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The Role of Tumor Immune Microenvironment in Cancer Cell Invasion and Metastases

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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 (30 July 2023) | Viewed by 21929

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Special Issue Editors

Dr. Artur Mezheyeuski

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Guest Editor

Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
Interests: cancer metastasis; bioinformatics; tumors; metastasis

Dr. Laia Caja Puigsubira

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Guest Editor

Researcher, Department of Medical Biochemistry and Microbiology, Biochemistry and Cell- and Tumour Biology, Uppsala University, Uppsala, Sweden
Interests: glioblastoma; oxidative stress; NADPH oxidases; TGF-beta; EMT; cancer stem cells; microenvironment

Special Issue Information

Dear Colleagues,

With almost 10 million deaths worldwide in 2020, cancer is one of the leading causes of mortality and large clinical and economic burden. Thanks to advances in surgical techniques and neo-adjuvant therapies, the treatment of localized cancer has improved dramatically during last decades. However, more than half of the cancers are diagnosed at stage III or IV, when the tumor already disseminated to local lymph nodes or to distant organs. Moreover, many early-stage patients develop metastases during disease progression. Metastatic cancers are difficult to cure, and they lead to the majority of cancer-related deaths.

In the fight with cancer, a number of milestones have been achieved. We realized that a tumor is a complex dynamic system, composed of malignant cells embedded in a microenvironment of extracellular matrix, resident mesenchymal cells, endothelial cells, and infiltrating immune cells. An understanding of tumor biology helped to develop targeted therapy, the first step on the long way towards personalized cancer treatment. A number of novel therapies have been recently developed directed against non-cancerous elements of the tumor microenvironment. Recently, we entered the era of immunotherapy which has revolutionized the treatment in some cancers. These novel methods were accompanied by great expectations and remarkable achievements; however, they have almost always been followed by deep disappointment, due to inability to identify initially refractory diseases or those that develop resistance.

To improve treatment for patients with advanced cancer stages, we need to understand better the multi-stage process of metastasis formation, and complex interaction of cancer cells with host tissue at metastatic places and the immune system of the patient.

This Special Issue is focused on the processes of cancer cell invasion, metastasis formation, and metastasis progression and the role of the local (immune) microenvironment of host tissue. Up-to-date review articles and experimental papers are welcome.

Dr. Artur Mezheyeuski
Dr. Laia Caja Puigsubira
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. 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 cell invasion
tumor cell survival
tumor microenvironment
immune microenvironment
immunoscore
immune checkpoint inhibitors
cancer associated fibroblasts
cancer metastasis
metastatic niche
metastases and inflammation
metastatic disease
adjuvant treatment
cancer recurrence
cancer progression

Published Papers (7 papers)

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Research

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17 pages, 3574 KiB

Open AccessArticle

(-)-Epigallocatechin-3-Gallate Prevents IL-1β-Induced uPAR Expression and Invasiveness via the Suppression of NF-κB and AP-1 in Human Bladder Cancer Cells

by Dhiraj Kumar Sah, Pham Ngoc Khoi, Shinan Li, Archana Arjunan, Jae-Uk Jeong and Young Do Jung

Int. J. Mol. Sci. 2022, 23(22), 14008; https://doi.org/10.3390/ijms232214008 - 13 Nov 2022

Cited by 7 | Viewed by 1572

Abstract

(-)-Epigallocatechin-3-O-gallate (EGCG), a primary green tea polyphenol, has powerful iron scavengers, belongs to the family of flavonoids with antioxidant properties, and can be used to prevent cancer. Urokinase-type plasminogen activator receptors (uPARs) are glycosylphosphatidylinositol (GPI)-anchored cell membrane receptors that have crucial roles in cell invasion and metastasis of several cancers including bladder cancer. The mechanism of action of EGCG on uPAR expression has not been reported clearly yet. In this study, we investigated the effect of EGCG on interleukin (IL)-1β-induced cell invasion and uPAR activity in T24 human bladder cancer cells. Interestingly, nuclear factor (NF)-κB and activator protein (AP)-1 transcription factors were critically required for IL-1β-induced high uPAR expression, and EGCG suppressed the transcriptional activity of both the ERK1/2 and JNK signaling pathways with the AP-1 subunit c-Jun. EGCG blocked the IL-1β-stimulated reactive oxygen species (ROS) production, in turn suppressing NF-κB signaling and anti-invasion effects by inhibiting uPAR expression. These results suggest that EGCG may exert at least part of its anticancer effect by controlling uPAR expression through the suppression of ERK1/2, JNK, AP-1, and NF-κB. Full article

(This article belongs to the Special Issue The Role of Tumor Immune Microenvironment in Cancer Cell Invasion and Metastases)

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24 pages, 7697 KiB

Open AccessArticle

ADAM10 and ADAM17—Novel Players in Retinoblastoma Carcinogenesis

by Dario Van Meenen, Annika Doege, Emily Alefeld, André Haase, Manfred Beier, Tobias Kiefer, Eva Biewald, Klaus Metz, Oliver Dräger, Maike Anna Busch and Nicole Dünker

Int. J. Mol. Sci. 2022, 23(20), 12621; https://doi.org/10.3390/ijms232012621 - 20 Oct 2022

Cited by 1 | Viewed by 2797

Abstract

A disintegrin and metalloproteinase (ADAM) family proteins, acting as sheddases, are important factors in a number of pathologies, including cancer, and have been suggested as promising therapeutic targets. The study presented focuses on the involvement of ADAM10 and ADAM17 in retinoblastoma (RB), the most common malignant intraocular childhood tumor. A significant correlation between ADAM17 expression levels and RB laterality and RB staging was observed. Levels of ADAM10 or ADAM17 regulating miRNAs miR-145, -152, and -365 were significantly downregulated in RB cell lines, and reduced miR levels with simultaneously upregulated ADAM10 and ADAM17 expression were found in RB patients. The involvement of both ADAMs analyzed in ectodomain shedding of the neuronal cell adhesion molecule L1 (L1CAM), shown to induce pro-tumorigenic effects in RB, was confirmed. Lentiviral ADAM10 and ADAM17 single or ADAM10/17 double knockdown (KD) induced caspase-dependent apoptosis and reduced cell viability, proliferation, growth, and colony formation capacity of RB cells. Moreover, differential phosphorylation of the serine/threonine kinase AKT was observed following ADAM17 KD in RB cells. Chicken chorioallantoic membrane (CAM) assays revealed that ADAM17 and ADAM10/17 depletion decreases the tumorigenic and migration potential of RB cells in vivo. Thus, ADAMs are potential novel targets for future therapeutic RB approaches. Full article

(This article belongs to the Special Issue The Role of Tumor Immune Microenvironment in Cancer Cell Invasion and Metastases)

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14 pages, 11570 KiB

Open AccessArticle

Monitoring Therapeutic Responses to Silicified Cancer Cell Immunotherapy Using PET/MRI in a Mouse Model of Disseminated Ovarian Cancer

by Erik N. Taylor, Colin M. Wilson, Stefan Franco, Henning De May, Lorél Y. Medina, Yirong Yang, Erica B. Flores, Eric Bartee, Reed G. Selwyn and Rita E. Serda

Int. J. Mol. Sci. 2022, 23(18), 10525; https://doi.org/10.3390/ijms231810525 - 10 Sep 2022

Viewed by 1814

Abstract

Current imaging approaches used to monitor tumor progression can lack the ability to distinguish true progression from pseudoprogression. Simultaneous metabolic 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG) positron emission tomography (PET) and magnetic resonance imaging (MRI) offers new opportunities to overcome this challenge by refining tumor identification and monitoring therapeutic responses to cancer immunotherapy. In the current work, spatial and quantitative analysis of tumor burden were performed using simultaneous [¹⁸F]FDG-PET/MRI to monitor therapeutic responses to a novel silicified cancer cell immunotherapy in a mouse model of disseminated serous epithelial ovarian cancer. Tumor progression was validated by bioluminescence imaging of luciferase expressing tumor cells, flow cytometric analysis of immune cells in the tumor microenvironment, and histopathology. While PET demonstrated the presence of metabolically active cancer cells through [¹⁸F]FDG uptake, MRI confirmed cancer-related accumulation of ascites and tissue anatomy. This approach provides complementary information on disease status without a confounding signal from treatment-induced inflammation. This work provides a possible roadmap to facilitate accurate monitoring of therapeutic responses to cancer immunotherapies. Full article

(This article belongs to the Special Issue The Role of Tumor Immune Microenvironment in Cancer Cell Invasion and Metastases)

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13 pages, 3361 KiB

Open AccessArticle

CXCL14 Attenuates Triple-Negative Breast Cancer Progression by Regulating Immune Profiles of the Tumor Microenvironment in a T Cell-Dependent Manner

by Carla Gibbs, Jae Young So, Abdul Ahad, Aleksandra M. Michalowski, Deok-Soo Son and Yang Li

Int. J. Mol. Sci. 2022, 23(16), 9314; https://doi.org/10.3390/ijms23169314 - 18 Aug 2022

Cited by 4 | Viewed by 1997

Abstract

Triple-negative breast cancer (TNBC) is aggressive and has a poor overall survival due to a lack of therapeutic targets compared to other subtypes. Chemokine signature revealed that TNBC had low levels of CXCL14, an orphan homeostatic chemokine to regulate the immune network. Here, we investigated if CXCL14 plays a critical role in TNBC progression, focusing on survival rates, tumor growth and metastasis, and immune profiles in the tumor microenvironment. Analysis of human breast-cancer datasets showed that low CXCL14 expression levels were associated with poor survival rates in patients with breast cancer, particularly for TNBC subtypes. Overexpression of CXCL14 in TNBC 4T1 orthotopic mouse model significantly reduced tumor weights and inhibited lung metastasis. Furthermore, the CXCL14 overexpression altered immune profiles in the tumor microenvironment as follows: decreased F4/80+ macrophages and CD4+CD25+ Treg cells, and increased CD8+T cells in primary tumors; decreased Ly6C+ myeloid cells and CD4+CD25+ Treg cells and increased CD4+ and CD8+T cells in lung metastatic tumors. CXCL14-induced reduction of tumor growth and metastasis was diminished in T cell-deficient nude mice. Taken together, our data demonstrate that CXCL14 inhibits TNBC progression through altering immune profiles in the tumor microenvironment and it is mediated in a T cell-dependent manner. Thus, CXCL14 could be used as a biomarker for prognosis. Full article

(This article belongs to the Special Issue The Role of Tumor Immune Microenvironment in Cancer Cell Invasion and Metastases)

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Review

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21 pages, 698 KiB

Open AccessReview

New Therapeutics for HCC: Does Tumor Immune Microenvironment Matter?

by Arshi Khanam and Shyam Kottilil

Int. J. Mol. Sci. 2023, 24(1), 437; https://doi.org/10.3390/ijms24010437 - 27 Dec 2022

Cited by 12 | Viewed by 2351

Abstract

The incidence of liver cancer is continuously rising where hepatocellular carcinoma (HCC) remains the most common form of liver cancer accounting for approximately 80–90% of the cases. HCC is strongly prejudiced by the tumor microenvironment and being an inflammation-associated condition, the contribution of various immune mechanisms is critical in its development, progression, and metastasis. The tumor immune microenvironment is initially inflammatory which is subsequently replenished by the immunosuppressive cells contributing to tumor immune escape. Regardless of substantial advancement in systemic therapy, HCC has poor prognosis and outcomes attributed to the drug resistance, recurrence, and its metastatic behavior. Therefore, currently, new immunotherapeutic strategies are extensively targeted in preclinical and clinical settings in order to elicit robust HCC-specific immune responses and appear to be quite effective, extending current treatment alternatives. Understanding the complex interplay between the tumor and the immune cells and its microenvironment will provide new insights into designing novel immunotherapeutics to overcome existing treatment hurdles. In this review, we have provided a recent update on immunological mechanisms associated with HCC and discussed potential advancement in immunotherapies for HCC treatment. Full article

(This article belongs to the Special Issue The Role of Tumor Immune Microenvironment in Cancer Cell Invasion and Metastases)

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35 pages, 6767 KiB

Open AccessReview

Dual Role of Fibroblasts Educated by Tumour in Cancer Behavior and Therapeutic Perspectives

by Belén Toledo, Manuel Picon-Ruiz, Juan Antonio Marchal and Macarena Perán

Int. J. Mol. Sci. 2022, 23(24), 15576; https://doi.org/10.3390/ijms232415576 - 8 Dec 2022

Cited by 10 | Viewed by 4343

Abstract

Tumours are complex systems with dynamic interactions between tumour cells, non-tumour cells, and extracellular components that comprise the tumour microenvironment (TME). The majority of TME’s cells are cancer-associated fibroblasts (CAFs), which are crucial in extracellular matrix (ECM) construction, tumour metabolism, immunology, adaptive chemoresistance, and tumour cell motility. CAF subtypes have been identified based on the expression of protein markers. CAFs may act as promoters or suppressors in tumour cells depending on a variety of factors, including cancer stage. Indeed, CAFs have been shown to promote tumour growth, survival and spread, and secretome changes, but they can also slow tumourigenesis at an early stage through mechanisms that are still poorly understood. Stromal–cancer interactions are governed by a variety of soluble factors that determine the outcome of the tumourigenic process. Cancer cells release factors that enhance the ability of fibroblasts to secrete multiple tumour-promoting chemokines, acting on malignant cells to promote proliferation, migration, and invasion. This crosstalk between CAFs and tumour cells has given new prominence to the stromal cells, from being considered as mere physical support to becoming key players in the tumour process. Here, we focus on the concept of cancer as a non-healing wound and the relevance of chronic inflammation to tumour initiation. In addition, we review CAFs heterogeneous origins and markers together with the potential therapeutic implications of CAFs “re-education” and/or targeting tumour progression inhibition. Full article

(This article belongs to the Special Issue The Role of Tumor Immune Microenvironment in Cancer Cell Invasion and Metastases)

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28 pages, 3469 KiB

Open AccessReview

IL-1RAP, a Key Therapeutic Target in Cancer

by Jame Frenay, Pierre-Simon Bellaye, Alexandra Oudot, Alex Helbling, Camille Petitot, Christophe Ferrand, Bertrand Collin and Alexandre M. M. Dias

Int. J. Mol. Sci. 2022, 23(23), 14918; https://doi.org/10.3390/ijms232314918 - 29 Nov 2022

Cited by 4 | Viewed by 6226

Abstract

Cancer is a major cause of death worldwide and especially in high- and upper-middle-income countries. Despite recent progress in cancer therapies, such as chimeric antigen receptor T (CAR-T) cells or antibody-drug conjugate (ADC), new targets expressed by the tumor cells need to be identified in order to selectively drive these innovative therapies to tumors. In this context, IL-1RAP recently showed great potential to become one of these new targets for cancer therapy. IL-1RAP is highly involved in the inflammation process through the interleukins 1, 33, and 36 (IL-1, IL-33, IL-36) signaling pathways. Inflammation is now recognized as a hallmark of carcinogenesis, suggesting that IL-1RAP could play a role in cancer development and progression. Furthermore, IL-1RAP was found overexpressed on tumor cells from several hematological and solid cancers, thus confirming its potential involvement in carcinogenesis. This review will first describe the structure and genetics of IL-1RAP as well as its role in tumor development. Finally, a focus will be made on the therapies based on IL-1RAP targeting, which are now under preclinical or clinical development. Full article

(This article belongs to the Special Issue The Role of Tumor Immune Microenvironment in Cancer Cell Invasion and Metastases)

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