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Tumor Microenvironment: Molecular Mechanisms and Signaling Pathways Involved in Metastatic Progression

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (20 April 2023) | Viewed by 14419

Special Issue Editor

Dr. Elizabeth Thomas

E-Mail Website
Guest Editor
Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
Interests: therapeutic intervention of breast cancer and prostate cancer; cell signalling pathways in cancer; cancer stem cells and its role in metastasis

Special Issue Information

Dear Colleagues,

The tumor microenvironment including the extracellular matrix, the immune cells, normal cells, molecules and the blood vessels plays a significant role in tumor growth and metastasis. Modulating the microenvironment is a key strategy by which many tumors evade host immune response as well as a variety of therapeutic drugs. Understanding the intricate interaction between the tumor cells and its microenvironment can improve the tumor intervention strategies. Establishing pre-metastatic niches is a key strategy by which the tumor cells evade and modulate the host immune response. Further, the extracellular matrix and the stromal cells associated with the tumor microenvironment steer clear of many of the chemotherapeutic agents and render them less efficient. Garnering reports suggest that the cancer stem cells that drive metastasis and recurrence significantly rely on the stromal cells within the microenvironment. Finally, several studies demonstrate the role of stroma-derived extracellular vesicles in driving or impeding cancer progression, largely due to the unique set of miRNA packed within the vesicles.

Currently, the strategies to selectively target the stromal cells such as cancer-associated fibroblasts or the cancer stem cells are in the early stages of development and not many options are available.

The special issue welcomes original research and review articles targeted to:

  • Unravel the complex interaction between the tumor cells and the stroma
  • Therapeutic molecules that interfere with the cell signaling between the tumor cells, cancer stem cells and the stromal cells
  • Release and enrichment of Cancer-derived extracellular vesicles by stroma
  • Role of miRNA in modulating the tumor microenvironment.

Dr. Elizabeth Thomas
Guest Editor

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • tumor microenvironment
  • metastasis
  • cancer stem cells
  • miRNA in cancer
  • cancer-derived extracellular vesicles

Published Papers (7 papers)

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Research

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16 pages, 6080 KiB  
Article
Microcystin-LR-Induced Interaction between M2 Tumor-Associated Macrophage and Colorectal Cancer Cell Promotes Colorectal Cancer Cell Migration through Regulating the Expression of TGF-β1 and CST3
by Xinying Jiang, Hailing Zhang, Hengshuo Zhang, Fan Wang, Xiaochang Wang, Tong Ding, Xuxiang Zhang and Ting Wang
Int. J. Mol. Sci. 2023, 24(13), 10527; https://doi.org/10.3390/ijms241310527 - 23 Jun 2023
Cited by 2 | Viewed by 1144
Abstract
Microcystin-LR (MC-LR) is a toxic secondary metabolite produced by cyanobacteria that has been demonstrated to promote colorectal cancer (CRC). However, the mechanism by which MC-LR enhances CRC in the tumor microenvironment (TME) is poorly understood. To elucidate its role in TME, a co-culture [...] Read more.
Microcystin-LR (MC-LR) is a toxic secondary metabolite produced by cyanobacteria that has been demonstrated to promote colorectal cancer (CRC). However, the mechanism by which MC-LR enhances CRC in the tumor microenvironment (TME) is poorly understood. To elucidate its role in TME, a co-culture system was established using CRC cells and M2 macrophages in a Transwell chamber. The study found that MC-LR promotes CRC cell migration by upregulating TGF-β1 expression and secretion in M2 macrophages and downregulating CST3 in CRC cells. Neutralizing TGF-β1 increased CST3 expression in CRC cells, while overexpressing CST3 in CRC cells suppressed TGF-β1 expression in M2 macrophages, both of which weakened MC-LR-induced cellular motility in the co-culture system. In vivo, the mice in the MC-LR/AOM/DSS group had more tumor nodules, deeper tumor invasion, and higher M2 macrophage infiltration compared to the AOM/DSS group, and the expression of TGF-β1 and CST3 in tumors was consistent with the cellular level. Overall, this study provides insights into the regulatory mechanism of MC-LR on TME, revealing that MC-LR upregulates the expression and secretion of TGF-β1 in M2 macrophages, which in turn inhibits the expression of CST3 in CRC cells to promote migration. Full article
(This article belongs to the Special Issue Tumor Microenvironment: Molecular Mechanisms and Signaling Pathways Involved in Metastatic Progression)
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23 pages, 5974 KiB  
Article
EMT Molecular Signatures of Pancreatic Neuroendocrine Neoplasms
by Abhirami Venugopal, Agnes Michalczyk, Mustafa Khasraw and M. Leigh Ackland
Int. J. Mol. Sci. 2022, 23(21), 13645; https://doi.org/10.3390/ijms232113645 - 07 Nov 2022
Cited by 4 | Viewed by 1688
Abstract
Neuroendocrine neoplasms (NENs) are relatively rare neoplasms occurring predominantly in the gastrointestinal tract and pancreas. Their heterogeneity poses challenges for diagnosis and treatment. There is a paucity of markers for characterisation of NEN tumours. For routine diagnosis, immunohistochemistry of the NEN-specific markers CgA [...] Read more.
Neuroendocrine neoplasms (NENs) are relatively rare neoplasms occurring predominantly in the gastrointestinal tract and pancreas. Their heterogeneity poses challenges for diagnosis and treatment. There is a paucity of markers for characterisation of NEN tumours. For routine diagnosis, immunohistochemistry of the NEN-specific markers CgA and synaptophysin and the proliferation marker Ki-67 are used. These parameters, however, are qualitative and lack the capacity to fully define the tumour phenotype. Molecules of epithelial–mesenchymal transition (EMT) are potential candidates for improved tumour characterisation. Using qRT-PCR, we measured mRNA levels of 27 tumour markers, including 25 EMT-associated markers, in tumour tissue and matched non-tumour tissues for 13 patients with pancreatic NENs. Tissue from patients with three different grades of tumour had distinctly different mRNA profiles. Of the 25 EMT-associated markers analysed, 17 were higher in G3 tissue relative to matched non-tumour tissue, including CD14, CD24, CD31, CD44, CD45, CD56, CK6, CK7, CK13, CK20, NSE, CDX2, CgA, DAXX, PCNA, laminin and Ki-67. The differences in levels of seven EMT-associated markers, Ki-67, DAXX, CD24, CD44, vimentin, laminin and PDX1 plus CgA and NSE (neuroendocrine markers) enabled a distinct molecular signature for each tumour grade to be generated. EMT molecules differentially expressed in three tumour grades have potential for use in tumour stratification and prognostication and as therapeutic targets for treatment of neuroendocrine cancers, following validation with additional samples. Full article
(This article belongs to the Special Issue Tumor Microenvironment: Molecular Mechanisms and Signaling Pathways Involved in Metastatic Progression)
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19 pages, 5746 KiB  
Article
Bufalin Inhibits Tumorigenesis, Stemness, and Epithelial–Mesenchymal Transition in Colorectal Cancer through a C-Kit/Slug Signaling Axis
by Ling Ding, Yuning Yang, Qin Lu, Dongfeng Qu, Parthasarathy Chandrakesan, Hailan Feng, Hong Chen, Xuzheng Chen, Zhuhui Liao, Jian Du, Zhiyun Cao and Nathaniel Weygant
Int. J. Mol. Sci. 2022, 23(21), 13354; https://doi.org/10.3390/ijms232113354 - 01 Nov 2022
Cited by 6 | Viewed by 1719
Abstract
Colorectal cancer (CRC) is a major source of morbidity and mortality, characterized by intratumoral heterogeneity and the presence of cancer stem cells (CSCs). Bufalin has potent activity against many tumors, but studies of its effect on CRC stemness are limited. We explored bufalin’s [...] Read more.
Colorectal cancer (CRC) is a major source of morbidity and mortality, characterized by intratumoral heterogeneity and the presence of cancer stem cells (CSCs). Bufalin has potent activity against many tumors, but studies of its effect on CRC stemness are limited. We explored bufalin’s function and mechanism using CRC patient-derived organoids (PDOs) and cell lines. In CRC cells, bufalin prevented nuclear translocation of β-catenin and down-regulated CSC markers (CD44, CD133, LGR5), pluripotency factors, and epithelial–mesenchymal transition (EMT) markers (N-Cadherin, Slug, ZEB1). Functionally, bufalin inhibited CRC spheroid formation, aldehyde dehydrogenase activity, migration, and invasion. Network analysis identified a C-Kit/Slug signaling axis accounting for bufalin’s anti-stemness activity. Bufalin treatment significantly downregulated C-Kit, as predicted. Furthermore, overexpression of C-Kit induced Slug expression, spheroid formation, and bufalin resistance. Similarly, overexpression of Slug resulted in increased expression of C-Kit and identical functional effects, demonstrating a pro-stemness feedback loop. For further study, we established PDOs from diagnostic colonoscopy. Bufalin differentially inhibited PDO growth and proliferation, induced apoptosis, restored E-cadherin, and downregulated CSC markers CD133 and C-Myc, dependent on C-Kit/Slug. These findings suggest that the C-Kit/Slug axis plays a pivotal role in regulating CRC stemness, and reveal that targeting this axis can inhibit CRC growth and progression. Full article
(This article belongs to the Special Issue Tumor Microenvironment: Molecular Mechanisms and Signaling Pathways Involved in Metastatic Progression)
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18 pages, 4130 KiB  
Article
Comprehensive Analysis of hsa-miR-654-5p’s Tumor-Suppressing Functions
by Chuanyang Liu, Lu Min, Jingyu Kuang, Chushu Zhu, Xinyuan Qiu, Xiaomin Wu, Tianyi Zhang, Sisi Xie and Lingyun Zhu
Int. J. Mol. Sci. 2022, 23(12), 6411; https://doi.org/10.3390/ijms23126411 - 08 Jun 2022
Cited by 2 | Viewed by 1698
Abstract
The pivotal roles of miRNAs in carcinogenesis, metastasis, and prognosis have been demonstrated recently in various cancers. This study intended to investigate the specific roles of hsa-miR-654-5p in lung cancer, which is, in general, rarely discussed. A series of closed-loop bioinformatic functional analyses [...] Read more.
The pivotal roles of miRNAs in carcinogenesis, metastasis, and prognosis have been demonstrated recently in various cancers. This study intended to investigate the specific roles of hsa-miR-654-5p in lung cancer, which is, in general, rarely discussed. A series of closed-loop bioinformatic functional analyses were integrated with in vitro experimental validation to explore the overall biological functions and pan-cancer regulation pattern of miR-654-5p. We found that miR-654-5p abundance was significantly elevated in LUAD tissues and correlated with patients’ survival. A total of 275 potential targets of miR-654-5p were then identified and the miR-654-5p-RNF8 regulation axis was validated in vitro as a proof of concept. Furthermore, we revealed the tumor-suppressing roles of miR-654-5p and demonstrated that miR-654-5p inhibited the lung cancer cell epithelial-mesenchymal transition (EMT) process, cell proliferation, and migration using target-based, abundance-based, and ssGSEA-based bioinformatic methods and in vitro validation. Following the construction of a protein–protein interaction network, 11 highly interconnected hub genes were identified and a five-genes risk scoring model was developed to assess their potential prognostic ability. Our study does not only provide a basic miRNA-mRNA-phenotypes reference map for understanding the function of miR-654-5p in different cancers but also reveals the tumor-suppressing roles and prognostic values of miR-654-5p. Full article
(This article belongs to the Special Issue Tumor Microenvironment: Molecular Mechanisms and Signaling Pathways Involved in Metastatic Progression)
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Review

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20 pages, 2682 KiB  
Review
Strategies for Engineering of Extracellular Vesicles
by Anna A. Danilushkina, Charles C. Emene, Nicolai A. Barlev and Marina O. Gomzikova
Int. J. Mol. Sci. 2023, 24(17), 13247; https://doi.org/10.3390/ijms241713247 - 26 Aug 2023
Cited by 8 | Viewed by 2056
Abstract
Extracellular vesicles (EVs) are membrane vesicles released by cells into the extracellular space. EVs mediate cell-to-cell communication through local and systemic transportation of biomolecules such as DNA, RNA, transcription factors, cytokines, chemokines, enzymes, lipids, and organelles within the human body. EVs gained a [...] Read more.
Extracellular vesicles (EVs) are membrane vesicles released by cells into the extracellular space. EVs mediate cell-to-cell communication through local and systemic transportation of biomolecules such as DNA, RNA, transcription factors, cytokines, chemokines, enzymes, lipids, and organelles within the human body. EVs gained a particular interest from cancer biology scientists because of their role in the modulation of the tumor microenvironment through delivering bioactive molecules. In this respect, EVs represent an attractive therapeutic target and a means for drug delivery. The advantages of EVs include their biocompatibility, small size, and low immunogenicity. However, there are several limitations that restrict the widespread use of EVs in therapy, namely, their low specificity and payload capacity. Thus, in order to enhance the therapeutic efficacy and delivery specificity, the surface and composition of extracellular vesicles should be modified accordingly. In this review, we describe various approaches to engineering EVs, and further discuss their advantages and disadvantages to promote the application of EVs in clinical practice. Full article
(This article belongs to the Special Issue Tumor Microenvironment: Molecular Mechanisms and Signaling Pathways Involved in Metastatic Progression)
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11 pages, 831 KiB  
Review
Bone Metastasis and Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer (NSCLC): Microenvironment and Possible Clinical Implications
by Alessandro Del Conte, Elisa De Carlo, Elisa Bertoli, Brigida Stanzione, Alberto Revelant, Manuela Bertola, Michele Spina and Alessandra Bearz
Int. J. Mol. Sci. 2022, 23(12), 6832; https://doi.org/10.3390/ijms23126832 - 20 Jun 2022
Cited by 17 | Viewed by 2933
Abstract
Patients with non-small cell lung cancer (NSCLC) develop bone metastasis (BoM) in more than 50% of cases during the course of the disease. This metastatic site can lead to the development of skeletal related events (SREs), such as severe pain, pathological fractures, spinal [...] Read more.
Patients with non-small cell lung cancer (NSCLC) develop bone metastasis (BoM) in more than 50% of cases during the course of the disease. This metastatic site can lead to the development of skeletal related events (SREs), such as severe pain, pathological fractures, spinal compression, and hypercalcemia, which reduce the patient’s quality of life. Recently, the treatment of advanced NSCLC has radically changed due to the advent of immunotherapy. Immune checkpoint inhibitors (ICI) alone or in combination with chemotherapy have become the main therapeutic strategy for advanced or metastatic NSCLC without driver gene mutations. Since survival has increased, it has become even more important to treat bone metastasis to prevent SRE. We know that the presence of bone metastasis is a negative prognostic factor. The lower efficacy of immunotherapy treatments in BoM+ patients could be induced by the presence of a particular immunosuppressive tumor and bone microenvironment. This article reviews the most important pre-clinical and clinical scientific evidence on the reasons for this lower sensitivity to immunotherapy and the need to combine bone target therapies (BTT) with immunotherapy to improve patient outcome. Full article
(This article belongs to the Special Issue Tumor Microenvironment: Molecular Mechanisms and Signaling Pathways Involved in Metastatic Progression)
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15 pages, 501 KiB  
Review
Brain Metastases Management in Oncogene-Addicted Non-Small Cell Lung Cancer in the Targeted Therapies Era
by Elisa De Carlo, Elisa Bertoli, Alessandro Del Conte, Brigida Stanzione, Eleonora Berto, Alberto Revelant, Michele Spina and Alessandra Bearz
Int. J. Mol. Sci. 2022, 23(12), 6477; https://doi.org/10.3390/ijms23126477 - 09 Jun 2022
Cited by 7 | Viewed by 2418
Abstract
The therapeutic landscape in patients with advanced non-small-cell lung cancer harboring oncogenic biomarkers has radically changed with the development of targeted therapies. Although lung cancers are known to frequently metastasize to the brain, oncogene-driven non-small-cell lung cancer patients show a higher incidence of [...] Read more.
The therapeutic landscape in patients with advanced non-small-cell lung cancer harboring oncogenic biomarkers has radically changed with the development of targeted therapies. Although lung cancers are known to frequently metastasize to the brain, oncogene-driven non-small-cell lung cancer patients show a higher incidence of both brain metastases at baseline and a further risk of central nervous system progression/relapse. Recently, a new generation of targeted agents, highly active in the central nervous system, has improved the control of intracranial disease. The intracranial activity of these drugs poses a crucial issue in determining the optimal management sequence in oncogene-addicted non-small-cell lung cancer patients with brain metastases, with a potential change of paradigm from primary brain irradiation to central nervous system penetrating targeted inhibitors. Full article
(This article belongs to the Special Issue Tumor Microenvironment: Molecular Mechanisms and Signaling Pathways Involved in Metastatic Progression)
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