expression analyses in 3D cancer models
  • drug discover and toxicity testing in 3D cancer models
  • challenges of 3D cancer models

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Published Papers (7 papers)

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Research

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14 pages, 3768 KiB  
Article
Establishment of a 3D Model to Characterize the Radioresponse of Patient-Derived Glioblastoma Cells
by Zoe Strand, Finn Schrickel, Sophie Dobiasch, Andreas R. Thomsen, Katja Steiger, Jens Gempt, Bernhard Meyer, Stephanie E. Combs and Daniela Schilling
Cancers 2023, 15(16), 4051; https://doi.org/10.3390/cancers15164051 - 10 Aug 2023
Cited by 1 | Viewed by 1652
Abstract
Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults. Despite modern, multimodal therapeutic options of surgery, chemotherapy, tumor-treating fields (TTF), and radiotherapy, the 5-year survival is below 10%. In order to develop new therapies, better preclinical models are needed [...] Read more.
Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults. Despite modern, multimodal therapeutic options of surgery, chemotherapy, tumor-treating fields (TTF), and radiotherapy, the 5-year survival is below 10%. In order to develop new therapies, better preclinical models are needed that mimic the complexity of a tumor. In this work, we established a novel three-dimensional (3D) model for patient-derived GBM cell lines. To analyze the volume and growth pattern of primary GBM cells in 3D culture, a CoSeedisTM culture system was used, and radiation sensitivity in comparison to conventional 2D colony formation assay (CFA) was analyzed. Both culture systems revealed a dose-dependent reduction in survival, but the high variance in colony size and shape prevented reliable evaluation of the 2D cultures. In contrast, the size of 3D spheroids could be measured accurately. Immunostaining of spheroids grown in the 3D culture system showed an increase in the DNA double-strand-break marker γH2AX one hour after irradiation. After 24 h, a decrease in DNA damage was observed, indicating active repair mechanisms. In summary, this new translational 3D model may better reflect the tumor complexity and be useful for analyzing the growth, radiosensitivity, and DNA repair of patient-derived GBM cells. Full article
(This article belongs to the Special Issue 3D Cell Culture Cancer Models: Development and Applications 2.0)
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16 pages, 3294 KiB  
Article
Therapeutic Potential of Targeting the Cytochrome P450 Enzymes Using Lopinavir/Ritonavir in Colorectal Cancer: A Study in Monolayers, Spheroids and In Vivo Models
by Maryam Alaei, Seyedeh Elnaz Nazari, Ghazaleh Pourali, AliReza Asadnia, Mehrdad Moetamani-Ahmadi, Hamid Fiuji, Hamid Tanzadehpanah, Fereshteh Asgharzadeh, Fatemeh Babaei, Fatemeh Khojasteh-Leylakoohi, Ibrahim Saeed Gataa, Mohammad Ali Kiani, Gordon A. Ferns, Alfred King-yin Lam, Seyed Mahdi Hassanian, Majid Khazaei, Elisa Giovannetti and Amir Avan
Cancers 2023, 15(15), 3939; https://doi.org/10.3390/cancers15153939 - 2 Aug 2023
Cited by 1 | Viewed by 1919
Abstract
Cytochrome P450 (CYP450) enzyme has been shown to be expressed in colorectal cancer (CRC) and its dysregulation is linked to tumor progression and a poor prognosis. Here we investigated the therapeutic potential of targeting CYP450 using lopinavir/ritonavir in CRC. The integrative systems biology [...] Read more.
Cytochrome P450 (CYP450) enzyme has been shown to be expressed in colorectal cancer (CRC) and its dysregulation is linked to tumor progression and a poor prognosis. Here we investigated the therapeutic potential of targeting CYP450 using lopinavir/ritonavir in CRC. The integrative systems biology method and RNAseq were utilized to investigate the differential levels of genes associated with patients with colorectal cancer. The antiproliferative activity of lopinavir/ritonavir was evaluated in both monolayer and 3-dimensional (3D) models, followed by wound-healing assays. The effectiveness of targeting CYP450 was examined in a mouse model, followed by histopathological analysis, biochemical tests (MDA, SOD, thiol, and CAT), and RT-PCR. The data of dysregulation expressed genes (DEG) revealed 1268 upregulated and 1074 down-regulated genes in CRC. Among the top-score genes and dysregulated pathways, CYPs were detected and associated with poor prognosis of patients with CRC. Inhibition of CYP450 reduced cell proliferation via modulating survivin, Chop, CYP13a, and induction of cell death, as detected by AnnexinV/PI staining. This agent suppressed the migratory behaviors of cells by induction of E-cadherin. Moreover, lopinavir/ritonavir suppressed tumor growth and fibrosis, which correlated with a reduction in SOD/thiol levels and increased MDA levels. Our findings illustrated the therapeutic potential of targeting the CYP450 using lopinavir/ritonavir in colorectal cancer, supporting future investigations on this novel therapeutic approach for the treatment of CRC. Full article
(This article belongs to the Special Issue 3D Cell Culture Cancer Models: Development and Applications 2.0)
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13 pages, 2638 KiB  
Article
Advancing Cancer Therapy Predictions with Patient-Derived Organoid Models of Metastatic Breast Cancer
by Cansu E. Önder, Teresa J. Ziegler, Ronja Becker, Sara Y. Brucker, Andreas D. Hartkopf, Tobias Engler and André Koch
Cancers 2023, 15(14), 3602; https://doi.org/10.3390/cancers15143602 - 13 Jul 2023
Cited by 4 | Viewed by 2706
Abstract
The poor outcome of metastasized breast cancer (BC) stresses the need for reliable personalized oncology and the significance of models recapitulating the heterogeneous nature of BC. Here, we cultured metastatic tumor cells derived from advanced BC patients with malignant ascites (MA) or malignant [...] Read more.
The poor outcome of metastasized breast cancer (BC) stresses the need for reliable personalized oncology and the significance of models recapitulating the heterogeneous nature of BC. Here, we cultured metastatic tumor cells derived from advanced BC patients with malignant ascites (MA) or malignant pleural effusion (MPE) using organoid technology. We identified the characteristics of tumor organoids by applying immunohistochemistry and mutation analysis. Tumor organoids preserved their expression patterns and hotspot mutations when compared to their original metastatic counterpart and are consequently a well-suited in vitro model for metastasized BC. We treated the tumor organoids to implement a reliable application for drug screenings of metastasized cells. Drug assays revealed that responses are not always in accord with expression patterns, pathway activation, and hotspot mutations. The discrepancy between characterization and functional testing underlines the relevance of linking IHC stainings and mutational analysis of metastasized BC with in vitro drug assays. Our metastatic BC organoids recapitulate the characteristics of their original sample derived from MA and MPE and serve as an invaluable tool that can be utilized in a preclinical setting for guiding therapy decisions. Full article
(This article belongs to the Special Issue 3D Cell Culture Cancer Models: Development and Applications 2.0)
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20 pages, 6447 KiB  
Article
Three-Dimensional Breast Cancer Model to Investigate CCL5/CCR1 Expression Mediated by Direct Contact between Breast Cancer Cells and Adipose-Derived Stromal Cells or Adipocytes
by Martin Watzling, Lorenz Klaus, Tamara Weidemeier, Hannes Horder, Regina Ebert, Torsten Blunk and Petra Bauer-Kreisel
Cancers 2023, 15(13), 3501; https://doi.org/10.3390/cancers15133501 - 5 Jul 2023
Cited by 4 | Viewed by 2363
Abstract
The tumor microenvironment (TME) in breast cancer is determined by the complex crosstalk of cancer cells with adipose tissue-inherent cells such as adipose-derived stromal cells (ASCs) and adipocytes resulting from the local invasion of tumor cells in the mammary fat pad. This leads [...] Read more.
The tumor microenvironment (TME) in breast cancer is determined by the complex crosstalk of cancer cells with adipose tissue-inherent cells such as adipose-derived stromal cells (ASCs) and adipocytes resulting from the local invasion of tumor cells in the mammary fat pad. This leads to heterotypic cellular contacts between these cell types. To adequately mimic the specific cell-to-cell interaction in an in vivo-like 3D environment, we developed a direct co-culture spheroid model using ASCs or differentiated adipocytes in combination with MDA-MB-231 or MCF-7 breast carcinoma cells. Co-spheroids were generated in a well-defined and reproducible manner in a high-throughput process. We compared the expression of the tumor-promoting chemokine CCL5 and its cognate receptors in these co-spheroids to indirect and direct standard 2D co-cultures. A marked up-regulation of CCL5 and in particular the receptor CCR1 with strict dependence on cell–cell contacts and culture dimensionality was evident. Furthermore, the impact of direct contacts between ASCs and tumor cells and the involvement of CCR1 in promoting tumor cell migration were demonstrated. Overall, these results show the importance of direct 3D co-culture models to better represent the complex tumor–stroma interaction in a tissue-like context. The unveiling of tumor-specific markers that are up-regulated upon direct cell–cell contact with neighboring stromal cells, as demonstrated in the 3D co-culture spheroids, may represent a promising strategy to find new targets for the diagnosis and treatment of invasive breast cancer. Full article
(This article belongs to the Special Issue 3D Cell Culture Cancer Models: Development and Applications 2.0)
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21 pages, 6461 KiB  
Article
Transcriptional Landscape of 3D vs. 2D Ovarian Cancer Cell Models
by Rachel Kerslake, Birhanu Belay, Suzana Panfilov, Marcia Hall, Ioannis Kyrou, Harpal S. Randeva, Jari Hyttinen, Emmanouil Karteris and Cristina Sisu
Cancers 2023, 15(13), 3350; https://doi.org/10.3390/cancers15133350 - 26 Jun 2023
Cited by 7 | Viewed by 3504
Abstract
Three-dimensional (3D) cancer models are revolutionising research, allowing for the recapitulation of an in vivo-like response through the use of an in vitro system, which is more complex and physiologically relevant than traditional monolayer cultures. Cancers such as ovarian (OvCa) are prone to [...] Read more.
Three-dimensional (3D) cancer models are revolutionising research, allowing for the recapitulation of an in vivo-like response through the use of an in vitro system, which is more complex and physiologically relevant than traditional monolayer cultures. Cancers such as ovarian (OvCa) are prone to developing resistance, are often lethal, and stand to benefit greatly from the enhanced modelling emulated by 3D cultures. However, the current models often fall short of the predicted response, where reproducibility is limited owing to the lack of standardised methodology and established protocols. This meta-analysis aims to assess the current scope of 3D OvCa models and the differences in the genetic profiles presented by a vast array of 3D cultures. An analysis of the literature (Pubmed.gov) spanning 2012–2022 was used to identify studies with paired data of 3D and 2D monolayer counterparts in addition to RNA sequencing and microarray data. From the data, 19 cell lines were found to show differential regulation in their gene expression profiles depending on the bio-scaffold (i.e., agarose, collagen, or Matrigel) compared to 2D cell cultures. The top genes differentially expressed in 2D vs. 3D included C3, CXCL1, 2, and 8, IL1B, SLP1, FN1, IL6, DDIT4, PI3, LAMC2, CCL20, MMP1, IFI27, CFB, and ANGPTL4. The top enriched gene sets for 2D vs. 3D included IFN-α and IFN-γ response, TNF-α signalling, IL-6-JAK-STAT3 signalling, angiogenesis, hedgehog signalling, apoptosis, epithelial–mesenchymal transition, hypoxia, and inflammatory response. Our transversal comparison of numerous scaffolds allowed us to highlight the variability that can be induced by these scaffolds in the transcriptional landscape and identify key genes and biological processes that are hallmarks of cancer cells grown in 3D cultures. Future studies are needed to identify which is the most appropriate in vitro/preclinical model to study tumour microenvironments. Full article
(This article belongs to the Special Issue 3D Cell Culture Cancer Models: Development and Applications 2.0)
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20 pages, 5152 KiB  
Article
Pixelated Microfluidics for Drug Screening on Tumour Spheroids and Ex Vivo Microdissected Tumour Explants
by Dina Dorrigiv, Pierre-Alexandre Goyette, Amélie St-Georges-Robillard, Anne-Marie Mes-Masson and Thomas Gervais
Cancers 2023, 15(4), 1060; https://doi.org/10.3390/cancers15041060 - 7 Feb 2023
Cited by 4 | Viewed by 2076
Abstract
Anticancer drugs have the lowest success rate of approval in drug development programs. Thus, preclinical assays that closely predict the clinical responses to drugs are of utmost importance in both clinical oncology and pharmaceutical research. 3D tumour models preserve the tumoral architecture and [...] Read more.
Anticancer drugs have the lowest success rate of approval in drug development programs. Thus, preclinical assays that closely predict the clinical responses to drugs are of utmost importance in both clinical oncology and pharmaceutical research. 3D tumour models preserve the tumoral architecture and are cost- and time-efficient. However, the short-term longevity, limited throughput, and limitations of live imaging of these models have so far driven researchers towards less realistic tumour models such as monolayer cell cultures. Here, we present an open-space microfluidic drug screening platform that enables the formation, culture, and multiplexed delivery of several reagents to various 3D tumour models, namely cancer cell line spheroids and ex vivo primary tumour fragments. Our platform utilizes a microfluidic pixelated chemical display that creates isolated adjacent flow sub-units of reagents, which we refer to as fluidic ‘pixels’, over tumour models in a contact-free fashion. Up to nine different treatment conditions can be tested over 144 samples in a single experiment. We provide a proof-of-concept application by staining fixed and live tumour models with multiple cellular dyes. Furthermore, we demonstrate that the response of the tumour models to biological stimuli can be assessed using the platform. Upscaling the microfluidic platform to larger areas can lead to higher throughputs, and thus will have a significant impact on developing treatments for cancer. Full article
(This article belongs to the Special Issue 3D Cell Culture Cancer Models: Development and Applications 2.0)
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Review

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27 pages, 1202 KiB  
Review
Three Dimensional Models of Endocrine Organs and Target Tissues Regulated by the Endocrine System
by Edlira Luca, Kathrin Zitzmann, Stefan Bornstein, Patrick Kugelmeier, Felix Beuschlein, Svenja Nölting and Constanze Hantel
Cancers 2023, 15(18), 4601; https://doi.org/10.3390/cancers15184601 - 17 Sep 2023
Cited by 3 | Viewed by 3732
Abstract
Immortalized cell lines originating from tumors and cultured in monolayers in vitro display consistent behavior and response, and generate reproducible results across laboratories. However, for certain endpoints, these cell lines behave quite differently from the original solid tumors. Thereby, the homogeneity of immortalized [...] Read more.
Immortalized cell lines originating from tumors and cultured in monolayers in vitro display consistent behavior and response, and generate reproducible results across laboratories. However, for certain endpoints, these cell lines behave quite differently from the original solid tumors. Thereby, the homogeneity of immortalized cell lines and two-dimensionality of monolayer cultures deters from the development of new therapies and translatability of results to the more complex situation in vivo. Organoids originating from tissue biopsies and spheroids from cell lines mimic the heterogeneous and multidimensional characteristics of tumor cells in 3D structures in vitro. Thus, they have the advantage of recapitulating the more complex tissue architecture of solid tumors. In this review, we discuss recent efforts in basic and preclinical cancer research to establish methods to generate organoids/spheroids and living biobanks from endocrine tissues and target organs under endocrine control while striving to achieve solutions in personalized medicine. Full article
(This article belongs to the Special Issue 3D Cell Culture Cancer Models: Development and Applications 2.0)
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