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Cellular Crosstalk in the Tumor Microenvironment
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Cellular Crosstalk in the Tumor Microenvironment

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

Deadline for manuscript submissions: closed (20 December 2024) | Viewed by 17952

Special Issue Editors

Dr. Ehnman Monika

E-Mail Website1 Website2
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

E-Mail Website
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

E-Mail Website
Guest Editor
Department of Laboratory Medicine, Karolinska Institutet, Division of Pathology, 14186 Stockholm, Sweden
Interests: epithelial–mesenchymal transition; TGFB; breast cancer; metastasis; inflammation
Special Issues, Collections and Topics in MDPI journals

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

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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

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Published Papers (7 papers)

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Research

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20 pages, 4893 KiB  
Article
Impact of Proton Irradiation Depending on Breast Cancer Subtype in Patient-Derived Cell Lines
by Marika Musielak, Kinga Graczyk, Małgorzata Liszka, Athanasia Christou, Monika A. Rosochowicz, Michał S. Lach, Beata Adamczyk, Wiktoria M. Suchorska, Tomasz Piotrowski, Bo Stenerlöw and Julian Malicki
Int. J. Mol. Sci. 2024, 25(19), 10494; https://doi.org/10.3390/ijms251910494 - 29 Sep 2024
Cited by 2 | Viewed by 1357
Abstract
Research on different types of ionizing radiation’s effects has been ongoing for years, revealing its efficacy in damaging cancer cells. Solid tumors comprise diverse cell types, each being able to respond differently to radiation. This study evaluated the radiobiological response of established (MDA-MB-231 [...] Read more.
Research on different types of ionizing radiation’s effects has been ongoing for years, revealing its efficacy in damaging cancer cells. Solid tumors comprise diverse cell types, each being able to respond differently to radiation. This study evaluated the radiobiological response of established (MDA-MB-231 (Triple negative breast cancer, TNBC), MCF-7 (Luminal A)) and patient-derived malignant cell lines, cancer-associated fibroblasts, and skin fibroblasts following proton IRR. All cell line types were irradiated with the proton dose of 2, 4, and 6 Gy. The radiobiological response was assessed using clonogenic assay, γH2AX, and p53 staining. It was noticeable that breast cancer lines of different molecular subtypes displayed no significant variations in their response to proton IRR. In terms of cancer-associated fibroblasts extracted from the tumor tissue, the line derived from a TNBC subtype tumor demonstrated higher resistance to ionizing radiation compared to lines isolated from luminal A tumors. Fibroblasts extracted from patients’ skin responded identically to all doses of proton radiation. This study emphasizes that tumor response is not exclusively determined by the elimination of breast cancer cells, but also takes into account tumor microenvironmental variables and skin reactions. Full article
(This article belongs to the Special Issue Cellular Crosstalk in the Tumor Microenvironment)
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17 pages, 2628 KiB  
Article
The Crosstalk Analysis between mPSCs and Panc1 Cells Identifies CCN1 as a Positive Regulator of Gemcitabine Sensitivity in Pancreatic Cancer Cells
by Beate Gündel, Xinyuan Liu, Anna Pfützenreuter, Veronika Engelsberger, Ralf Weiskirchen, J.-Matthias Löhr and Rainer Heuchel
Int. J. Mol. Sci. 2024, 25(17), 9369; https://doi.org/10.3390/ijms25179369 - 29 Aug 2024
Viewed by 1391
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease that is almost entirely resistant to conventional chemotherapy and radiation therapy. A significant factor in this resistance appears to be the dense desmoplastic stroma, which contains various cancer-associated fibroblast (CAF) populations. However, our understanding of [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease that is almost entirely resistant to conventional chemotherapy and radiation therapy. A significant factor in this resistance appears to be the dense desmoplastic stroma, which contains various cancer-associated fibroblast (CAF) populations. However, our understanding of the communication between tumor cells and CAFs that contributes to this aggressive malignancy is still developing. Recently, we used an advanced three-dimensional heterospecies, heterospheroid co-culture model to investigate the signaling between human pancreatic tumor Panc1 cells and mouse pancreatic stellate cells (mPSCs) through global expression profiling. Upon discovering that CCN1 was significantly upregulated in Panc1 cells during co-culture, we decided to explore the role of CCN1 using CRISPR-Cas9 knockout technology. Panc1 cells lacking CCN1 showed reduced differentiation and decreased sensitivity to gemcitabine, primarily due to lower expression of genes involved in gemcitabine transport and metabolism. Additionally, we observed that stimulation with TGF-β1 and lysophosphatidic acid increased CCN1 expression in Panc1 cells and induced a shift in mPSCs towards a more myofibroblastic CAF-like phenotype. Full article
(This article belongs to the Special Issue Cellular Crosstalk in the Tumor Microenvironment)
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14 pages, 3885 KiB  
Article
Ropivacaine Administration Suppressed A549 Lung Adenocarcinoma Cell Proliferation and Migration via ACE2 Upregulation and Inhibition of the Wnt1 Pathway
by Masae Iwasaki, Makiko Yamamoto, Masahiro Tomihari and Masashi Ishikawa
Int. J. Mol. Sci. 2024, 25(17), 9334; https://doi.org/10.3390/ijms25179334 - 28 Aug 2024
Viewed by 1006
Abstract
Background: Previous studies have suggested that perioperative anesthesia could have direct impacts on cancer cell biology. The present study investigated the effects of ropivacaine administration on lung adenocarcinoma cells. Methods: Ropivacaine was administered to A549 cells at concentrations of 0.1, 1, and 6 [...] Read more.
Background: Previous studies have suggested that perioperative anesthesia could have direct impacts on cancer cell biology. The present study investigated the effects of ropivacaine administration on lung adenocarcinoma cells. Methods: Ropivacaine was administered to A549 cells at concentrations of 0.1, 1, and 6 mM for 2 h. Angiotensin-converting enzyme 2 (ACE2) small interfering RNA (siRNA) transfection was performed 6 h prior to ropivacaine administration. Cell proliferation and migration were assessed with cell counting kit 8 (CCK-8) and a wound healing assay at 0 and 24 h after anesthesia exposure. PCR arrays were performed, followed by PCR validation. Results: Ropivacaine administration inhibited A549 cell proliferation and migration in a concentration-dependent manner, with ACE2 upregulation and HIF1α (hypoxia-inducible factor 1α) downregulation. The anticancer effect of ropivacaine was canceled out via ACE2 siRNA transfection. PCR arrays showed specific gene change patterns in the ropivacaine and respective ACE2-knockdown groups. EGFR (epidermal growth factor receptor), BAX (Bcl-2-associated X protein) and BCL2 (B-cell/CLL lymphoma 2) were suppressed with ropivacaine administration; these effects were reversed via ACE2 siRNA induction. Conclusion: Ropivacaine administration inhibited A549 cell biology in conjunction with ACE2 upregulation via the inhibition of the Wnt1 (wingless/Integrated 1) pathway. Full article
(This article belongs to the Special Issue Cellular Crosstalk in the Tumor Microenvironment)
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17 pages, 3717 KiB  
Article
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
Cited by 1 | Viewed by 1504
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 [...] Read more.
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  
Article
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 2 | Viewed by 2492
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 [...] Read more.
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 p47PHOX 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  
Article
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 7 | Viewed by 2510
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 [...] Read more.
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  
Review
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 - 2 Jun 2022
Cited by 42 | Viewed by 5621
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 [...] Read more.
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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