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The Role of Stromal Microenvironment in Tumour Angiogenesis: Biological Pathways and Therapeutic Implications

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 16722

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Special Issue Editor

Prof. Dr. Girolamo Ranieri

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Department of Interventional and Integrated Medical Oncology, National Cancer Research Centre, IRCCS Istituto Tumori “Giovanni Paolo II”, Viale Orazio Flacco 65, 70124 Bari, Italy
Interests: primary and metastatic liver tumors; pancreatic tumors; colorectal cancers; breast cancers; intra-arterial chemotherapy; chemoembolization; translational oncology angiogenesis
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Dear Colleagues,

An innovative concept developed in the last decades identifies malignant tumors as entities composed of two tissue compartments: the first one is represented by proliferating tumor cells, the second one is constituted by the stromal microenvironment. In the latter compartment, angiogenesis takes place and plays a central role in tumor development and progression. These compartments interact and influence each other in a paracrine manner. In the stromal compartment, mast cells, macrophages, and fibroblasts can stimulate both endothelial cells and pericytes proliferation, participating in angiogenesis. The number of the above inflammatory stromal cells increases in the transition from normal tissue to tumor tissue when angiogenesis occurs. In this context, these cellular types and the related pro-angiogenic factors such as tryptase, vascular endothelial growth factor, platelet-derived endothelial cell growth factor/thymidine phosphorylase, and others could be distinct targets for therapeutic interventions. On this basis, the stromal microenvironment could be considered a multi-target tissue for novel anti-angiogenic therapies. In this Special Issue, I welcome your contributions in the form of original papers and review manuscripts, from bench to bedside, on all topics related to “The Role of Stromal Microenvironment in Tumour Angiogenesis: Biological Pathways and Therapeutic Implications”.

Prof. Dr. Girolamo Ranieri
Guest Editor

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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.

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Keywords

tumor microenvironment
stromal cells
mast cells
macrophages
fibroblasts
pro-angiogenic factors
angiogenesis
anti-angiogenesis

Published Papers (3 papers)

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Research

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26 pages, 5625 KiB

Open AccessArticle

Simulated Microgravity Influences VEGF, MAPK, and PAM Signaling in Prostate Cancer Cells

by Trine Engelbrecht Hybel, Dorothea Dietrichs, Jayashree Sahana, Thomas J. Corydon, Mohamed Z. Nassef, Markus Wehland, Marcus Krüger, Nils E. Magnusson, Johann Bauer, Kirsten Utpatel, Manfred Infanger, Daniela Grimm and Sascha Kopp

Int. J. Mol. Sci. 2020, 21(4), 1263; https://doi.org/10.3390/ijms21041263 - 13 Feb 2020

Cited by 30 | Viewed by 5213

Abstract

Prostate cancer is one of the leading causes of cancer mortality in men worldwide. An unusual but unique environment for studying tumor cell processes is provided by microgravity, either in space or simulated by ground-based devices like a random positioning machine (RPM). In this study, prostate adenocarcinoma-derived PC-3 cells were cultivated on an RPM for time periods of 3 and 5 days. We investigated the genes associated with the cytoskeleton, focal adhesions, extracellular matrix, growth, survival, angiogenesis, and metastasis. The gene expression of signaling factors of the vascular endothelial growth factor (VEGF), mitogen-activated protein kinase (MAPK), and PI3K/AKT/mTOR (PAM) pathways was investigated using qPCR. We performed immunofluorescence to study the cytoskeleton, histological staining to examine the morphology, and a time-resolved immunofluorometric assay to analyze the cell culture supernatants. When PC-3 cells were exposed to simulated microgravity (s-µg), some cells remained growing as adherent cells (AD), while most cells detached from the cell culture flask bottom and formed multicellular spheroids (MCS). After 3-day RPM exposure, PC-3 cells revealed significant downregulation of the VEGF, SRC1, AKT, MTOR, and COL1A1 gene expression in MCS, whereas FLT1, RAF1, MEK1, ERK1, FAK1, RICTOR, ACTB, TUBB, and TLN1 mRNAs were not significantly changed. ERK2 and TLN1 were elevated in AD, and FLK1, LAMA3, COL4A5, FN1, VCL, CDH1, and NGAL mRNAs were significantly upregulated in AD and MCS after 3 days. After a 5-day culture in s-µg, the PC-3 cells showed significant downregulations of VEGF mRNA in AD and MCS, and FN1, CDH1, and LAMA3 in AD and SCR1 in MCS. In addition, we measured significant upregulations in FLT1, AKT, ERK1, ERK2, LCN2, COL1A1, TUBB, and VCL mRNAs in AD and MCS, and increases in FLK1, FN1, and COL4A5 in MCS as well as LAMB2, CDH1, RAF1, MEK1, SRC1, and MTOR mRNAs in AD. FAK1 and RICTOR were not altered by s-µg. In parallel, the secretion rate of VEGFA and NGAL proteins decreased. Cytoskeletal alterations (F-actin) were visible, as well as a deposition of collagen in the MCS. In conclusion, RPM-exposure of PC-3 cells induced changes in their morphology, cytoskeleton, and extracellular matrix protein synthesis, as well as in their focal adhesion complex and growth behavior. The significant upregulation of genes belonging to the PAM pathway indicated their involvement in the cellular changes occurring in microgravity. Full article

(This article belongs to the Special Issue The Role of Stromal Microenvironment in Tumour Angiogenesis: Biological Pathways and Therapeutic Implications)

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Review

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15 pages, 1882 KiB

Open AccessReview

Bone Marrow Stromal Cells-Induced Drug Resistance in Multiple Myeloma

by Roberto Ria and Angelo Vacca

Int. J. Mol. Sci. 2020, 21(2), 613; https://doi.org/10.3390/ijms21020613 - 17 Jan 2020

Cited by 34 | Viewed by 5738

Abstract

Multiple myeloma is a B-cell lineage cancer in which neoplastic plasma cells expand in the bone marrow and pathophysiological interactions with components of microenvironment influence many biological aspects of the malignant phenotype, including apoptosis, survival, proliferation, and invasion. Despite the therapeutic progress achieved in the last two decades with the introduction of a more effective and safe new class of drugs (i.e., immunomodulators, proteasome inhibitors, monoclonal antibodies), there is improvement in patient survival, and multiple myeloma (MM) remains a non-curable disease. The bone marrow microenvironment is a complex structure composed of cells, extracellular matrix (ECM) proteins, and cytokines, in which tumor plasma cells home and expand. The role of the bone marrow (BM) microenvironment is fundamental during MM disease progression because modification induced by tumor plasma cells is crucial for composing a “permissive” environment that supports MM plasma cells proliferation, migration, survival, and drug resistance. The “activated phenotype” of the microenvironment of multiple myeloma is functional to plasma cell proliferation and spreading and to plasma cell drug resistance. Plasma cell drug resistance induced by bone marrow stromal cells is mediated by stress-managing pathways, autophagy, transcriptional rewiring, and non-coding RNAs dysregulation. These processes represent novel targets for the ever-increasing anti-MM therapeutic armamentarium. Full article

(This article belongs to the Special Issue The Role of Stromal Microenvironment in Tumour Angiogenesis: Biological Pathways and Therapeutic Implications)

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29 pages, 1699 KiB

Open AccessReview

The Crowded Crosstalk between Cancer Cells and Stromal Microenvironment in Gynecological Malignancies: Biological Pathways and Therapeutic Implication

by Rosalba De Nola, Alessio Menga, Alessandra Castegna, Vera Loizzi, Girolamo Ranieri, Ettore Cicinelli and Gennaro Cormio

Int. J. Mol. Sci. 2019, 20(10), 2401; https://doi.org/10.3390/ijms20102401 - 15 May 2019

Cited by 60 | Viewed by 5377

Abstract

The tumor microenvironment plays a pillar role in the progression and the distance dissemination of cancer cells in the main malignancies affecting women—epithelial ovarian cancer, endometrial cancer and cervical cancer. Their milieu acquires specific properties thanks to intense crosstalk between stromal and cancer cells, leading to a vicious circle. Fibroblasts, pericytes, lymphocytes and tumor associated-macrophages orchestrate most of the biological pathways. In epithelial ovarian cancer, high rates of activated pericytes determine a poorer prognosis, defining a common signature promoting ovarian cancer proliferation, local invasion and distant spread. Mesenchymal cells also release chemokines and cytokines under hormonal influence, such as estrogens that drive most of the endometrial cancers. Interestingly, the architecture of the cervical cancer milieu is shaped by the synergy of high-risk Human Papilloma Virus oncoproteins and the activity of stromal estrogen receptor α. Lymphocytes represent a shield against cancer cells but some cell subpopulation could lead to immunosuppression, tumor growth and dissemination. Cytotoxic tumor infiltrating lymphocytes can be eluded by over-adapted cancer cells in a scenario of immune-tolerance driven by T-regulatory cells. Therefore, the tumor microenvironment has a high translational potential offering many targets for biological and immunological therapies. Full article

(This article belongs to the Special Issue The Role of Stromal Microenvironment in Tumour Angiogenesis: Biological Pathways and Therapeutic Implications)

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