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Cellular Crosstalk in the Tumor Microenvironment

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

Deadline for manuscript submissions: 15 May 2024 | Viewed by 8932

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Special Issue Editors

Dr. Ehnman Monika

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Guest Editor

Department of Oncology-Pathology, Karolinska Institutet, 17177 Stockholm, Sweden
Interests: sarcoma model systems; tumor microenvironment; immune cells; stromal cells; multiplex imaging

Dr. Rainer Heuchel

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Guest Editor

Department of Clinical Science, Intervention and Technology, CLINTEC Surgery, 14186 Stockholm, Sweden
Interests: pancreatic cancer; cancer stroma cell crosstalk; preclinical in vitro and in vivo models; drug testing

Dr. Jonas Fuxe

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Guest Editor

Department of Laboratory Medicine, Karolinska Institutet, Division of Pathology, 14186 Stockholm, Sweden
Interests: epithelial–mesenchymal transition; TGFB; breast cancer; metastasis; inflammation
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Special Issue Information

Dear Colleagues,

Understanding the molecular communication between malignant cells, their tumor microenvironment, and surrounding tissue is essential for successful therapy development. Targeted therapies, immunomodulatory agents, and biomarkers are all examples of intense research efforts that originate from molecular biology and have successfully translated into clinical practice in specific settings. However, tumor heterogeneity and adverse effects of aggressive treatments remain an obstacle. Metastatic growth is particularly challenging to combat, especially if the molecular landscape of the tumor is unknown.

For this Special Issue, we aim to address present challenges and opportunities within the tumor microenvironment field from mainly a molecular and biochemical perspective. We encourage submissions of high-quality original articles and review articles on cellular crosstalk with topics including innovative model systems and techniques. Signaling pathways, their relevance, and mechanisms of actions in selected tumor microenvironments will particularly be discussed. Our hope is to collect comprehensive up-to-date knowledge on the underlying biology controlling disease progression and, ultimately, patient survival.

Dr. Ehnman Monika
Dr. Rainer Heuchel
Dr. Jonas Fuxe
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

cancer
metastasis
inflammation
cancer-associated fibroblasts
biomarkers
multiplex imaging
in vitro models
animal models
immunotherapy

Published Papers (4 papers)

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Research

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17 pages, 3717 KiB

Open AccessArticle

Role of Epiregulin on Lipopolysaccharide-Induced Hepatocarcinogenesis as a Mediator via EGFR Signaling in the Cancer Microenvironment

by Takahiro Kubo, Norihisa Nishimura, Kosuke Kaji, Fumimasa Tomooka, Akihiko Shibamoto, Satoshi Iwai, Junya Suzuki, Hideto Kawaratani, Tadashi Namisaki, Takemi Akahane and Hitoshi Yoshiji

Int. J. Mol. Sci. 2024, 25(8), 4405; https://doi.org/10.3390/ijms25084405 - 17 Apr 2024

Viewed by 253

Abstract

Lipopolysaccharides (LPSs) have been reported to be important factors in promoting the progression of hepatocellular carcinoma (HCC), but the corresponding molecular mechanisms remain to be elucidated. We hypothesize that epiregulin (EREG), an epidermal growth factor (EGF) family member derived from hepatic stellate cells (HSCs) and activated by LPS stimulation, is a crucial mediator of HCC progression with epidermal growth factor receptor (EGFR) expression in the tumor microenvironment. We used a mouse xenograft model of Huh7 cells mixed with half the number of LX-2 cells, with/without intraperitoneal LPS injection, to elucidate the role of EREG in LPS-induced HCC. In the mouse model, LPS administration significantly enlarged the size of xenografted tumors and elevated the expression of EREG in tumor tissues compared with those in negative controls. Moreover, CD34 immunostaining and the gene expressions of angiogenic markers by a reverse transcription polymerase chain reaction revealed higher vascularization, with increased interleukin-8 (IL-8) expression in the tumors of the mice group treated with LPS compared to those without LPS. Our data collectively suggested that EREG plays an important role in the cancer microenvironment under the influence of LPS to increase not only the tumor cell growth and migration/invasion of EGFR-positive HCC cells but also tumor neovascularization via IL-8 signaling. Full article

(This article belongs to the Special Issue Cellular Crosstalk in the Tumor Microenvironment)

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24 pages, 7751 KiB

Open AccessArticle

Caspase Inhibition Modulates Monocyte-Derived Macrophage Polarization in Damaged Tissues

by Stéphanie Solier, Michele Mondini, Lydia Meziani, Arnaud Jacquel, Catherine Lacout, Tom Vanden Berghe, Yvon Julé, Jean-Claude Martinou, Gérard Pierron, Julie Rivière, Marc Deloger, Corinne Dupuy, Anny Slama-Schwok, Nathalie Droin, Peter Vandenabeele, Patrick Auberger, Eric Deutsch, Jamel El-Benna, Pham My-Chan Dang and Eric Solary

Int. J. Mol. Sci. 2023, 24(4), 4151; https://doi.org/10.3390/ijms24044151 - 19 Feb 2023

Cited by 1 | Viewed by 1571

Abstract

Circulating monocytes are recruited in damaged tissues to generate macrophages that modulate disease progression. Colony-stimulating factor-1 (CSF-1) promotes the generation of monocyte-derived macrophages, which involves caspase activation. Here, we demonstrate that activated caspase-3 and caspase-7 are located to the vicinity of the mitochondria in CSF1-treated human monocytes. Active caspase-7 cleaves p47^PHOX at aspartate 34, which promotes the formation of the NADPH (nicotinamide adenine dinucleotide phosphate) oxidase complex NOX2 and the production of cytosolic superoxide anions. Monocyte response to CSF-1 is altered in patients with a chronic granulomatous disease, which are constitutively defective in NOX2. Both caspase-7 down-regulation and radical oxygen species scavenging decrease the migration of CSF-1-induced macrophages. Inhibition or deletion of caspases prevents the development of lung fibrosis in mice exposed to bleomycin. Altogether, a non-conventional pathway that involves caspases and activates NOX2 is involved in CSF1-driven monocyte differentiation and could be therapeutically targeted to modulate macrophage polarization in damaged tissues. Full article

(This article belongs to the Special Issue Cellular Crosstalk in the Tumor Microenvironment)

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15 pages, 3401 KiB

Open AccessArticle

Tumorigenicity of EGFR- and/or HER2-Positive Breast Cancers Is Mediated by Recruitment of Tumor-Associated Macrophages

by Daeun You, Hyungjoo Kim, Yisun Jeong, Sun Young Yoon, Eunji Lo, Sangmin Kim and Jeong Eon Lee

Int. J. Mol. Sci. 2023, 24(2), 1443; https://doi.org/10.3390/ijms24021443 - 11 Jan 2023

Cited by 3 | Viewed by 1633

Abstract

Basal-like breast cancer (BLBC) has a clinically aggressive nature. It is prevalent in young women and is known to often relapse rapidly. To date, the molecular mechanisms regarding the aggressiveness of BLBC have not been fully understood. In the present study, mechanisms of aggressiveness of BLBC involving EGFR and/or HER2 expression and interactions between tumor and tumor-associated macrophages (TAMs) were explored. The prognosis of breast cancer patients who underwent surgery at Samsung Medical Center was analyzed. It was found that the co-expression of EGFR and HER2 was associated with a worse prognosis. Therefore, we generated EGFR-positive BLBC cells with stable HER2 overexpression and analyzed the profile of secretory cytokines. Chemokine (C-C motif) ligand 2 (CCL2) expression was increased in HER2-overexpressed BLBC cells. Recombinant human CCL2 treatment augmented the motility of TAMs. In addition, the conditioned culture media of HER2-overexpressed BLBC cells increased the motility of TAMs. Furthermore, activation of TAMs by CCL2 or the conditioned culture media of HER2-overexpressed cells resulted in the production of pro-inflammatory cytokines, such as IL-8 and IL-1β. These observations reveal that CCL2 derived from EGFR and HER2 co-expressed BLBC cells can lead to increased TAM recruitment and the induction of IL-8 and IL-1β from recruited TAMs, triggering the tumorigenesis of breast cancer with the expression of both EGFR and HER2. Our findings demonstrate that EGFR+ and HER2+ BLBC aggressiveness is partially mediated through the interaction between BLBC and TAMs recruited by CCL2. Full article

(This article belongs to the Special Issue Cellular Crosstalk in the Tumor Microenvironment)

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Review

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17 pages, 3654 KiB

Open AccessReview

Roles of Notch Signaling in the Tumor Microenvironment

by Antonino B. D’Assoro, Roberto Leon-Ferre, Eike-Benjamin Braune and Urban Lendahl

Int. J. Mol. Sci. 2022, 23(11), 6241; https://doi.org/10.3390/ijms23116241 - 02 Jun 2022

Cited by 25 | Viewed by 4046

Abstract

The Notch signaling pathway is an architecturally simple signaling mechanism, well known for its role in cell fate regulation during organ development and in tissue homeostasis. In keeping with its importance for normal development, dysregulation of Notch signaling is increasingly associated with different types of tumors, and proteins in the Notch signaling pathway can act as oncogenes or tumor suppressors, depending on the cellular context and tumor type. In addition to a role as a driver of tumor initiation and progression in the tumor cells carrying oncogenic mutations, it is an emerging realization that Notch signaling also plays a role in non-mutated cells in the tumor microenvironment. In this review, we discuss how aberrant Notch signaling can affect three types of cells in the tumor stroma—cancer-associated fibroblasts, immune cells and vascular cells—and how this influences their interactions with the tumor cells. Insights into the roles of Notch in cells of the tumor environment and the impact on tumor-stroma interactions will lead to a deeper understanding of Notch signaling in cancer and inspire new strategies for Notch-based tumor therapy. Full article

(This article belongs to the Special Issue Cellular Crosstalk in the Tumor Microenvironment)

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