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Cells
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Extracellular Matrix in the Tumor Microenvironment and Its Impact on...
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Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Motility and Adhesion".

Deadline for manuscript submissions: closed (28 February 2023) | Viewed by 11075

Special Issue Editors

Dr. Dong-Joo Cheon

E-Mail Website
Guest Editor
Department of Regenerative and Cancer Cell Biology, Mail Code 165, Room MS-338, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208, USA
Interests: ovarian cancer; chemoresistance; metastasis; tumor-stroma interaction; tumor microenvironment; collagen; cancer-associated fibroblasts; biomarkers; targeted therapy
Dr. John M. Lamar

E-Mail Website
Guest Editor
Department of Molecular and Cellular Physiology, Mail Code 8, Room ME-600B5, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208, USA
Interests: hippo-YAP/TAZ pathway; metastasis; epithelioid hemangioendothelioma (EHE); melanoma; breast cancer; tumor microenvironment; ECM
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The extracellular matrix (ECM) is a major structural component of the tumor microenvironment (TME) and comprised of a network of biochemically distinct components, including fibrous proteins, glycoproteins, proteoglycans, and polysaccharides. The ECM is a highly dynamic structure, constantly undergoing a remodeling process where ECM components are deposited, degraded, or modified. In cancer, abnormal ECM dynamics are caused by alterations in ECM synthesis and secretion as well as the expression or function of matrix-remodeling enzymes. Tumor ECM is mechanically and biochemically distinct in composition then normal ECM. 

Increasing evidence suggests that ECM proteins establish a physical and biochemical niche for cancer cells and cancer stem cells to promote tumor progression and therapeutic resistance. Dense and stiff ECM exerts mechanical forces on cancer cells activating signaling cascades that promote proliferation, survival, motility, and therapeutic resistance. Stiff ECM can also promote an immunosuppressive TME and physically protect cancer cells from immune cell attack and cytotoxic drugs. Stiff linear collagen fibers serve as fast migratory tracks for stromal cells and cancer cells. Thus, to develop novel therapeutic strategies, it is crucial to understand the role of ECM in tumor-stroma interaction and therapeutic resistance. 

This special issue of Cells aims to explore the role of the ECM in regulating cancer cells and various TME components and how it affects cancer therapy. We welcome review articles and original basic, translational, or clinical research articles. Research areas include (but are not limited to): the role of ECM molecules and ECM modifying enzymes in regulating physical and chemical properties of TME or metastatic niche; ECM regulation of cellular and molecular phenotypes of cancer cells, stoma cells, or immune cells in the TME; the role of ECM in cancer stemness; the impact of ECM on tumor-stroma interaction; molecular mechanisms by which ECM promotes therapeutic resistance; novel techniques for visualization or investigation of ECM functions in cancer in vitro or in vivo; use of  ECM as a diagnostic or prognostic tool; and novel ECM-targeting therapeutic strategies for cancer.

We look forward to receiving your expert contributions.

Dr. Dong-Joo Cheon
Dr. John M. Lamar
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. Cells 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 2700 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

  • extracellular matrix
  • matrix remodeling
  • matrix stiffness
  • collagen
  • MMP
  • integrin
  • therapy resistance
  • cell migration
  • immune exclusion

Published Papers (4 papers)

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Research

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17 pages, 7647 KiB  
Article
Dynamic Changes in the Extracellular Matrix in Primary, Metastatic, and Recurrent Ovarian Cancers
by Arkadiusz Gertych, Ann E. Walts, Keyi Cheng, Manyun Liu, Joshi John, Jenny Lester, Beth Y. Karlan and Sandra Orsulic
Cells 2022, 11(23), 3769; https://doi.org/10.3390/cells11233769 - 25 Nov 2022
Cited by 2 | Viewed by 1885
Abstract
Cancer-associated fibroblasts (CAFs) and their extracellular matrix are active participants in cancer progression. While it is known that functionally different subpopulations of CAFs co-exist in ovarian cancer, it is unclear whether certain CAF subsets are enriched during metastatic progression and/or chemotherapy. Using computational [...] Read more.
Cancer-associated fibroblasts (CAFs) and their extracellular matrix are active participants in cancer progression. While it is known that functionally different subpopulations of CAFs co-exist in ovarian cancer, it is unclear whether certain CAF subsets are enriched during metastatic progression and/or chemotherapy. Using computational image analyses of patient-matched primary high-grade serous ovarian carcinomas, synchronous pre-chemotherapy metastases, and metachronous post-chemotherapy metastases from 42 patients, we documented the dynamic spatiotemporal changes in the extracellular matrix, fibroblasts, epithelial cells, immune cells, and CAF subsets expressing different extracellular matrix components. Among the different CAF subsets, COL11A1+ CAFs were associated with linearized collagen fibers and exhibited the greatest enrichment in pre- and post-chemotherapy metastases compared to matched primary tumors. Although pre- and post-chemotherapy metastases were associated with increased CD8+ T cell infiltration, the infiltrate was not always evenly distributed between the stroma and cancer cells, leading to an increased frequency of the immune-excluded phenotype where the majority of CD8+ T cells are present in the tumor stroma but absent from the tumor parenchyma. Overall, most of the differences in the tumor microenvironment were observed between primary tumors and metastases, while fewer differences were observed between pre- and post-treatment metastases. These data suggest that the tumor microenvironment is largely determined by the primary vs. metastatic location of the tumor while chemotherapy does not have a significant impact on the host microenvironment. Full article
(This article belongs to the Special Issue Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy)
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20 pages, 4921 KiB  
Article
Multiplexed Imaging Reveals the Spatial Relationship of the Extracellular Acidity-Targeting pHLIP with Necrosis, Hypoxia, and the Integrin-Targeting cRGD Peptide
by Zhao-Hui Jin, Atsushi B. Tsuji, Mélissa Degardin, Pascal Dumy, Didier Boturyn and Tatsuya Higashi
Cells 2022, 11(21), 3499; https://doi.org/10.3390/cells11213499 - 04 Nov 2022
Cited by 1 | Viewed by 2271
Abstract
pH (low) insertion peptides (pHLIPs) have been developed for cancer imaging and therapy targeting the acidic extracellular microenvironment. However, the characteristics of intratumoral distribution (ITD) of pHLIPs are not yet fully understood. This study aimed to reveal the details of the ITD of [...] Read more.
pH (low) insertion peptides (pHLIPs) have been developed for cancer imaging and therapy targeting the acidic extracellular microenvironment. However, the characteristics of intratumoral distribution (ITD) of pHLIPs are not yet fully understood. This study aimed to reveal the details of the ITD of pHLIPs and their spatial relationship with other tumor features of concern. The fluorescent dye-labeled pHLIPs were intravenously administered to subcutaneous xenograft mouse models of U87MG and IGR-OV1 expressing αVβ3 integrins (using large necrotic tumors). The αVβ3 integrin-targeting Cy5.5-RAFT-c(-RGDfK-)4 was used as a reference. In vivo and ex vivo fluorescence imaging, whole-tumor section imaging, fluorescence microscopy, and multiplexed fluorescence colocalization analysis were performed. The ITD of fluorescent dye-labeled pHLIPs was heterogeneous, having a high degree of colocalization with necrosis. A direct one-to-one comparison of highly magnified images revealed the cellular localization of pHLIP in pyknotic, karyorrhexis, and karyolytic necrotic cells. pHLIP and hypoxia were spatially contiguous but not overlapping cellularly. The hypoxic region was found between the ITDs of pHLIP and the cRGD peptide and the Ki-67 proliferative activity remained detectable in the pHLIP-accumulated regions. The results provide a better understanding of the characteristics of ITD of pHLIPs, leading to new insights into the theranostic applications of pHLIPs. Full article
(This article belongs to the Special Issue Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy)
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23 pages, 4228 KiB  
Article
Mechanomimetic 3D Scaffolds as a Humanized In Vitro Model for Ovarian Cancer
by Francesca Paradiso, Stefania Lenna, S. Andrea Gazze, Jezabel Garcia Parra, Kate Murphy, Lavinia Margarit, Deyarina Gonzalez, Lewis Francis and Francesca Taraballi
Cells 2022, 11(5), 824; https://doi.org/10.3390/cells11050824 - 26 Feb 2022
Cited by 3 | Viewed by 3753
Abstract
The mechanical homeostasis of tissues can be altered in response to trauma or disease, such as cancer, resulting in altered mechanotransduction pathways that have been shown to impact tumor development, progression, and the efficacy of therapeutic approaches. Specifically, ovarian cancer progression is parallel [...] Read more.
The mechanical homeostasis of tissues can be altered in response to trauma or disease, such as cancer, resulting in altered mechanotransduction pathways that have been shown to impact tumor development, progression, and the efficacy of therapeutic approaches. Specifically, ovarian cancer progression is parallel to an increase in tissue stiffness and fibrosis. With in vivo models proving difficult to study, tying tissue mechanics to altered cellular and molecular properties necessitate advanced, tunable, in vitro 3D models able to mimic normal and tumor mechanic features. First, we characterized normal human ovary and high-grade serous (HGSC) ovarian cancer tissue stiffness to precisely mimic their mechanical features on collagen I-based sponge scaffolds, soft (NS) and stiff (MS), respectively. We utilized three ovarian cancer cell lines (OVCAR-3, Caov-3, and SKOV3) to evaluate changes in viability, morphology, proliferation, and sensitivity to doxorubicin and liposomal doxorubicin treatment in response to a mechanically different microenvironment. High substrate stiffness promoted the proliferation of Caov-3 and SKOV3 cells without changing their morphology, and upregulated mechanosensors YAP/TAZ only in SKOV3 cells. After 7 days in culture, both OVCAR3 and SKOV3 decreased the MS scaffold storage modulus (stiffness), suggesting a link between cell proliferation and the softening of the matrix. Finally, high matrix stiffness resulted in higher OVCAR-3 and SKOV3 cell cytotoxicity in response to doxorubicin. This study demonstrates the promise of biomimetic porous scaffolds for effective inclusion of mechanical parameters in 3D cancer modeling. Furthermore, this work establishes the use of porous scaffolds for studying ovarian cancer cells response to mechanical changes in the microenvironment and as a meaningful platform from which to investigate chemoresistance and drug response. Full article
(This article belongs to the Special Issue Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy)
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Review

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27 pages, 893 KiB  
Review
The Extracellular Matrix and Neuroblastoma Cell Communication—A Complex Interplay and Its Therapeutic Implications
by Irena Horwacik
Cells 2022, 11(19), 3172; https://doi.org/10.3390/cells11193172 - 10 Oct 2022
Cited by 6 | Viewed by 2275
Abstract
Neuroblastoma (NB) is a pediatric neuroendocrine neoplasm. It arises from the sympatho-adrenal lineage of neural-crest-derived multipotent progenitor cells that fail to differentiate. NB is the most common extracranial tumor in children, and it manifests undisputed heterogeneity. Unsatisfactory outcomes of high-risk (HR) NB patients [...] Read more.
Neuroblastoma (NB) is a pediatric neuroendocrine neoplasm. It arises from the sympatho-adrenal lineage of neural-crest-derived multipotent progenitor cells that fail to differentiate. NB is the most common extracranial tumor in children, and it manifests undisputed heterogeneity. Unsatisfactory outcomes of high-risk (HR) NB patients call for more research to further inter-relate treatment and molecular features of the disease. In this regard, it is well established that in the tumor microenvironment (TME), malignant cells are engaged in complex and dynamic interactions with the extracellular matrix (ECM) and stromal cells. The ECM can be a source of both pro- and anti-tumorigenic factors to regulate tumor cell fate, such as survival, proliferation, and resistance to therapy. Moreover, the ECM composition, organization, and resulting signaling networks are vastly remodeled during tumor progression and metastasis. This review mainly focuses on the molecular mechanisms and effects of interactions of selected ECM components with their receptors on neuroblastoma cells. Additionally, it describes roles of enzymes modifying and degrading ECM in NB. Finally, the article gives examples on how the knowledge is exploited for prognosis and to yield new treatment options for NB patients. Full article
(This article belongs to the Special Issue Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy)
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