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Bioengineering the Cellular and Matrix Microenvironment of the Tumor-Stroma

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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 November 2021) | Viewed by 27570

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Special Issue Editor

Prof. Dr. Umber Cheema

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Guest Editor

UCL Centre for 3D Models of Health and Disease, Division of Surgery and Interventional Sciences, University College London, London WC1E 6BT, UK
Interests: 3D models; bioengineering; tumouroids; vascular network engineering; collagen; hypoxia

Special Issue Information

Dear Colleagues,

The importance of the native stroma to cancer and tumor progression is well established. The interplay of cancerous cells with both cells and the matrix of the native stroma can both aid and prevent the progression of cancer. The development of complex, biomimetic and humanized tumor models will advance our understanding of this process.

This Special Issue will highlight critical research in this area, where advanced 3D models are utilized to shed light on the interplay of the tumor with the surrounding stroma. Biomimetic factors include matrix composition, stiffness, oxygen state, geometry, chemotactic and haptotactic gradients as well as the cellular composition of the stroma. In particular the introduction of an active immune component and functional vasculature to both tumor and stroma models will provide opportunities to thoroughly interrogate the interplay between these two interdependent components. The development of biomimetic models will provide breakthroughs in our understanding of fundamental cancer biology.

Prof. Dr. Umber Cheema
Guest Editor

Manuscript Submission Information

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Keywords

3D models
organoids
tumoroids
extracellular matrix
tumor stroma
immune component
engineered vascular networks

Published Papers (6 papers)

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Research

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21 pages, 9053 KiB

Open AccessArticle

The Origin of Stroma Influences the Biological Characteristics of Oral Squamous Cell Carcinoma

by Haruka Omori, Qiusheng Shan, Kiyofumi Takabatake, Keisuke Nakano, Hotaka Kawai, Shintaro Sukegawa, Hidetsugu Tsujigiwa and Hitoshi Nagatsuka

Cancers 2021, 13(14), 3491; https://doi.org/10.3390/cancers13143491 - 12 Jul 2021

Cited by 6 | Viewed by 2640

Abstract

Normal stromal cells surrounding the tumor parenchyma, such as the extracellular matrix (ECM), normal fibroblasts, mesenchymal stromal cells, and osteoblasts, play a significant role in the progression of cancers. However, the role of gingival and periodontal ligament tissue-derived stromal cells in OSCC progression is unclear. In this study, the effect of G-SCs and P-SCs on the differentiation, proliferation, invasion, and migration of OSCC cells in vitro was examined by Giemsa staining, Immunofluorescence (IF), (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) (MTS), invasion, and migration assays. Furthermore, the effect of G-SCs and P-SCs on the differentiation, proliferation, and bone invasion by OSCC cells in vivo was examined by hematoxylin-eosin (HE) staining, immunohistochemistry (IHC), and tartrate-resistant acid phosphatase (TRAP) staining, respectively. Finally, microarray data and bioinformatics analyses identified potential genes that caused the different effects of G-SCs and P-SCs on OSCC progression. The results showed that both G-SCs and P-SCs inhibited the differentiation and promoted the proliferation, invasion, and migration of OSCC in vitro and in vivo. In addition, genes, including CDK1, BUB1B, TOP2A, DLGAP5, BUB1, and CCNB2, are probably involved in causing the different effects of G-SCs and P-SCs on OSCC progression. Therefore, as a potential regulatory mechanism, both G-SCs and P-SCs can promote OSCC progression. Full article

(This article belongs to the Special Issue Bioengineering the Cellular and Matrix Microenvironment of the Tumor-Stroma)

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20 pages, 2318 KiB

Open AccessArticle

Organ-Specific, Fibroblast-Derived Matrix as a Tool for Studying Breast Cancer Metastasis

by Adina R. D. Jensen, Edward R. Horton, Lene H. Blicher, Elin J. Pietras, Cornelia Steinhauer, Raphael Reuten, Erwin M. Schoof and Janine T. Erler

Cancers 2021, 13(13), 3331; https://doi.org/10.3390/cancers13133331 - 2 Jul 2021

Cited by 6 | Viewed by 4358

Abstract

During the metastatic process, breast cancer cells must come into contact with the extra-cellular matrix (ECM) at every step. The ECM provides both structural support and biochemical cues, and cell–ECM interactions can lead to changes in drug response. Here, we used fibroblast-derived ECM (FDM) to perform high throughput drug screening of 4T1 breast cancer cells on metastatic organ ECM (lung), and we see that drug response differs from treatment on plastic. The FDMs that we can produce from different organs are abundant in and contains a complex mixture of ECM proteins. We also show differences in ECM composition between the primary site and secondary organ sites. Furthermore, we show that global kinase signalling of 4T1 cells on the ECM is relatively unchanged between organs, while changes in signalling compared to plastic are significant. Our study highlights the importance of context when testing drug response in vitro, showing that consideration of the ECM is critically important. Full article

(This article belongs to the Special Issue Bioengineering the Cellular and Matrix Microenvironment of the Tumor-Stroma)

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Review

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27 pages, 950 KiB

Open AccessReview

Stromal Co-Cultivation for Modeling Breast Cancer Dormancy in the Bone Marrow

by Robert Wieder

Cancers 2022, 14(14), 3344; https://doi.org/10.3390/cancers14143344 - 9 Jul 2022

Cited by 5 | Viewed by 2316

Abstract

Cancers metastasize to the bone marrow before primary tumors can be detected. Bone marrow micrometastases are resistant to therapy, and while they are able to remain dormant for decades, they recur steadily and result in incurable metastatic disease. The bone marrow microenvironment maintains the dormancy and chemoresistance of micrometastases through interactions with multiple cell types and through structural and soluble factors. Modeling dormancy in vitro can identify the mechanisms of these interactions. Modeling also identifies mechanisms able to disrupt these interactions or define novel interactions that promote the reawakening of dormant cells. The in vitro modeling of the interactions of cancer cells with various bone marrow elements can generate hypotheses on the mechanisms that control dormancy, treatment resistance and reawakening in vivo. These hypotheses can guide in vivo murine experiments that have high probabilities of succeeding in order to verify in vitro findings while minimizing the use of animals in experiments. This review outlines the existing data on predominant stromal cell types and their use in 2D co-cultures with cancer cells. Full article

(This article belongs to the Special Issue Bioengineering the Cellular and Matrix Microenvironment of the Tumor-Stroma)

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19 pages, 912 KiB

Open AccessReview

Modeling the Role of Cancer-Associated Fibroblasts in Tumor Cell Invasion

by Stephanie Poon and Laurie E. Ailles

Cancers 2022, 14(4), 962; https://doi.org/10.3390/cancers14040962 - 15 Feb 2022

Cited by 14 | Viewed by 5959

Abstract

The major cause of cancer-related deaths can be attributed to the metastatic spread of tumor cells—a dynamic and complex multi-step process beginning with tumor cells acquiring an invasive phenotype to allow them to travel through the blood and lymphatic vessels to ultimately seed at a secondary site. Over the years, various in vitro models have been used to characterize specific steps in the cascade to collectively begin providing a clearer picture of the puzzle of metastasis. With the discovery of the TME’s supporting role in activating tumor cell invasion and metastasis, these models have evolved in parallel to accommodate features of the TME and to observe its interactions with tumor cells. In particular, CAFs that reside in reactive tumor stroma have been shown to play a substantial pro-invasive role through their matrix-modifying functions; accordingly, this warranted further investigation with the development and use of invasion assays that could include these stromal cells. This review explores the growing toolbox of assays used to study tumor cell invasion, from the simple beginnings of a tumor cell and extracellular matrix set-up to the advent of models that aim to more closely recapitulate the interplay between tumor cells, CAFs and the extracellular matrix. These models will prove to be invaluable tools to help tease out the intricacies of tumor cell invasion. Full article

(This article belongs to the Special Issue Bioengineering the Cellular and Matrix Microenvironment of the Tumor-Stroma)

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20 pages, 1344 KiB

Open AccessReview

Decellularized Colorectal Cancer Matrices as Bioactive Scaffolds for Studying Tumor-Stroma Interactions

by Ângela Marques-Magalhães, Tânia Cruz, Ângela Margarida Costa, Diogo Estêvão, Elisabete Rios, Pedro Amoroso Canão, Sérgia Velho, Fátima Carneiro, Maria José Oliveira and Ana Patrícia Cardoso

Cancers 2022, 14(2), 359; https://doi.org/10.3390/cancers14020359 - 12 Jan 2022

Cited by 11 | Viewed by 2942

Abstract

More than a physical structure providing support to tissues, the extracellular matrix (ECM) is a complex and dynamic network of macromolecules that modulates the behavior of both cancer cells and associated stromal cells of the tumor microenvironment (TME). Over the last few years, several efforts have been made to develop new models that accurately mimic the interconnections within the TME and specifically the biomechanical and biomolecular complexity of the tumor ECM. Particularly in colorectal cancer, the ECM is highly remodeled and disorganized and constitutes a key component that affects cancer hallmarks, such as cell differentiation, proliferation, angiogenesis, invasion and metastasis. Therefore, several scaffolds produced from natural and/or synthetic polymers and ceramics have been used in 3D biomimetic strategies for colorectal cancer research. Nevertheless, decellularized ECM from colorectal tumors is a unique model that offers the maintenance of native ECM architecture and molecular composition. This review will focus on innovative and advanced 3D-based models of decellularized ECM as high-throughput strategies in colorectal cancer research that potentially fill some of the gaps between in vitro 2D and in vivo models. Our aim is to highlight the need for strategies that accurately mimic the TME for precision medicine and for studying the pathophysiology of the disease. Full article

(This article belongs to the Special Issue Bioengineering the Cellular and Matrix Microenvironment of the Tumor-Stroma)

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28 pages, 2755 KiB

Open AccessReview

The Functional Role of Extracellular Matrix Proteins in Cancer

by Nadezhda V. Popova and Manfred Jücker

Cancers 2022, 14(1), 238; https://doi.org/10.3390/cancers14010238 - 4 Jan 2022

Cited by 66 | Viewed by 8382

Abstract

The extracellular matrix (ECM) is highly dynamic as it is constantly deposited, remodeled and degraded to maintain tissue homeostasis. ECM is a major structural component of the tumor microenvironment, and cancer development and progression require its extensive reorganization. Cancerized ECM is biochemically different in its composition and is stiffer compared to normal ECM. The abnormal ECM affects cancer progression by directly promoting cell proliferation, survival, migration and differentiation. The restructured extracellular matrix and its degradation fragments (matrikines) also modulate the signaling cascades mediated by the interaction with cell-surface receptors, deregulate the stromal cell behavior and lead to emergence of an oncogenic microenvironment. Here, we summarize the current state of understanding how the composition and structure of ECM changes during cancer progression. We also describe the functional role of key proteins, especially tenascin C and fibronectin, and signaling molecules involved in the formation of the tumor microenvironment, as well as the signaling pathways that they activate in cancer cells. Full article

(This article belongs to the Special Issue Bioengineering the Cellular and Matrix Microenvironment of the Tumor-Stroma)

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