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Organotypic 3D In Vitro Tumor Models: Bioengineering and Applications

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

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 17711

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Special Issue Editors

Dr. Vítor Gaspar

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Guest Editor

Department of Chemistry, CICECO—Aveiro Institute of Materials, University of Aveiro, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal
Interests: biomaterials; 3D in vitro tumor models; tumor microenvironment; high-throughput drug screening; 3D bioprinting; organ-on-a-chip platforms; tissue engineering; controlled delivery of bioactive molecules; nano/micro technologies

Prof. Dr. João F. Mano

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Guest Editor

Department of Chemistry, CICECO-Aveiro Institute of Materials, University of Aveiro, 3810-193 Aveiro, Portugal
Interests: biomaterials; tissue engineering; 3D in vitro models; controlled delivery of bioactive molecules; nature-based biodegradable polymers; biomimetic and nano/micro-technology approaches
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Special Issue Information

Dear Colleagues,

The development of organotypic 3D tumor models that can recapitulate the unique complexity of human in vivo tumors in an in vitro setting provides a unique opportunity to overcome the current limitations of gold standard platforms employed for fundamental cancer research and therapies discovery/screening. Bioengineered organotypic microtumors have been rapidly emerging as next-generation tumor modelling in in vitro platforms, owing to their potential for recapitulating human tumors microenvironment, including the complex tumor-ECM biophysical/biomolecular cues, as well as the diversity of malignant and stomal components in a tri-dimensional setting.

This Special Issue aims to merge advanced biomaterials and tissue bioengineering technologies with state-of-the-art medical knowledge, to showcase disruptive approaches for generating physiomimetic 3D in vitro tumor surrogates and to demonstrate their applicability in preclinical screening and tumor microenvironment modelling. It is envisioned that highlighting advanced bioengineering technologies will contribute to identifying the key building-blocks required for mimicking native tumors physiology, and for leveraging microtumors’ predictive potential in the foreseeable future. Reviews, articles and innovative protocols that explore advanced bioengineering approaches for generating organotypic 3D in vitro models that recapitulate the complexity of the tumor microenvironment, while being suitable for preclinical therapies screening, are welcome.

Dr. Vítor Gaspar
Prof. Dr. João F. Mano
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 short 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

organotypic tumor models
tumor microenvironment
preclinical screening
precision oncology
predictive in vitro models
high-throughput analysis
vascularized microtumors
invasion/metastasis models
3D spheroids
3D organoids (iPSC and patient-derived)
bioengineering
ECM-mimetic biomaterials
3D bioprinting
organ-on-a-chip

Published Papers (5 papers)

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Research

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13 pages, 2349 KiB

Open AccessArticle

Pre-Clinical In Vitro Models Used in Cancer Research: Results of a Worldwide Survey

by Sarai Martinez-Pacheco and Lorraine O’Driscoll

Cancers 2021, 13(23), 6033; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13236033 - 30 Nov 2021

Cited by 20 | Viewed by 2937

Abstract

To develop and subsequently get cancer researchers to use organotypic three-dimensional (3D) models that can recapitulate the complexity of human in vivo tumors in an in vitro setting, it is important to establish what in vitro model(s) researchers are currently using and the reasons why. Thus, we developed a survey on this topic, obtained ethics approval, and circulated it throughout the world. The survey was completed by 101 researchers, across all career stages, in academia, clinical or industry settings. It included 40 questions, many with multiple options. Respondents reported on their field of cancer research; type of cancers studied; use of two-dimensional (2D)/monolayer, 2.5D and/or 3D cultures; if using co-cultures, the cell types(s) they co-culture; if using 3D cultures, whether these involve culturing the cells in a particular way to generate spheroids, or if they use additional supports/scaffolds; techniques used to analyze the 2D/2.5D/3D; and their downstream applications. Most researchers (>66%) only use 2D cultures, mainly due to lack of experience and costs. Despite most cancer researchers currently not using the 3D format, >80% recognize their importance and would like to progress to using 3D models. This suggests an urgent need to standardize reliable, robust, reproducible methods for establishing cost-effective 3D cell culture models and their subsequent characterization. Full article

(This article belongs to the Special Issue Organotypic 3D In Vitro Tumor Models: Bioengineering and Applications)

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18 pages, 2956 KiB

Open AccessArticle

Human Breast Extracellular Matrix Microstructures and Protein Hydrogel 3D Cultures of Mammary Epithelial Cells

by Chandler R. Keller, Yang Hu, Kelsey F. Ruud, Anika E. VanDeen, Steve R. Martinez, Barry T. Kahn, Zhiwu Zhang, Roland K. Chen and Weimin Li

Cancers 2021, 13(22), 5857; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13225857 - 22 Nov 2021

Cited by 5 | Viewed by 2474

Abstract

Tissue extracellular matrix (ECM) is a structurally and compositionally unique microenvironment within which native cells can perform their natural biological activities. Cells grown on artificial substrata differ biologically and phenotypically from those grown within their native tissue microenvironment. Studies examining human tissue ECM structures and the biology of human tissue cells in their corresponding tissue ECM are lacking. Such investigations will improve our understanding about human pathophysiological conditions for better clinical care. We report here human normal breast tissue and invasive ductal carcinoma tissue ECM structural features. For the first time, a hydrogel was successfully fabricated using whole protein extracts of human normal breast ECM. Using immunofluorescence staining of type I collagen (Col I) and machine learning of its fibrous patterns in the polymerized human breast ECM hydrogel, we have defined the microstructural characteristics of the hydrogel and compared the microstructures with those of other native ECM hydrogels. Importantly, the ECM hydrogel supported 3D growth and cell-ECM interaction of both normal and cancerous mammary epithelial cells. This work represents further advancement toward full reconstitution of the human breast tissue microenvironment, an accomplishment that will accelerate the use of human pathophysiological tissue-derived matrices for individualized biomedical research and therapeutic development. Full article

(This article belongs to the Special Issue Organotypic 3D In Vitro Tumor Models: Bioengineering and Applications)

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20 pages, 34028 KiB

Open AccessArticle

Novel 3D µtissues Mimicking the Fibrotic Stroma in Pancreatic Cancer to Study Cellular Interactions and Stroma-Modulating Therapeutics

by Kunal P. Pednekar, Marcel A. Heinrich, Joop van Baarlen and Jai Prakash

Cancers 2021, 13(19), 5006; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13195006 - 06 Oct 2021

Cited by 3 | Viewed by 2739

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumor type with low patient survival due to the low efficacy of current treatment options. Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) create a dense fibrotic environment around the tumor cells, preventing therapies from reaching their target. Novel 3D in vitro models are needed that mimic this fibrotic barrier for the development of therapies in a biologically relevant environment. Here, novel PDAC microtissues (µtissues) consisting of pancreatic cancer cell core surrounded by a CAF-laden collagen gel are presented, that is based on the cells own contractility to form a hard-to-penetrate barrier. The contraction of CAFs is demonstrated facilitating the embedding of tumor cells in the center of the µtissue as observed in patients. The µtissues displayed a PDAC-relevant gene expression by comparing their gene profile with transcriptomic patient data. Furthermore, the CAF-dependent proliferation of cancer cells is presented, as well as the suitability of the µtissues to serve as a platform for the screening of CAF-modulating therapies in combination with other (nano)therapies. It is envisioned that these PDAC µtissues can serve as a high-throughput platform for studying cellular interactions in PDAC and for evaluating different treatment strategies in the future. Full article

(This article belongs to the Special Issue Organotypic 3D In Vitro Tumor Models: Bioengineering and Applications)

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15 pages, 2759 KiB

Open AccessArticle

Paracrine Signaling from a Three-Dimensional Model of Bladder Carcinoma and from Normal Bladder Switch the Phenotype of Stromal Fibroblasts

by Sandra Camargo, Ofer N. Gofrit, Assaf Assis and Eduardo Mitrani

Cancers 2021, 13(12), 2972; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13122972 - 14 Jun 2021

Cited by 2 | Viewed by 2718

Abstract

We present a three-dimensional model based on acellular scaffolds to recreate bladder carcinoma in vitro that closely describes the in vivo behavior of carcinoma cells. The integrity of the basement membrane and protein composition of the bladder scaffolds were examined by Laminin immunostaining and LC–MS/MS. Human primary bladder carcinoma cells were then grown on standard monolayer cultures and also seeded on the bladder scaffolds. Apparently, carcinoma cells adhered to the scaffold basement membrane and created a contiguous one-layer epithelium (engineered micro-carcinomas (EMCs)). Surprisingly, the gene expression pattern displayed by EMCs was similar to the profile expressed by the carcinoma cells cultured on plastic. However, the pattern of secreted growth factors was significantly different, as VEGF, FGF, and PIGF were secreted at higher levels by EMCs. We found that only the combination of factors secreted by EMCs, but not the carcinoma cells grown on plastic dishes, was able to induce either the pro-inflammatory phenotype or the myofibroblast phenotype depending on the concentration of the secreted factors. We found that the pro-inflammatory phenotype could be reversed. We propose a unique platform that allows one to decipher the paracrine signaling of bladder carcinoma and how this molecular signaling can switch the phenotypes of fibroblasts. Full article

(This article belongs to the Special Issue Organotypic 3D In Vitro Tumor Models: Bioengineering and Applications)

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Review

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49 pages, 2362 KiB

Open AccessEditor’s ChoiceReview

3D Cancer Models: Depicting Cellular Crosstalk within the Tumour Microenvironment

by Teresa Franchi-Mendes, Rodrigo Eduardo, Giacomo Domenici and Catarina Brito

Cancers 2021, 13(18), 4610; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13184610 - 14 Sep 2021

Cited by 27 | Viewed by 5552

Abstract

The tumour microenvironment plays a critical role in tumour progression and drug resistance processes. Non-malignant cell players, such as fibroblasts, endothelial cells, immune cells and others, interact with each other and with the tumour cells, shaping the disease. Though the role of each cell type and cell communication mechanisms have been progressively studied, the complexity of this cellular network and its role in disease mechanism and therapeutic response are still being unveiled. Animal models have been mainly used, as they can represent systemic interactions and conditions, though they face recognized limitations in translational potential due to interspecies differences. In vitro 3D cancer models can surpass these limitations, by incorporating human cells, including patient-derived ones, and allowing a range of experimental designs with precise control of each tumour microenvironment element. We summarize the role of each tumour microenvironment component and review studies proposing 3D co-culture strategies of tumour cells and non-malignant cell components. Moreover, we discuss the potential of these modelling approaches to uncover potential therapeutic targets in the tumour microenvironment and assess therapeutic efficacy, current bottlenecks and perspectives. Full article

(This article belongs to the Special Issue Organotypic 3D In Vitro Tumor Models: Bioengineering and Applications)

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