Tumor Models and Drug Targeting In Vitro

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

Deadline for manuscript submissions: closed (15 September 2022) | Viewed by 25699

Special Issue Editors


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Guest Editor
Bioreactors and Applied Microgravity Research, Department for Microgravity and Translational Regenerative Medicine, Clinic for Plastic, Aesthetic and Hand Surgery, Otto-von-Guericke University, 39120 Magdeburg, Germany
Interests: cancer biology; microgravity; bioreactors; in vitro models; tissue engineering
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Guest Editor
Environmental Cell Biology Group, Department of Microgravity and Translational Regenerative Medicine, Otto von Guericke University, 39106 Magdeburg, Germany
Interests: cell biology; cancer biology; environmental influences; microgravity; cellular communication; photodynamic therapy; cancer treatment; antimicrobial resistance; tumor microbiome
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Meaningful preclinical models are of extremely great importance for new therapeutic approaches against cancers. Far too often, promising substances fail in later clinical trials. Therefore, it is appropriate to use the advantages of advanced in vitro models to enhance the clinical success of drugs identified in basic research by better predicting their responses in patients.

Today, technological and scientific developments allow researchers to better understand the complex biology of cancer and the molecular relationships in tumors and during metastasis. Particularly, three-dimensional tumor and metastatic models, closely mimicking the in vivo tumor tissue, have become an indispensable platform for investigating the tumor microenvironment, mechanical properties, biochemical factors, as well as dynamic cell–cell and cell–ECM interactions. These offer unique advantages in fundamental and clinical biomedical studies as well as in drug development.

This Special Issue aims to highlight recent advances in the development and applications of in vitro tumor models. We welcome the submission of original research and review manuscripts.

Dr. Sascha Kopp
Dr. Marcus Krüger
Guest Editors

Manuscript Submission Information

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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

  • 3D in vitro tumors
  • cancer metastasis modeling
  • tumor engineering
  • tumor-on-a-chip
  • drug targeting
  • drug delivery mechanisms
  • tumor microenvironment
  • cellular interactions

Published Papers (10 papers)

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Editorial

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5 pages, 831 KiB  
Editorial
Tumor Models and Drug Targeting In Vitro—Where Are We Today? Where Do We Go from Here?
by Marcus Krüger and Sascha Kopp
Cancers 2023, 15(6), 1768; https://doi.org/10.3390/cancers15061768 - 15 Mar 2023
Cited by 2 | Viewed by 1192
Abstract
Cancer is one of the leading causes of death worldwide [...] Full article
(This article belongs to the Special Issue Tumor Models and Drug Targeting In Vitro)
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Research

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25 pages, 18494 KiB  
Article
Dexamethasone Selectively Inhibits Detachment of Metastatic Thyroid Cancer Cells during Random Positioning
by Daniela Melnik, José Luis Cortés-Sánchez, Viviann Sandt, Stefan Kahlert, Sascha Kopp, Daniela Grimm and Marcus Krüger
Cancers 2023, 15(6), 1641; https://doi.org/10.3390/cancers15061641 - 7 Mar 2023
Cited by 4 | Viewed by 2315
Abstract
We recently reported that synthetic glucocorticoid dexamethasone (DEX) is able to suppress metastasis-like spheroid formation in a culture of follicular thyroid cancer (FTC)-133 cells cultured under random positioning. We now show that this inhibition was selective for two metastatic thyroid carcinoma cells, FTC-133 [...] Read more.
We recently reported that synthetic glucocorticoid dexamethasone (DEX) is able to suppress metastasis-like spheroid formation in a culture of follicular thyroid cancer (FTC)-133 cells cultured under random positioning. We now show that this inhibition was selective for two metastatic thyroid carcinoma cells, FTC-133 and WRO, whereas benign Nthy-ori 3-1 thyrocytes and recurrent ML-1 follicular thyroid cancer cells were not affected by DEX. We then compare Nthy-ori 3-1 and FTC-133 cells concerning their adhesion and mechanosignaling. We demonstrate that DEX disrupts random positioning-triggered p38 stress signaling in FTC-133 cells, thereby antagonizing a variety of biological functions. Thus, DEX treatment of FTC-133 cells is associated with increased adhesiveness, which is mainly caused by the restored, pronounced formation of a normal number of tight junctions. Moreover, we show that Nthy-ori 3-1 and ML-1 cells upregulate the anti-adhesion protein mucin-1 during random positioning, presumably as a protection against mechanical stress. In summary, mechanical stress seems to be an important component in this metastasis model system that is processed differently by metastatic and healthy cells. The balance between adhesion, anti-adhesion and cell–cell connections enables detachment of adherent human cells on the random positioning machine—or not, allowing selective inhibition of thyroid in vitro metastasis by DEX. Full article
(This article belongs to the Special Issue Tumor Models and Drug Targeting In Vitro)
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24 pages, 3246 KiB  
Article
In Vitro Setup for Determination of Nanoparticle-Mediated Magnetic Cell and Drug Accumulation in Tumor Spheroids under Flow Conditions
by Jessica Behr, Lucas R. Carnell, Rene Stein, Felix Pfister, Bernhard Friedrich, Christian Huber, Stefan Lyer, Julia Band, Eveline Schreiber, Christoph Alexiou and Christina Janko
Cancers 2022, 14(23), 5978; https://doi.org/10.3390/cancers14235978 - 3 Dec 2022
Cited by 5 | Viewed by 1899
Abstract
Superparamagnetic iron oxide nanoparticles (SPIONs) are used in nanomedicine as transporter systems for therapeutic cargos, or to magnetize cells to make them magnetically guidable. In cancer treatment, the site-directed delivery of chemotherapeutics or immune effector cells to the tumor can increase the therapeutic [...] Read more.
Superparamagnetic iron oxide nanoparticles (SPIONs) are used in nanomedicine as transporter systems for therapeutic cargos, or to magnetize cells to make them magnetically guidable. In cancer treatment, the site-directed delivery of chemotherapeutics or immune effector cells to the tumor can increase the therapeutic efficacy in the target region, and simultaneously reduce toxic side-effects in the rest of the body. To enable the transfer of new methods, such as the nanoparticle-mediated transport from bench to bedside, suitable experimental setups must be developed. In vivo, the SPIONs or SPION-loaded cells must be applied into the blood stream, to finally reach the tumor: consequently, targeting and treatment efficacy should be analyzed under conditions which are as close to in vivo as possible. Here, we established an in vitro method, including tumor spheroids placed in a chamber system under the influence of a magnetic field, and adapted to a peristaltic pump, to mimic the blood flow. This enabled us to analyze the magnetic capture and antitumor effects of magnetically targeted mitoxantrone and immune cells under dynamic conditions. We showed that the magnetic nanoparticle-mediated accumulation increased the anti-tumor effects, and reduced the unspecific distribution of both mitoxantrone and cells. Especially for nanomedical research, investigation of the site-specific targeting of particles, cells or drugs under circulation is important. We conclude that our in vitro setup improves the screening process of nanomedical candidates for cancer treatment. Full article
(This article belongs to the Special Issue Tumor Models and Drug Targeting In Vitro)
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12 pages, 17688 KiB  
Article
Pharmacologic Targeting of MMP2/9 Decreases Peritoneal Metastasis Formation of Colorectal Cancer in a Human Ex Vivo Peritoneum Culture Model
by Jana Koch, Dina Mönch, Annika Maaß, Alina Mangold, Miodrag Gužvić, Thomas Mürdter, Tobias Leibold, Marc-H. Dahlke and Philipp Renner
Cancers 2022, 14(15), 3760; https://doi.org/10.3390/cancers14153760 - 2 Aug 2022
Cited by 8 | Viewed by 2089
Abstract
Background: Matrix metalloproteinases (MMPs) play a crucial role in tumour initiation, progression, and metastasis, including peritoneal carcinosis (PC) formation. MMPs serve as biomarkers for tumour progression in colorectal cancer (CRC), and MMP overexpression is associated with advanced-stage metastasis and poor survival. However, the [...] Read more.
Background: Matrix metalloproteinases (MMPs) play a crucial role in tumour initiation, progression, and metastasis, including peritoneal carcinosis (PC) formation. MMPs serve as biomarkers for tumour progression in colorectal cancer (CRC), and MMP overexpression is associated with advanced-stage metastasis and poor survival. However, the molecular mechanisms of PC from CRC remain largely unclear. Methods: We investigated the role of MMPs during peritoneal colonisation by CRC cell lines in a human ex vivo peritoneum model and in patient-derived CRC and corresponding PC samples. MMP2 and MMP9 were inhibited using the small-molecule inhibitors batimastat and the specific MMP2/9 inhibitor III. Results: MMP2 and MMP9 were strongly upregulated in patient-derived samples and following peritoneal colonisation by CRC cells in the ex vivo model. MMP inhibition with batimastat reduced colonisation of HT29 and Colo205 cells by 36% and 68%, respectively (p = 0.0073 and p = 0.0002), while MMP2/9 inhibitor III reduced colonisation by 50% and 41%, respectively (p = 0.0003 and p = 0.0051). Fibronectin cleavage was enhanced in patient-derived samples of PC and during peritoneal colonisation in the ex vivo model, and this was inhibited by MMP2/9 inhibition. Conclusion: MMPs were upregulated in patient-derived samples and during peritoneal attachment of CRC cell lines in our ex vivo model. MMP2/9 inhibition prevented fibronectin cleavage and peritoneal colonisation by CRC cells. MMP inhibitors might thus offer a potential treatment strategy for patients with PC. Full article
(This article belongs to the Special Issue Tumor Models and Drug Targeting In Vitro)
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20 pages, 5479 KiB  
Article
Mesothelioma Mouse Models with Mixed Genomic States of Chromosome and Microsatellite Instability
by Yurong Song, Shaneen S. Baxter, Lisheng Dai, Chelsea Sanders, Sandra Burkett, Ryan N. Baugher, Stephanie D. Mellott, Todd B. Young, Heidi E. Lawhorn, Simone Difilippantonio, Baktiar Karim, Yuwaraj Kadariya, Ligia A. Pinto, Joseph R. Testa and Robert H. Shoemaker
Cancers 2022, 14(13), 3108; https://doi.org/10.3390/cancers14133108 - 24 Jun 2022
Cited by 4 | Viewed by 2542
Abstract
Malignant mesothelioma (MMe) is a rare malignancy originating from the linings of the pleural, peritoneal and pericardial cavities. The best-defined risk factor is exposure to carcinogenic mineral fibers (e.g., asbestos). Genomic studies have revealed that the most frequent genetic lesions in human MMe [...] Read more.
Malignant mesothelioma (MMe) is a rare malignancy originating from the linings of the pleural, peritoneal and pericardial cavities. The best-defined risk factor is exposure to carcinogenic mineral fibers (e.g., asbestos). Genomic studies have revealed that the most frequent genetic lesions in human MMe are mutations in tumor suppressor genes. Several genetically engineered mouse models have been generated by introducing the same genetic lesions found in human MMe. However, most of these models require specialized breeding facilities and long-term exposure of mice to asbestos for MMe development. Thus, an alternative model with high tumor penetrance without asbestos is urgently needed. We characterized an orthotopic model using MMe cells derived from Cdkn2a+/−;Nf2+/− mice chronically injected with asbestos. These MMe cells were tumorigenic upon intraperitoneal injection. Moreover, MMe cells showed mixed chromosome and microsatellite instability, supporting the notion that genomic instability is relevant in MMe pathogenesis. In addition, microsatellite markers were detectable in the plasma of tumor-bearing mice, indicating a potential use for early cancer detection and monitoring the effects of interventions. This orthotopic model with rapid development of MMe without asbestos exposure represents genomic instability and specific molecular targets for therapeutic or preventive interventions to enable preclinical proof of concept for the intervention in an immunocompetent setting. Full article
(This article belongs to the Special Issue Tumor Models and Drug Targeting In Vitro)
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16 pages, 1849 KiB  
Article
Interpatient Heterogeneity in Drug Response and Protein Biomarker Expression of Recurrent Ovarian Cancer
by Oliver Ingo Hoffmann, Manuel Regenauer, Bastian Czogalla, Christine Brambs, Alexander Burges and Barbara Mayer
Cancers 2022, 14(9), 2279; https://doi.org/10.3390/cancers14092279 - 3 May 2022
Cited by 6 | Viewed by 1939
Abstract
Recurrent ovarian-cancer patients face low 5-year survival rates despite chemotherapy. A variety of guideline-recommended second-line therapies are available, but they frequently result in trial-and-error treatment. Alterations and adjustments are common in the treatment of recurrent ovarian cancer. The drug response of 30 lesions [...] Read more.
Recurrent ovarian-cancer patients face low 5-year survival rates despite chemotherapy. A variety of guideline-recommended second-line therapies are available, but they frequently result in trial-and-error treatment. Alterations and adjustments are common in the treatment of recurrent ovarian cancer. The drug response of 30 lesions obtained from 22 relapsed ovarian cancer patients to different chemotherapeutic and molecular agents was analyzed with the patient-derived ovarian-cancer spheroid model. The profile of druggable biomarkers was immunohistochemically assessed. The second-line combination therapy of carboplatin with gemcitabine was significantly superior to the combination of carboplatin with PEGylated liposomal doxorubicin (p < 0.0001) or paclitaxel (p = 0.0007). Except for treosulfan, all nonplatinum treatments tested showed a lesser effect on tumor spheroids compared to that of platinum-based therapies. Treosulfan showed the highest efficacy of all nonplatinum agents, with significant advantage over vinorelbine (p < 0.0001) and topotecan (p < 0.0001), the next best agents. The comparative testing of a variety of treatment options in the ovarian-cancer spheroid model resulted in the identification of more effective regimens for 30% of patients compared to guideline-recommended therapies. Recurrent cancers obtained from different patients revealed profound interpatient heterogeneity in the expression pattern of druggable protein biomarkers. In contrast, different lesions obtained from the same patient revealed a similar drug response and biomarker expression profile. Biological heterogeneity observed in recurrent ovarian cancers might explain the strong differences in the clinical drug response of these patients. Preclinical drug testing and biomarker profiling in the ovarian-cancer spheroid model might help in optimizing treatment management for individual patients. Full article
(This article belongs to the Special Issue Tumor Models and Drug Targeting In Vitro)
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26 pages, 5033 KiB  
Article
EMT, Stemness, and Drug Resistance in Biological Context: A 3D Tumor Tissue/In Silico Platform for Analysis of Combinatorial Treatment in NSCLC with Aggressive KRAS-Biomarker Signatures
by Matthias Peindl, Claudia Göttlich, Samantha Crouch, Niklas Hoff, Tamara Lüttgens, Franziska Schmitt, Jesús Guillermo Nieves Pereira, Celina May, Anna Schliermann, Corinna Kronenthaler, Danjouma Cheufou, Simone Reu-Hofer, Andreas Rosenwald, Elena Weigl, Thorsten Walles, Julia Schüler, Thomas Dandekar, Sarah Nietzer and Gudrun Dandekar
Cancers 2022, 14(9), 2176; https://doi.org/10.3390/cancers14092176 - 27 Apr 2022
Cited by 9 | Viewed by 3462
Abstract
Epithelial-to-mesenchymal transition (EMT) is discussed to be centrally involved in invasion, stemness, and drug resistance. Experimental models to evaluate this process in its biological complexity are limited. To shed light on EMT impact and test drug response more reliably, we use a lung [...] Read more.
Epithelial-to-mesenchymal transition (EMT) is discussed to be centrally involved in invasion, stemness, and drug resistance. Experimental models to evaluate this process in its biological complexity are limited. To shed light on EMT impact and test drug response more reliably, we use a lung tumor test system based on a decellularized intestinal matrix showing more in vivo-like proliferation levels and enhanced expression of clinical markers and carcinogenesis-related genes. In our models, we found evidence for a correlation of EMT with drug resistance in primary and secondary resistant cells harboring KRASG12C or EGFR mutations, which was simulated in silico based on an optimized signaling network topology. Notably, drug resistance did not correlate with EMT status in KRAS-mutated patient-derived xenograft (PDX) cell lines, and drug efficacy was not affected by EMT induction via TGF-β. To investigate further determinants of drug response, we tested several drugs in combination with a KRASG12C inhibitor in KRASG12C mutant HCC44 models, which, besides EMT, display mutations in P53, LKB1, KEAP1, and high c-MYC expression. We identified an aurora-kinase A (AURKA) inhibitor as the most promising candidate. In our network, AURKA is a centrally linked hub to EMT, proliferation, apoptosis, LKB1, and c-MYC. This exemplifies our systemic analysis approach for clinical translation of biomarker signatures. Full article
(This article belongs to the Special Issue Tumor Models and Drug Targeting In Vitro)
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Review

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16 pages, 1341 KiB  
Review
Organoids for Modeling (Colorectal) Cancer in a Dish
by Florian Rathje, Stefan Klingler and Fritz Aberger
Cancers 2022, 14(21), 5416; https://doi.org/10.3390/cancers14215416 - 3 Nov 2022
Cited by 4 | Viewed by 2590
Abstract
Functional studies of primary cancer have been limited to animal models for a long time making it difficult to study aspects specific to human cancer biology. The development of organoid technology enabled us to culture human healthy and tumor cells as three-dimensional self-organizing [...] Read more.
Functional studies of primary cancer have been limited to animal models for a long time making it difficult to study aspects specific to human cancer biology. The development of organoid technology enabled us to culture human healthy and tumor cells as three-dimensional self-organizing structures in vitro for a prolonged time. Organoid cultures conserve the heterogeneity of the originating epithelium regarding cell types and tumor clonality. Therefore, organoids are considered an invaluable tool to study and genetically dissect various aspects of human cancer biology. In this review, we describe the applications, advantages, and limitations of organoids as human cancer models with the main emphasis on colorectal cancer. Full article
(This article belongs to the Special Issue Tumor Models and Drug Targeting In Vitro)
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14 pages, 1212 KiB  
Review
Advanced Cellular Models for Preclinical Drug Testing: From 2D Cultures to Organ-on-a-Chip Technology
by Valentina Foglizzo, Emiliano Cocco and Serena Marchiò
Cancers 2022, 14(15), 3692; https://doi.org/10.3390/cancers14153692 - 28 Jul 2022
Cited by 7 | Viewed by 2263
Abstract
Cancer is a complex disease arising from a homeostatic imbalance of cell-intrinsic and microenvironment-related mechanisms. A multimodal approach to treat cancer that includes surgery, chemotherapy, and radiation therapy often fails in achieving tumor remission and produces unbearable side effects including secondary malignancies. Novel [...] Read more.
Cancer is a complex disease arising from a homeostatic imbalance of cell-intrinsic and microenvironment-related mechanisms. A multimodal approach to treat cancer that includes surgery, chemotherapy, and radiation therapy often fails in achieving tumor remission and produces unbearable side effects including secondary malignancies. Novel strategies have been implemented in the past decades in order to replace conventional chemotherapeutics with targeted, less toxic drugs. Up to now, scientists have relied on results achieved in animal research before proceeding to clinical trials. However, the high failure rate of targeted drugs in early phase trials leaves no doubt about the inadequacy of those models. In compliance with the need of reducing, and possibly replacing, animal research, studies have been conducted in vitro with advanced cellular models that more and more mimic the tumor in vivo. We will here review those methods that allow for the 3D reconstitution of the tumor and its microenvironment and the implementation of the organ-on-a-chip technology to study minimal organ units in disease progression. We will make specific reference to the usability of these systems as predictive cancer models and report on recent applications in high-throughput screenings of innovative and targeted drug compounds. Full article
(This article belongs to the Special Issue Tumor Models and Drug Targeting In Vitro)
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24 pages, 1553 KiB  
Review
The Patient-Derived Cancer Organoids: Promises and Challenges as Platforms for Cancer Discovery
by JuneSung Bae, Yun Sik Choi, Gunsik Cho and Se Jin Jang
Cancers 2022, 14(9), 2144; https://doi.org/10.3390/cancers14092144 - 25 Apr 2022
Cited by 7 | Viewed by 3609
Abstract
The cancer burden is rapidly increasing in most countries, and thus, new anticancer drugs for effective cancer therapy must be developed. Cancer model systems that recapitulate the biological processes of human cancers are one of the cores of the drug development process. PDCO [...] Read more.
The cancer burden is rapidly increasing in most countries, and thus, new anticancer drugs for effective cancer therapy must be developed. Cancer model systems that recapitulate the biological processes of human cancers are one of the cores of the drug development process. PDCO has emerged as a unique model that preserves the genetic, physiological, and histologic characteristics of original cancer, including inter- and intratumoral heterogeneities. Due to these advantages, the PCDO model is increasingly investigated for anticancer drug screening and efficacy testing, preclinical patient stratification, and precision medicine for selecting the most effective anticancer therapy for patients. Here, we review the prospects and limitations of PDCO compared to the conventional cancer models. With advances in culture success rates, co-culture systems with the tumor microenvironment, organoid-on-a-chip technology, and automation technology, PDCO will become the most promising model to develop anticancer drugs and precision medicine. Full article
(This article belongs to the Special Issue Tumor Models and Drug Targeting In Vitro)
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