Topic Editors

Department of Urology, Affiliated Cancer Hospital of Nanjing Medical University, Nanjing 210009, China
Department of Urology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210009, China
Department of Thoracic Surgery, Peking University People's Hospital, Beijing, China
Dr. Wenzhi Li
Department of Urology, Shanghai First People's Hospital, Shanghai, China

Advances in Tumor Microenvironment

Abstract submission deadline
closed (20 October 2023)
Manuscript submission deadline
closed (20 December 2023)
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Topic Information

Dear Colleagues,

Interactions between stromal tissue cells and cancer cells are mutual, dynamic, and complicated rather than stromal tissue being merely a passive bystander in the process of cancer development, progression, and metastasis. It is often claimed that among them, a unique environment called a tumor microenvironment develops. Tumor cells, stromal cells, and portions of the extracellular matrix surrounding them make up the dynamic environment known as the TME.

Contributions are encouraged in areas including, but not limited to:

  • Molecular mechanism of tumor metastasis;
  • Composition of the tumor microenvironment;
  • Immunotherapy targeting the tumor microenvironment.

Dr. Hongzhou Cai
Prof. Dr. Lixin Hua
Dr. Mantang Qiu
Dr. Wenzhi Li
Topic Editors

Keywords

  • molecular mechanisms
  • tumor microenvironment
  • immune therapy
  • tumor cell
  • exosomes

Participating Journals

Journal Name Impact Factor CiteScore Launched Year First Decision (median) APC
Biology
biology
3.6 5.7 2012 16.1 Days CHF 2700
Cancers
cancers
4.5 8.0 2009 16.3 Days CHF 2900
Current Oncology
curroncol
2.8 3.3 1994 17.6 Days CHF 2200
Hematology Reports
hematolrep
1.1 0.9 2009 32.8 Days CHF 1600
Medical Sciences
medsci
- - 2013 25.6 Days CHF 1400

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Published Papers (25 papers)

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12 pages, 2332 KiB  
Article
Spatially Resolved Microglia/Macrophages in Recurrent Glioblastomas Overexpress Fatty Acid Metabolism and Phagocytic Genes
by Akshitkumar M. Mistry, Jonah Daneshmand, SeonYeong Jamie Seo, Norman L. Lehman, Donald M. Miller, Dylan A. Goodin, Hermann B. Frieboes, Joseph Chen, Adrianna Masters, Brian J. Williams and Kavitha Yaddanapudi
Curr. Oncol. 2024, 31(3), 1183-1194; https://doi.org/10.3390/curroncol31030088 - 23 Feb 2024
Viewed by 1480
Abstract
Background: Glioblastoma (GBM) tumors are rich in tumor-associated microglia/macrophages. Changes associated with treatment in this specific cell population are poorly understood. Therefore, we studied changes in gene expression of tumor-associated microglia/macrophages (Iba1+) cells in de novo versus recurrent GBMs. Methods: NanoString GeoMx® [...] Read more.
Background: Glioblastoma (GBM) tumors are rich in tumor-associated microglia/macrophages. Changes associated with treatment in this specific cell population are poorly understood. Therefore, we studied changes in gene expression of tumor-associated microglia/macrophages (Iba1+) cells in de novo versus recurrent GBMs. Methods: NanoString GeoMx® Digital Spatial Transcriptomic Profiling of microglia/macrophages (Iba1+) and glial cells (Gfap+) cells identified on tumor sections was performed on paired de novo and recurrent samples obtained from three IDH-wildtype GBM patients. The impact of differentially expressed genes on patient survival was evaluated using publicly available data. Results: Unsupervised analyses of the NanoString GeoMx® Digital Spatial Profiling data revealed clustering based on the transcriptomic data from Iba1+ and Gfap+ cells. As expected, conventional differential gene expression and enrichment analyses revealed upregulation of immune-function-related genes in Iba1+ cells compared to Gfap+ cells. A focused differential gene expression analysis revealed upregulation of phagocytosis and fatty acid/lipid metabolism genes in Iba1+ cells in recurrent GBM samples compared to de novo GBM samples. Importantly, of these genes, the lipid metabolism gene PLD3 consistently correlated with survival in multiple different publicly available datasets. Conclusion: Tumor-associated microglia/macrophages in recurrent GBM overexpress genes involved in fatty acid/lipid metabolism. Further investigation is needed to fully delineate the role of PLD phospholipases in GBM progression. Full article
(This article belongs to the Topic Advances in Tumor Microenvironment)
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12 pages, 2005 KiB  
Article
Comparative Study of the Immune Microenvironment in Heterotopic Tumor Models
by Melanie Kienzl, Kathrin Maitz, Arailym Sarsembayeva, Paulina Valadez-Cosmes, Eva Gruden, Dusica Ristic, Karolina Herceg, Julia Kargl and Rudolf Schicho
Cancers 2024, 16(2), 295; https://doi.org/10.3390/cancers16020295 - 10 Jan 2024
Cited by 2 | Viewed by 1658
Abstract
The tumor microenvironment (TME) is pivotal in cancer progression and the response to immunotherapy. A “hot” tumor typically contains immune cells that promote anti-tumor immunity, predicting positive prognosis. “Cold” tumors lack immune cells, suggesting a poor outlook across various cancers. Recent research has [...] Read more.
The tumor microenvironment (TME) is pivotal in cancer progression and the response to immunotherapy. A “hot” tumor typically contains immune cells that promote anti-tumor immunity, predicting positive prognosis. “Cold” tumors lack immune cells, suggesting a poor outlook across various cancers. Recent research has focused on converting “cold” tumors into “hot” tumors to enhance the success of immunotherapy. A prerequisite for the studies of the TME is an accurate knowledge of the cell populations of the TME. This study aimed to describe the immune TME of lung and colorectal cancer and melanoma, focusing on lymphoid and myeloid cell populations. We induced heterotopic immunocompetent tumors in C57BL/6 mice, using KP and LLC (Lewis lung carcinoma) cells for lung cancer, MC38 cells for colorectal cancer, and B16-F10 cells for melanoma. Immune cell infiltration was analyzed using multicolor flow cytometry in single-cell suspensions after tumor excision. KP cell tumors showed an abundance of neutrophils and eosinophils; however, they contained much less adaptive immune cells, while LLC cell tumors predominated in monocytes, neutrophils, and monocyte-derived dendritic cells. Monocytes and neutrophils, along with a significant T cell infiltration, were prevalent in MC38 tumors. Lastly, B16-F10 tumors were enriched in macrophages, while showing only moderate T cell presence. In conclusion, our data provide a detailed overview of the immune TME of various heterotopic tumors, highlighting the variabilities in the immune cell profiles of different tumor entities. Our data may be a helpful basis when investigating new immunotherapies, and thus, this report serves as a helpful tool for preclinical immunotherapy research design. Full article
(This article belongs to the Topic Advances in Tumor Microenvironment)
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22 pages, 813 KiB  
Review
Novel Therapies in Glioblastoma Treatment: Review of Glioblastoma; Current Treatment Options; and Novel Oncolytic Viral Therapies
by Siddharth Shah
Med. Sci. 2024, 12(1), 1; https://doi.org/10.3390/medsci12010001 - 23 Dec 2023
Cited by 4 | Viewed by 3388
Abstract
One of the most prevalent primary malignant brain tumors is glioblastoma (GB). About 6 incidents per 100,000 people are reported annually. Most frequently, these tumors are linked to a poor prognosis and poor quality of life. There has been little advancement in the [...] Read more.
One of the most prevalent primary malignant brain tumors is glioblastoma (GB). About 6 incidents per 100,000 people are reported annually. Most frequently, these tumors are linked to a poor prognosis and poor quality of life. There has been little advancement in the treatment of GB. In recent years, some innovative medicines have been tested for the treatment of newly diagnosed cases of GB and recurrent cases of GB. Surgery, radiotherapy, and alkylating chemotherapy are all common treatments for GB. A few of the potential alternatives include immunotherapy, tumor-treating fields (TTFs), and medications that target specific cellular receptors. To provide new multimodal therapies that focus on the molecular pathways implicated in tumor initiation and progression in GB, novel medications, delivery technologies, and immunotherapy approaches are being researched. Of these, oncolytic viruses (OVs) are among the most recent. Coupling OVs with certain modern treatment approaches may have significant benefits for GB patients. Here, we discuss several OVs and how they work in conjunction with other therapies, as well as virotherapy for GB. The study was based on the PRISMA guidelines. Systematic retrieval of information was performed on PubMed. A total of 307 articles were found in a search on oncolytic viral therapies for glioblastoma. Out of these 83 articles were meta-analyses, randomized controlled trials, reviews, and systematic reviews. A total of 42 articles were from the years 2018 to 2023. Appropriate studies were isolated, and important information from each of them was understood and entered into a database from which the information was used in this article. One of the most prevalent malignant brain tumors is still GB. Significant promise and opportunity exist for oncolytic viruses in the treatment of GB and in boosting immune response. Making the most of OVs in the treatment of GB requires careful consideration and evaluation of a number of its application factors. Full article
(This article belongs to the Topic Advances in Tumor Microenvironment)
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15 pages, 8966 KiB  
Article
Investigating the Role of Tumor-Infiltrating Lymphocytes as Predictors of Lymph Node Metastasis in Deep Submucosal Invasive Colorectal Cancer: A Retrospective Cross-Sectional Study
by Hirosato Tamari, Yasuhiko Kitadai, Hidehiko Takigawa, Ryo Yuge, Yuji Urabe, Fumio Shimamoto and Shiro Oka
Cancers 2023, 15(21), 5238; https://doi.org/10.3390/cancers15215238 - 31 Oct 2023
Viewed by 1019
Abstract
The role of tumor-infiltrating T cells (TILs) in colorectal cancer (CRC) and their significance in early-stage CRC remain unknown. We investigated the role of TILs in early-stage CRC, particularly in deep submucosal invasive (T1b) CRC. Sixty patients with CRC (20 each with intramucosal [...] Read more.
The role of tumor-infiltrating T cells (TILs) in colorectal cancer (CRC) and their significance in early-stage CRC remain unknown. We investigated the role of TILs in early-stage CRC, particularly in deep submucosal invasive (T1b) CRC. Sixty patients with CRC (20 each with intramucosal [IM group], submucosal invasive [SM group], and advanced cancer [AD group]) were randomly selected. We examined changes in TILs with tumor invasion and the relationship between TILs and LN metastasis risk. Eighty-four patients with T1b CRC who underwent initial surgical resection with LN dissection or additional surgical resection with LN dissection after endoscopic resection were then selected. TIL phenotype and number were evaluated using triple immunofluorescence for CD4, CD8, and Foxp3. All subtypes were more numerous according to the degree of CRC invasion and more abundant at the invasive front of the tumor (IF) than in the center of the tumor (CT) in the SM and AD groups. The increased Foxp3 cells at the IF and high ratios of Foxp3/CD4 and Foxp3/CD8 positively correlated with LN metastasis. In conclusion, tumor invasion positively correlated with the number of TILs in CRC. The number and ratio of Foxp3 cells at the IF may predict LN metastasis in T1b CRC. Full article
(This article belongs to the Topic Advances in Tumor Microenvironment)
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22 pages, 3012 KiB  
Article
Combining Mass Cytometry Data by CyTOFmerge Reveals Additional Cell Phenotypes in the Heterogeneous Ovarian Cancer Tumor Microenvironment: A Pilot Study
by Liv Cecilie Vestrheim Thomsen, Katrin Kleinmanns, Shamundeeswari Anandan, Stein-Erik Gullaksen, Tamim Abdelaal, Grete Alrek Iversen, Lars Andreas Akslen, Emmet McCormack and Line Bjørge
Cancers 2023, 15(20), 5106; https://doi.org/10.3390/cancers15205106 - 23 Oct 2023
Cited by 1 | Viewed by 1218
Abstract
The prognosis of high-grade serous ovarian carcinoma (HGSOC) is poor, and treatment selection is challenging. A heterogeneous tumor microenvironment (TME) characterizes HGSOC and influences tumor growth, progression, and therapy response. Better characterization with multidimensional approaches for simultaneous identification and categorization of the various [...] Read more.
The prognosis of high-grade serous ovarian carcinoma (HGSOC) is poor, and treatment selection is challenging. A heterogeneous tumor microenvironment (TME) characterizes HGSOC and influences tumor growth, progression, and therapy response. Better characterization with multidimensional approaches for simultaneous identification and categorization of the various cell populations is needed to map the TME complexity. While mass cytometry allows the simultaneous detection of around 40 proteins, the CyTOFmerge MATLAB algorithm integrates data sets and extends the phenotyping. This pilot study explored the potential of combining two datasets for improved TME phenotyping by profiling single-cell suspensions from ten chemo-naïve HGSOC tumors by mass cytometry. A 35-marker pan-tumor dataset and a 34-marker pan-immune dataset were analyzed separately and combined with the CyTOFmerge, merging 18 shared markers. While the merged analysis confirmed heterogeneity across patients, it also identified a main tumor cell subset, additionally to the nine identified by the pan-tumor panel. Furthermore, the expression of traditional immune cell markers on tumor and stromal cells was revealed, as were marker combinations that have rarely been examined on individual cells. This study demonstrates the potential of merging mass cytometry data to generate new hypotheses on tumor biology and predictive biomarker research in HGSOC that could improve treatment effectiveness. Full article
(This article belongs to the Topic Advances in Tumor Microenvironment)
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19 pages, 1789 KiB  
Review
Unveiling the Role of Tumor-Infiltrating T Cells and Immunotherapy in Hepatocellular Carcinoma: A Comprehensive Review
by Xiaokun Chen, Xiao Liu and Shunda Du
Cancers 2023, 15(20), 5046; https://doi.org/10.3390/cancers15205046 - 19 Oct 2023
Cited by 2 | Viewed by 1697
Abstract
Hepatocellular carcinoma (HCC) is a rapidly rising global health concern, ranking as the third-leading cause of cancer-related mortality. Despite medical advancements, the five-year survival rate remains a dismal 18%, with a daunting 70% recurrence rate within a five-year period. Current systematic treatments, including [...] Read more.
Hepatocellular carcinoma (HCC) is a rapidly rising global health concern, ranking as the third-leading cause of cancer-related mortality. Despite medical advancements, the five-year survival rate remains a dismal 18%, with a daunting 70% recurrence rate within a five-year period. Current systematic treatments, including first-line sorafenib, yield an overall response rate (ORR) below 10%. In contrast, immunotherapies have shown promise by improving ORR to approximately 30%. The IMbravel150 clinical trial demonstrates that combining atezolizumab and bevacizumab surpasses sorafenib in terms of median progression-free survival (PFS) and overall survival (OS). However, the therapeutic efficacy for HCC patients remains unsatisfactory, highlighting the urgent need for a comprehensive understanding of antitumor responses and immune evasion mechanisms in HCC. In this context, understanding the immune landscape of HCC is of paramount importance. Tumor-infiltrating T cells, including cytotoxic T cells, regulatory T cells, and natural killer T cells, are key components in the antitumor immune response. This review aims to shed light on their intricate interactions within the immunosuppressive tumor microenvironment and explores potential strategies for revitalizing dysfunctional T cells. Additionally, current immune checkpoint inhibitor (ICI)-based trials, ICI-based combination therapies, and CAR-T- or TCR-T-cell therapies for HCC are summarized, which might further improve OS and transform the management of HCC in the future. Full article
(This article belongs to the Topic Advances in Tumor Microenvironment)
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25 pages, 8255 KiB  
Review
Neuroblastoma Interaction with the Tumour Microenvironment and Its Implications for Treatment and Disease Progression
by Leila Jahangiri
Curr. Oncol. 2023, 30(10), 9116-9140; https://doi.org/10.3390/curroncol30100659 - 15 Oct 2023
Cited by 1 | Viewed by 1617
Abstract
Neuroblastoma, a paediatric malignancy of the peripheral nervous system, displays a wide range of clinical outcomes, including regression to fatality despite extensive treatment. Neuroblastoma tumours display a complex interplay with their surrounding environment, known as the tumour microenvironment, which may affect disease progression [...] Read more.
Neuroblastoma, a paediatric malignancy of the peripheral nervous system, displays a wide range of clinical outcomes, including regression to fatality despite extensive treatment. Neuroblastoma tumours display a complex interplay with their surrounding environment, known as the tumour microenvironment, which may affect disease progression and patient prognosis. This study aimed to dissect the ways in which neuroblastoma biology, treatment, prognosis, progression, and relapse are linked with the extracellular matrix, the dichotomous identities of neuroblastoma, various regulatory proteins and RNA, and extracellular vesicles within the backdrop of the tumour microenvironment. In addition, other aspects, such as immune cell infiltration, therapeutic options including monoclonal antibodies and small molecule inhibitors; and the ways in which these may affect disease progression and immunosuppression within the context of the neuroblastoma tumour microenvironment, are addressed. Such studies may shed light on useful therapeutic targets within the tumour microenvironment that may benefit groups of NB patients. Ultimately, a detailed understanding of these aspects will enable the neuroblastoma scientific community to improve treatment options, patient outcomes, and quality of life. Full article
(This article belongs to the Topic Advances in Tumor Microenvironment)
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8 pages, 764 KiB  
Case Report
Concurrence of Adenomyoepithelioma of the Breast and Gastrointestinal Stromal Tumor of the Stomach: A Case Report and Review of the Literature
by Fatma Althoubaity, Lamar A. Wazira, Hanin M. Y. Ahmad and Reyof T. Aljuhani
Med. Sci. 2023, 11(3), 57; https://doi.org/10.3390/medsci11030057 - 10 Sep 2023
Viewed by 1982
Abstract
Adenomyoepithelioma (AME) of the breast and gastrointestinal stromal tumors (GISTs) are rare benign (primarily) tumors observed in the breast and gastrointestinal tract, respectively. The coexistence of both of these rare tumors is extremely rare; therefore, the author describes the clinical presentation and pathophysiological [...] Read more.
Adenomyoepithelioma (AME) of the breast and gastrointestinal stromal tumors (GISTs) are rare benign (primarily) tumors observed in the breast and gastrointestinal tract, respectively. The coexistence of both of these rare tumors is extremely rare; therefore, the author describes the clinical presentation and pathophysiological findings of such a unique case in this study. A 56-year-old female patient with no medical history presented with a substantial right breast lump, severe nausea, and vomiting, and suffered from iron deficiency anemia. Radiological observation and a right breast excisional biopsy diagnosed the patient with AME associated with ductal carcinoma in situ (DCIS). Endoscopy and a CT scan of the stomach revealed the existence of GIST. This is the first reported case of concurrence of a huge mass of AME and GIST in a patient. Histological and immunohistochemistry tests using p63, SMA, calponin, and Ki67 markers for the breast tumor and DOG-1, CD34, and CD117 markers for the gastric tumor revealed the non-invasive benign state. The patient had a right breast mastectomy with a negative resection margin. AME of the breast and GIST pose diagnostic challenges due to their erratic morphological characteristics and can cause misinterpretation drawn solely from radiological tests. Effective and accurate diagnostics require assessing the histological and immunohistochemistry findings of the tumor to identify the invasiveness of the neoplasm and the associated risk levels. This report, thus, creates awareness among clinicians and pathologists for the consideration of such possibilities and, therefore, conducts the necessary diagnostics and prophylactic treatments. Full article
(This article belongs to the Topic Advances in Tumor Microenvironment)
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11 pages, 2850 KiB  
Article
Interaction between Macrophages and Adipose Stromal Cells Increases the Angiogenic and Proliferative Potential of Pregnancy-Associated Breast Cancers
by Michael Doyle, Noor Kwami, Jaitri Joshi, Lisa M. Arendt and Jessica McCready
Cancers 2023, 15(18), 4500; https://doi.org/10.3390/cancers15184500 - 10 Sep 2023
Viewed by 1111
Abstract
Pregnancy associated breast cancers (PABCs) exhibit increased aggressiveness and overall poorer survival. During lactation, changes take place in the breast tissue microenvironment that lead to increased macrophage recruitment and alterations in adipose stromal cells (ASC-Ls). The interaction of these cells in PABCs could [...] Read more.
Pregnancy associated breast cancers (PABCs) exhibit increased aggressiveness and overall poorer survival. During lactation, changes take place in the breast tissue microenvironment that lead to increased macrophage recruitment and alterations in adipose stromal cells (ASC-Ls). The interaction of these cells in PABCs could play a role in the increased aggressiveness of these cancers. We utilized an in vitro co-culture model to recreate the interactions of ASC-Ls and macrophages in vivo. We performed qRT-PCR to observe changes in gene expression and cytokine arrays to identify transcriptional changes that result in an altered microenvironment. Additionally, functional assays were performed to further elicit how these changes affect tumorigenesis. The co-culture of ASC-Ls and macrophages altered both mRNA expression and cytokine secretion in a tumor promoting manner. Tumorigenic cytokines, such as IL-6, CXCL1, CXCL5, and MMP-9 secretion levels, were enhanced in the co-culture. Additionally, conditioned media from the co-culture elevated the tumor cell proliferation and angiogenic potential of endothelial cells. These finds indicate that the changes seen in the microenvironment of PABC, specifically the secretion of cytokines, play a role in the increased tumorigenesis of PABCs by altering the microenvironment to become more favorable to tumor progression. Full article
(This article belongs to the Topic Advances in Tumor Microenvironment)
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27 pages, 6115 KiB  
Article
Characterization of the Intracellular Acidity Regulation of Brain Tumor Cells and Consequences for Therapeutic Optimization of Temozolomide
by Alaa Tafech, Pierre Jacquet, Céline Beaujean, Arnold Fertin, Yves Usson and Angélique Stéphanou
Biology 2023, 12(9), 1221; https://doi.org/10.3390/biology12091221 - 8 Sep 2023
Cited by 2 | Viewed by 1594
Abstract
A well-known feature of tumor cells is high glycolytic activity, leading to acidification of the tumor microenvironment through extensive lactate production. This acidosis promotes processes such as metastasis, aggressiveness, and invasiveness, which have been associated with a worse clinical prognosis. Moreover, the function [...] Read more.
A well-known feature of tumor cells is high glycolytic activity, leading to acidification of the tumor microenvironment through extensive lactate production. This acidosis promotes processes such as metastasis, aggressiveness, and invasiveness, which have been associated with a worse clinical prognosis. Moreover, the function and expression of transporters involved in regulation of intracellular pH might be altered. In this study, the capacity of tumor cells to regulate their intracellular pH when exposed to a range of pH from very acidic to basic was characterized in two glioma cell lines (F98 and U87) using a new recently published method of fluorescence imaging. Our results show that the regulation of acidity in tumors is not the same for the two investigated cell lines; U87 cells are able to reduce their intracellular acidity, whereas F98 cells do not exhibit this property. On the other hand, F98 cells show a higher level of resistance to acidity than U87 cells. Intracellular regulation of acidity appears to be highly cell-dependent, with different mechanisms activated to preserve cell integrity and function. This characterization was performed on 2D monolayer cultures and 3D spheroids. Spatial heterogeneities were exhibited in 3D, suggesting a spatially modulated regulation in this context. Based on the corpus of knowledge available in the literature, we propose plausible mechanisms to interpret our results, together with some new lines of investigation to validate our hypotheses. Our results might have implications on therapy, since the activity of temozolomide is highly pH-dependent. We show that the drug efficiency can be enhanced, depending on the cell type, by manipulating the extracellular pH. Therefore, personalized treatment involving a combination of temozolomide and pH-regulating agents can be considered. Full article
(This article belongs to the Topic Advances in Tumor Microenvironment)
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17 pages, 7373 KiB  
Article
ACLP Activates Cancer-Associated Fibroblasts and Inhibits CD8+ T-Cell Infiltration in Oral Squamous Cell Carcinoma
by Shohei Sekiguchi, Akira Yorozu, Fumika Okazaki, Takeshi Niinuma, Akira Takasawa, Eiichiro Yamamoto, Hiroshi Kitajima, Toshiyuki Kubo, Yui Hatanaka, Koyo Nishiyama, Kazuhiro Ogi, Hironari Dehari, Atsushi Kondo, Makoto Kurose, Kazufumi Obata, Akito Kakiuchi, Masahiro Kai, Yoshihiko Hirohashi, Toshihiko Torigoe, Takashi Kojima, Makoto Osanai, Kenichi Takano, Akihiro Miyazaki and Hiromu Suzukiadd Show full author list remove Hide full author list
Cancers 2023, 15(17), 4303; https://doi.org/10.3390/cancers15174303 - 28 Aug 2023
Cited by 1 | Viewed by 1477
Abstract
We previously showed that upregulation of adipocyte enhancer-binding protein 1 (AEBP1) in vascular endothelial cells promotes tumor angiogenesis. In the present study, we aimed to clarify the role of stromal AEBP1/ACLP expression in oral squamous cell carcinoma (OSCC). Immunohistochemical analysis [...] Read more.
We previously showed that upregulation of adipocyte enhancer-binding protein 1 (AEBP1) in vascular endothelial cells promotes tumor angiogenesis. In the present study, we aimed to clarify the role of stromal AEBP1/ACLP expression in oral squamous cell carcinoma (OSCC). Immunohistochemical analysis showed that ACLP is abundantly expressed in cancer-associated fibroblasts (CAFs) in primary OSCC tissues and that upregulated expression of ACLP is associated with disease progression. Analysis using CAFs obtained from surgically resected OSCCs showed that the expression of AEBP1/ACLP in CAFs is upregulated by co-culture with OSCC cells or treatment with TGF-β1, suggesting cancer-cell-derived TGF-β1 induces AEBP1/ACLP in CAFs. Collagen gel contraction assays showed that ACLP contributes to the activation of CAFs. In addition, CAF-derived ACLP promotes migration, invasion, and in vivo tumor formation by OSCC cells. Notably, tumor stromal ACLP expression correlated positively with collagen expression and correlated inversely with CD8+ T cell infiltration into primary OSCC tumors. Boyden chamber assays suggested that ACLP in CAFs may attenuate CD8+ T cell migration. Our results suggest that stromal ACLP contributes to the development of OSCCs, and that ACLP is a potential therapeutic target. Full article
(This article belongs to the Topic Advances in Tumor Microenvironment)
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23 pages, 20590 KiB  
Article
Crosstalk between Cancer Cells and Cancer-Associated Fibroblasts Mediated by TGF-β1–IGFBP7 Signaling Promotes the Progression of Infiltrative Gastric Cancer
by Zhijun Hong, Wen Xie, Huiqin Zhuo, Xujin Wei, Kang Wang, Jia Cheng, Lingyun Lin, Jingjing Hou, Xin Chen and Jianchun Cai
Cancers 2023, 15(15), 3965; https://doi.org/10.3390/cancers15153965 - 4 Aug 2023
Cited by 4 | Viewed by 1899
Abstract
Patients with infiltrative-type gastric cancer (GC) (Ming’s classification) have a poor prognosis due to more metastasis and recurrence. Cancer-associated fibroblasts (CAFs) in infiltrative-type extracellular matrix (ECM) have specific characteristics compared with those of expansive types with respect to metastasis, but the mechanism is [...] Read more.
Patients with infiltrative-type gastric cancer (GC) (Ming’s classification) have a poor prognosis due to more metastasis and recurrence. Cancer-associated fibroblasts (CAFs) in infiltrative-type extracellular matrix (ECM) have specific characteristics compared with those of expansive types with respect to metastasis, but the mechanism is still unclear. Based on our proteomics data, TCGA data analysis, and immunohistochemical staining results, significantly higher expression of IGFBP7 was observed in GC, especially in the infiltrative type, and was associated with a poor prognosis. Combining single-cell transcriptome data from GEO and multiple immunofluorescence staining on tissue showed that the differential expression of IGFBP7 mainly originated from myofibroblastic CAFs, the subgroup with higher expression of PDGFRB and α-SMA. After treating primary normal fibroblasts (NFs) with conditional medium or recombined protein, it was demonstrated that XGC-1-derived TGF-β1 upregulated the expression of IGFBP7 in the cells and its secretion via the P-Smad2/3 pathway and mediated its activation with higher FAP, PDGFRB, and α-SMA expression. Then, either conditional medium from CAFs with IGFBP7 overexpression or recombined IGFBP7 protein promoted the migration, invasion, colony formation, and sphere growth ability of XGC-1 and MGC-803, respectively. Moreover, IGFBP7 induced EMT in XGC-1. Therefore, our study clarified that in the tumor microenvironment, tumor-cell-derived TGF-β1 induces the appearance of the IGFBP7+ CAF subgroup, and its higher IGFBP7 extracellular secretion level accelerates the progression of tumors. Full article
(This article belongs to the Topic Advances in Tumor Microenvironment)
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14 pages, 1221 KiB  
Article
Tumor Budding Should Be in Oral Cavity Cancer Reporting: A Retrospective Cohort Study Based on Tumor Microenvironment
by Ayca Tan and Toros Taskin
Cancers 2023, 15(15), 3905; https://doi.org/10.3390/cancers15153905 - 1 Aug 2023
Cited by 4 | Viewed by 1424
Abstract
The utility of histological grading, which is useful in predicting prognosis in many tumors, is controversial for oral squamous cell carcinoma (OSCC). Therefore, new histopathological parameters should be added to histopathology reports of OSCCs. The study aimed to evaluate the parameters of worst [...] Read more.
The utility of histological grading, which is useful in predicting prognosis in many tumors, is controversial for oral squamous cell carcinoma (OSCC). Therefore, new histopathological parameters should be added to histopathology reports of OSCCs. The study aimed to evaluate the parameters of worst invasion pattern (WPOI) and tumor budding in patients with OSCC, to compare them with other histopathological parameters, clinical data and overall survival, and to evaluate these results within the literature. A total of 73 OSCC cases with excisional biopsies were included in this study. WPOI, tumor budding, cell nest size, tumor-stroma ratio, stromal lymphocyte infiltration and stroma type, as well as classical histopathological parameters, were evaluated on hematoxylin-eosin-stained sections. Perineural invasion, lymph node metastases, advanced stage, presence of more than five buds and single cell invasion pattern in univariate survival analyses are characterized by a shortened overall survival time. While there was no significant difference between WPOI results and survival in the survival analysis, WPOI 5 was associated with more frequent lymph node metastasis and advanced stage at the time of diagnosis compared to WPOI 4. We concluded that tumor budding and single-cell invasion should be considered prognostic histopathologic parameters in OSCC. Full article
(This article belongs to the Topic Advances in Tumor Microenvironment)
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31 pages, 2403 KiB  
Review
TIME Is Ticking for Cervical Cancer
by Vijay Kumar, Caitlin Bauer and John H. Stewart IV
Biology 2023, 12(7), 941; https://doi.org/10.3390/biology12070941 - 30 Jun 2023
Cited by 1 | Viewed by 1714
Abstract
Cervical cancer (CC) is a major health problem among reproductive-age females and comprises a leading cause of cancer-related deaths. Human papillomavirus (HPV) is the major risk factor associated with CC incidence. However, lifestyle is also a critical factor in CC pathogenesis. Despite HPV [...] Read more.
Cervical cancer (CC) is a major health problem among reproductive-age females and comprises a leading cause of cancer-related deaths. Human papillomavirus (HPV) is the major risk factor associated with CC incidence. However, lifestyle is also a critical factor in CC pathogenesis. Despite HPV vaccination introduction, the incidence of CC is increasing worldwide. Therefore, it becomes critical to understand the CC tumor immune microenvironment (TIME) to develop immune cell-based vaccination and immunotherapeutic approaches. The current article discusses the immune environment in the normal cervix of adult females and its role in HPV infection. The subsequent sections discuss the alteration of different immune cells comprising CC TIME and their targeting as future therapeutic approaches. Full article
(This article belongs to the Topic Advances in Tumor Microenvironment)
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15 pages, 2153 KiB  
Article
E-Cadherin Expression Varies Depending on the Location within the Primary Tumor and Is Higher in Colorectal Cancer with Lymphoid Follicles
by Adam R. Markowski, Konstancja Ustymowicz, Anna J. Markowska, Wiktoria Romańczyk and Katarzyna Guzińska-Ustymowicz
Cancers 2023, 15(12), 3260; https://doi.org/10.3390/cancers15123260 - 20 Jun 2023
Viewed by 1441
Abstract
Reliable indicators of cancer advancement have actively been sought recently. The detection of colorectal cancer progression markers is essential in improving diagnostic and therapeutic protocols. The aim of the study was to investigate the profile of E-cadherin expression in colorectal cancer tissue depending [...] Read more.
Reliable indicators of cancer advancement have actively been sought recently. The detection of colorectal cancer progression markers is essential in improving diagnostic and therapeutic protocols. The aim of the study was to investigate the profile of E-cadherin expression in colorectal cancer tissue depending on the TNM staging and its correlation with several clinical and histopathological features. The study included 55 colorectal cancer patients admitted to the surgical ward for elective surgery. Tissue samples were obtained from resected specimens. Different distributions of E-cadherin expression within tumors were observed; the highest percentage of positive E-cadherin expression was found in the invasive front and in the tumor center. Additionally, the different cellular distribution of E-cadherin expression was noticed; weak membranous E-cadherin expression was the highest in the invasive front and in the budding sites, but a strong membranous pattern was most frequent in the tumor center. Various distributions of E-cadherin expression depending on cancer progression were also found; E-cadherin expression in node-positive patients was lower in the tumor center and in the tumor invasive front, whereas, in patients with distant metastases, the expression of E-Cadherin was lower in the budding sites. In patients with higher TNM stages, E-cadherin expression was lower within the tumor (in the budding sites, tumor center, and invasive front). In tumors with lymphoid follicles, E-cadherin expression was higher in all localizations within the primary tumor. E-cadherin expression in the tumor center was also lower in tumors with some higher tumor budding parameters (areas of poorly differentiated components and poorly differentiated clusters). E-cadherin expression was found to be lower at the tumor center in younger individuals, at the budding sites in men, and at the surrounding lymph nodes in rectal tumors. Low E-cadherin expression appears to be a reliable indicator of higher cancer staging and progression. When assessing the advancement of cancer, apart from the TNM classification, it is beneficial to also consider the expression of E-cadherin. High tumor budding, the poverty of lymphoid follicles, and low E-cadherin expression analyzed simultaneously may contribute to a reliable assessment of colorectal cancer staging. These three histopathological features complement each other, and their investigation, together with conventional tumor staging and grading, may be very helpful in predicting the prognosis of colorectal cancer patients and qualifying them for the best treatment. The role of E-cadherin in the diagnosis and treatment of colorectal cancer, as a part of a personalized medicine strategy, still requires comprehensive, prospective clinical evaluations to precisely target the optimal therapies for the right patients at the right time. Full article
(This article belongs to the Topic Advances in Tumor Microenvironment)
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14 pages, 5878 KiB  
Article
Role of Immune Microenvironment in Pancreatic Ductal Adenocarcinoma: Could It Be Considered a Predictor of Prognosis?
by Ottavia De Simoni, Luca Dal Santo, Marco Scarpa, Giada Munari, Ylenia Camilla Spolverato, Antonio Scapinello, Sara Lonardi, Caterina Soldà, Francesca Bergamo, Alberto Fantin, Romeo Bardini, Pierluigi Pilati, Matteo Fassan and Mario Gruppo
Curr. Oncol. 2023, 30(6), 5515-5528; https://doi.org/10.3390/curroncol30060417 - 8 Jun 2023
Cited by 1 | Viewed by 1874
Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a highly immunosuppressive tumor microenvironment (TME). The aim of this study is to determine the potential significant TME immune markers of long-term survival. Methods: We retrospectively included patients with a diagnosis of resectable PDAC having [...] Read more.
Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a highly immunosuppressive tumor microenvironment (TME). The aim of this study is to determine the potential significant TME immune markers of long-term survival. Methods: We retrospectively included patients with a diagnosis of resectable PDAC having undergone upfront surgery. Immunohistochemical (IHC) staining using tissue microarray for PD-L1, CD3, CD4, CD8, FOXP3, CD20, iNOS and CD163 was performed in order to characterize the TME. The primary endpoint was long-term survival, defined as the Overall Survival > 24 months from surgery. Results: A total of 38 consecutive patients were included, and 14 (36%) of them were long-term survivors. Long-term survivors showed a higher density of CD8+ lymphocytes intra- and peri-acinar (p = 0.08), and a higher CD8/FOXP3 intra- and peri-tumoral ratio (p = 0.05). A low density of intra- and peri-tumoral FOXP3 infiltration is a good predictor of long-term survival (p = 0.04). A significant association of the low density of intra- and peri-tumoral tumor-associated macrophages (TAMs) iNOS+ with long-term survival was detected (p = 0.04). Conclusions: Despite the retrospective nature and small sample size, our study showed that the high infiltration of CD8+ lymphocytes and low infiltration of FOXP3+ and TAMs iNOS+ are predictors of good prognosis. A preoperative assessment of these potential immune markers could be useful and determinant in the staging process and in PDAC management. Full article
(This article belongs to the Topic Advances in Tumor Microenvironment)
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19 pages, 3041 KiB  
Article
Non-Canonical Activin A Signaling Stimulates Context-Dependent and Cellular-Specific Outcomes in CRC to Promote Tumor Cell Migration and Immune Tolerance
by Mark B. Wiley, Jessica Bauer, Kunaal Mehrotra, Jasmin Zessner-Spitzenberg, Zoe Kolics, Wenxuan Cheng, Karla Castellanos, Michael G. Nash, Xianyong Gui, Lyonell Kone, Ajay V. Maker, Guilin Qiao, Deepti Reddi, David N. Church, Rachel S. Kerr, David J. Kerr, Paul J. Grippo and Barbara Jung
Cancers 2023, 15(11), 3003; https://doi.org/10.3390/cancers15113003 - 31 May 2023
Cited by 4 | Viewed by 1913
Abstract
We have shown that activin A (activin), a TGF-β superfamily member, has pro-metastatic effects in colorectal cancer (CRC). In lung cancer, activin activates pro-metastatic pathways to enhance tumor cell survival and migration while augmenting CD4+ to CD8+ communications to promote cytotoxicity. Here, we [...] Read more.
We have shown that activin A (activin), a TGF-β superfamily member, has pro-metastatic effects in colorectal cancer (CRC). In lung cancer, activin activates pro-metastatic pathways to enhance tumor cell survival and migration while augmenting CD4+ to CD8+ communications to promote cytotoxicity. Here, we hypothesized that activin exerts cell-specific effects in the tumor microenvironment (TME) of CRC to promote anti-tumoral activity of immune cells and the pro-metastatic behavior of tumor cells in a cell-specific and context-dependent manner. We generated an Smad4 epithelial cell specific knockout (Smad4−/−) which was crossed with TS4-Cre mice to identify SMAD-specific changes in CRC. We also performed IHC and digital spatial profiling (DSP) of tissue microarrays (TMAs) obtained from 1055 stage II and III CRC patients in the QUASAR 2 clinical trial. We transfected the CRC cells to reduce their activin production and injected them into mice with intermittent tumor measurements to determine how cancer-derived activin alters tumor growth in vivo. In vivo, Smad4−/− mice displayed elevated colonic activin and pAKT expression and increased mortality. IHC analysis of the TMA samples revealed increased activin was required for TGF-β-associated improved outcomes in CRC. DSP analysis identified that activin co-localization in the stroma was coupled with increases in T-cell exhaustion markers, activation markers of antigen presenting cells (APCs), and effectors of the PI3K/AKT pathway. Activin-stimulated PI3K-dependent CRC transwell migration, and the in vivo loss of activin lead to smaller CRC tumors. Taken together, activin is a targetable, highly context-dependent molecule with effects on CRC growth, migration, and TME immune plasticity. Full article
(This article belongs to the Topic Advances in Tumor Microenvironment)
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19 pages, 13062 KiB  
Article
LHX2 Is a Potential Biomarker and Associated with Immune Infiltration in Breast Cancer
by Ziwei Zhang, Minghao Gu, Gao He, Xiafei Yu, Junzhe Yang, Xian Wu, Xiaoqiang Zhang, Kaining Lu, Fangze Qian, Xiaoyue Shi, Jialu Xu, Minyu Zhuang, Xiaoan Liu and Yanhui Zhu
Cancers 2023, 15(10), 2773; https://doi.org/10.3390/cancers15102773 - 16 May 2023
Viewed by 1544
Abstract
Worldwide, breast cancer is the most common malignancy. LHX2, a member of the LIM homeobox gene family and a transcription factor, plays a crucial role in numerous tumors, but the function of LHX2 in breast cancer progression remains unknown. In this study, we [...] Read more.
Worldwide, breast cancer is the most common malignancy. LHX2, a member of the LIM homeobox gene family and a transcription factor, plays a crucial role in numerous tumors, but the function of LHX2 in breast cancer progression remains unknown. In this study, we show that LHX2 is upregulated in breast cancer tissues and positively correlated with breast cancer progression. Meanwhile, the clinical characteristics of breast cancer and LHX2 expression showed a strong correlation. GSEA showed that a high LHX2 expression may activate the T-cell activation pathway, PI3K/AKT/mTOR signaling pathway, and apoptosis pathway. Moreover, ssGSEA showed that Th1 cells and Th2 cells had a positive correlation with LHX2 expression in breast cancer. Experiments showed that LHX2 promotes the proliferation, colony formation, migration, and invasion of breast cancer cells. Immunohistochemistry and immunofluorescence assays helped to analyze LHX2-associated immune infiltration in breast cancer. A Western blot assay proved that LHX2 activated the PI3K/AKT/mTOR pathway and the apoptosis pathway. A TUNEL assay confirmed that LHX2 inhibited apoptosis. Taken together, LHX2 plays a vital role in breast cancer’s progression and prognosis and could be an immune infiltration biomarker for breast cancer, and LHX2 activates the PI3K/AKT/mTOR pathway and apoptosis pathway in breast cancer. Full article
(This article belongs to the Topic Advances in Tumor Microenvironment)
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11 pages, 2028 KiB  
Article
Differential Anti-Tumor Effects of IFN-Inducible Chemokines CXCL9, CXCL10, and CXCL11 on a Mouse Squamous Cell Carcinoma Cell Line
by Ari Matsumoto, Miki Hiroi, Kazumasa Mori, Nobuharu Yamamoto and Yoshihiro Ohmori
Med. Sci. 2023, 11(2), 31; https://doi.org/10.3390/medsci11020031 - 25 Apr 2023
Viewed by 2085
Abstract
Chemokines are a group of cytokines involved in the mobilization of leukocytes, which play a role in host defense and a variety of pathological conditions, including cancer. Interferon (IFN)-inducible chemokines C-X-C motif ligand 9 (CXCL), CXCL10, and CXCL11 are anti-tumor chemokines; however, the [...] Read more.
Chemokines are a group of cytokines involved in the mobilization of leukocytes, which play a role in host defense and a variety of pathological conditions, including cancer. Interferon (IFN)-inducible chemokines C-X-C motif ligand 9 (CXCL), CXCL10, and CXCL11 are anti-tumor chemokines; however, the differential anti-tumor effects of IFN-inducible chemokines are not completely understood. In this study, we investigated the anti-tumor effects of IFN-inducible chemokines by transferring chemokine expression vectors into a mouse squamous cell carcinoma cell line, SCCVII, to generate a cell line stably expressing chemokines and transplanted it into nude mice. The results showed that CXCL9- and CXCL11-expressing cells markedly inhibited tumor growth, whereas CXCL10-expressing cells did not inhibit growth. The NH2-terminal amino acid sequence of mouse CXCL10 contains a cleavage sequence by dipeptidyl peptidase 4 (DPP4), an enzyme that cleaves the peptide chain of chemokines. IHC staining indicated DPP4 expression in the stromal tissue, suggesting CXCL10 inactivation. These results suggest that the anti-tumor effects of IFN-inducible chemokines are affected by the expression of chemokine-cleaving enzymes in tumor tissues. Full article
(This article belongs to the Topic Advances in Tumor Microenvironment)
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18 pages, 25840 KiB  
Article
Multi-Transcriptomic Analysis Reveals the Heterogeneity and Tumor-Promoting Role of SPP1/CD44-Mediated Intratumoral Crosstalk in Gastric Cancer
by Wen Xie, Jia Cheng, Zhijun Hong, Wangyu Cai, Huiqin Zhuo, Jingjing Hou, Lingyun Lin, Xujin Wei, Kang Wang, Xin Chen, Yucheng Song, Zhenfa Wang and Jianchun Cai
Cancers 2023, 15(1), 164; https://doi.org/10.3390/cancers15010164 - 27 Dec 2022
Cited by 15 | Viewed by 3380
Abstract
GC is a fatal disease with high heterogeneity and invasiveness. Recently, SPP1 has been reported to be involved in the tumor progression of multiple human cancers; however, the role of SPP1 in GC heterogeneity and whether it is associated with the invasiveness and [...] Read more.
GC is a fatal disease with high heterogeneity and invasiveness. Recently, SPP1 has been reported to be involved in the tumor progression of multiple human cancers; however, the role of SPP1 in GC heterogeneity and whether it is associated with the invasiveness and mortality of GC remain unclear. Here, we combined multiple RNA sequencing approaches to evaluate the impact of SPP1 on GC. Through bulk RNA sequencing (bulk RNA-seq) and immunohistochemistry (IHC), we found that SPP1 was highly expressed in GC, and high levels of SPP1 were associated with macrophage infiltration, an advanced tumor stage, and higher mortality for advanced GC patients. Furthermore, through simultaneous single-cell and spatial analysis, we demonstrated that SPP1+ macrophages are tumor-specific macrophages unique to cancer and enriched in the deep layer of GC tissue. Cell—cell communication analysis revealed that SPP1/CD44 interactions between SPP1+ macrophages and their localized tumor epithelial cells could activate downstream target genes in epithelial cells to promote dynamic changes in intratumor heterogeneity. Moreover, these activated genes were found to be closely associated with poor clinical GC outcomes and with cancer-related pathways that promote GC progression, as shown by survival analysis and enrichment analysis, respectively. Collectively, our study reveals that tumor-specific SPP1+ macrophages drive the architecture of intratumor heterogeneity to evolve with tumor progression and that SPP1 may serve as a prognostic marker for advanced GC patients, as well as a potential therapeutic target for GC. Full article
(This article belongs to the Topic Advances in Tumor Microenvironment)
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17 pages, 10617 KiB  
Article
Tumor Cell-Derived Exosomal circ-PRKCI Promotes Proliferation of Renal Cell Carcinoma via Regulating miR-545-3p/CCND1 Axis
by Yiguan Qian, Yang Li, Luwei Xu, Ke Chen, Ning Liu, Xiaobing Yang, Qian Lv, Rongfei Li, Changcheng Zhou, Zheng Xu, Ruipeng Jia and Yu-Zheng Ge
Cancers 2023, 15(1), 123; https://doi.org/10.3390/cancers15010123 - 25 Dec 2022
Cited by 11 | Viewed by 1963
Abstract
Renal cell carcinoma (RCC) originates from the epithelial cells of the renal tubules and has a high degree of malignancy and heterogeneity. Recent studies have found that exosomes regulate intercellular communication via transferring various bioactive molecules, such as circular RNAs (circRNAs), which are [...] Read more.
Renal cell carcinoma (RCC) originates from the epithelial cells of the renal tubules and has a high degree of malignancy and heterogeneity. Recent studies have found that exosomes regulate intercellular communication via transferring various bioactive molecules, such as circular RNAs (circRNAs), which are critical for cancer progression. However, the role of tumor cell-derived exosomal circRNAs in RCC remains unclear. In this study, we reported the high expression of circ-PRKCI in RCC tissues and serum exosomes. We also found that circ-PRKCI could be transferred exosomally from highly malignant RCC cells to relatively less malignant RCC cells. Tumor cell-derived exosomal circ-PRKCI promoted the proliferation, migration, and invasion of RCC cells, while inhibiting their apoptosis. Mechanistically, we found that circ-PRKCI promoted the proliferation of RCC via the miR-545-3p/CCND1 signaling pathway. Our study is the first to report the potential mechanisms of tumor cell-derived exosomal circ-PRKCI in RCC. In conclusion, this study will provide a new understanding about the molecular mechanisms of RCC progression. Full article
(This article belongs to the Topic Advances in Tumor Microenvironment)
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20 pages, 5752 KiB  
Article
Bone Marrow Mesenchymal Stem Cell-Derived Exosomes Inhibit Triple-Negative Breast Cancer Cell Stemness and Metastasis via an ALKBH5-Dependent Mechanism
by Yun Hu, Hanyuan Liu, Xiudi Xiao, Qiao Yu, Rong Deng, Lixin Hua, Jinhua Wang and Xinwei Wang
Cancers 2022, 14(24), 6059; https://doi.org/10.3390/cancers14246059 - 9 Dec 2022
Cited by 12 | Viewed by 2453
Abstract
Background: Abnormal N6-methyladenosine (m6A) modification caused by m6A regulators is a common characteristic in various tumors. However, little is known about the role of m6A regulator AlkB homolog 5 (ALKBH5) in triple-negative breast cancer (TNBC). In this study, we analyzed the influence of [...] Read more.
Background: Abnormal N6-methyladenosine (m6A) modification caused by m6A regulators is a common characteristic in various tumors. However, little is known about the role of m6A regulator AlkB homolog 5 (ALKBH5) in triple-negative breast cancer (TNBC). In this study, we analyzed the influence of ALKBH5 on the stemness of TNBC and the molecular mechanism using bioinformatics analysis and in vivo animal experiments. Methods: RNA expression data and single-cell RNA sequencing (scRNA-seq) data were downloaded from the TCGA and GEO databases. Following intersection analysis, key genes involved in the TNBC cell stemness were determined, which was followed by functional enrichment analysis, PPI and survival analysis. Exosomes were extracted from bone marrow mesenchymal stem cells (BMSC-Exos) where ALKBH5 inhibition assay was conducted to verify their function in the biological characteristics of TNBC cells. Results: Bioinformatics analysis revealed 45 key genes of ALKBH5 regulating TNBC cell stemness. In addition, UBE2C was predicted as a key downstream gene and p53 was predicted as a downstream signaling of ALKBH5. In vivo data confirmed that ALKBH5 upregulated UBE2C expression by regulating the m6A modification of UBE2C and reduced p53 expression, thus promoting the stemness, growth and metastasis of TNBC cells. BMSC-Exos suppressed the tumor stemness, growth and metastasis of TNBC cells and ALKBH5 shRNA-loaded BMSC-Exos showed a more significant suppressive role. Conclusion: Taken together, our findings indicated that ALKBH5 shRNA-loaded BMSC-Exos reduced TNBC cell stemness, growth and metastasis and define a promising strategy to treat TNBC. Full article
(This article belongs to the Topic Advances in Tumor Microenvironment)
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17 pages, 3438 KiB  
Article
circRNF10 Regulates Tumorigenic Properties and Natural Killer Cell-Mediated Cytotoxicity against Breast Cancer through the miR-934/PTEN/PI3k-Akt Axis
by Fei Liu, Yang Sang, Yang Zheng, Lina Gu, Lingjiao Meng, Ziyi Li, Yuyang Dong, Zishuan Wei, Cuizhi Geng and Meixiang Sang
Cancers 2022, 14(23), 5862; https://doi.org/10.3390/cancers14235862 - 28 Nov 2022
Cited by 5 | Viewed by 1679
Abstract
Circular RNA (circRNA), a type of non-coding RNA, has received a great deal of attention with regard to the initiation and progression of tumors. However, the molecular mechanism and function of circRNAs in breast cancer (BC) remain unclear. In the current study, we [...] Read more.
Circular RNA (circRNA), a type of non-coding RNA, has received a great deal of attention with regard to the initiation and progression of tumors. However, the molecular mechanism and function of circRNAs in breast cancer (BC) remain unclear. In the current study, we discovered that hsa_circ_0028899 (also called circRNF10) was significantly reduced in BC tissues, and a higher level of circRNF10 was markedly related to a favorable prognosis. The results of CCK8, colony formation, Transwell, ELISA, and NK cell-mediated cytotoxicity assays indicated that increased circRNF10 expression could significantly repress the proliferation, invasion, and migration of BC cells and enhance the killing efficiency of NK cells against BC cells. According to these biological functions, the possible role and molecular mechanism of circRNF10 in BC cells were further investigated. We used bioinformatics prediction tools to predict circRNF10-bound miRNAs, which were verified by many experimental studies, including FISH, luciferase reporter assays, RIP, and Western blots. These data suggest that circRNF10 serves as a molecular sponge for miR-934 to further regulate PTEN expression and PI3k/Akt/MICA signaling in vitro and tumor growth in vivo. Altogether, these findings reveal that circRNF10 functions as a novel anti-oncogene in BC via sponging miR-934 and suppressing the PI3K/Akt/MICA pathway. Full article
(This article belongs to the Topic Advances in Tumor Microenvironment)
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20 pages, 4990 KiB  
Article
Integrated Analysis of TME and Hypoxia Identifies a Classifier to Predict Prognosis and Therapeutic Biomarkers in Soft Tissue Sarcomas
by Ruiling Xu, Lin Qi, Xiaolei Ren, Wenchao Zhang, Chenbei Li, Zhongyue Liu, Chao Tu and Zhihong Li
Cancers 2022, 14(22), 5675; https://doi.org/10.3390/cancers14225675 - 18 Nov 2022
Cited by 1 | Viewed by 1894
Abstract
Soft tissue sarcoma (STS) is one of the rarest but most aggressive cancer. It is important to note that intratumoral hypoxia and tumor microenvironment (TME) infiltration play a significant role in the growth and therapeutic resistance of STS. The goal of this study [...] Read more.
Soft tissue sarcoma (STS) is one of the rarest but most aggressive cancer. It is important to note that intratumoral hypoxia and tumor microenvironment (TME) infiltration play a significant role in the growth and therapeutic resistance of STS. The goal of this study was therefore to determine whether linking hypoxia-related parameters to TME cells could provide a more accurate prediction of prognosis and therapeutic response. An analysis of 109 hypoxia-related genes and 64 TME cells was conducted in STS. Hypoxia-TME classifier was constructed based on 6 hypoxia prognostic genes and 8 TME cells. As a result, we evaluated the prognosis, tumor, and immune characteristics, as well as the effectiveness of therapies in Hypoxia-TME-defined subgroups. The Lowplus group showed a better prognosis and therapeutic response than any other subgroup. It is possible to unravel these differences based on immune-related molecules and somatic mutations in tumors. Further validation of Hypoxia-TME was done in an additional cohort of 225 STS patients. Additionally, we identified five key genes through differential analysis and RT-qPCR, namely, ACSM5, WNT7B, CA9, MMP13, and RAC3, which could be targeted for therapy. As a whole, the Hypoxia-TME classifier demonstrated a pretreatment predictive value for prognosis and therapeutic outcome, providing new approaches to therapy strategizing for patients. Full article
(This article belongs to the Topic Advances in Tumor Microenvironment)
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12 pages, 673 KiB  
Article
Resemblance of the Recurrence Patterns in Primary Systemic, Primary Surgery and Secondary Oncoplastic Surgery
by Davut Dayan, Kristina Ernst, Bahriye Aktas, Raffaela Baierl, Susanne Briest, Martin Dengler, Daniela Dieterle, Amelie Endres, Kathrin Engelken, Andree Faridi, Hannes Frenz, Peer Hantschmann, Wolfgang Janni, Christina Kaiser, Thorsten Kokott, Stefanie Laufhütte, Florian Schober and Florian Ebner
Curr. Oncol. 2022, 29(11), 8874-8885; https://doi.org/10.3390/curroncol29110698 - 17 Nov 2022
Cited by 1 | Viewed by 2007
Abstract
Purpose: Surgical interventions tend to have an effect on the generation of recurrences in tumor patients due to the anesthesia involved as well as tissue damage and subsequent inflammation. This can also be found in patients with breast cancer. Methods: In this multicenter [...] Read more.
Purpose: Surgical interventions tend to have an effect on the generation of recurrences in tumor patients due to the anesthesia involved as well as tissue damage and subsequent inflammation. This can also be found in patients with breast cancer. Methods: In this multicenter study, we investigated data of 632 patients with breast cancer and the subsequent diagnosis of a recurrence. The patient data were acquired from 1 January 2006 to 31 December 2019 in eight different centers in Germany. The data sets were separated into those with primary surgery, primary systemic therapy with subsequent surgery, and reconstructive surgery. Three different starting points for observation were defined: the date of diagnosis, the date of first surgery, and the date of reconstructive surgery, if applicable. The observational period was divided into steps of six months and maxima of recurrences were compared. Furthermore, the variance was calculated using the difference of the distribution in percent. Results: The descriptive analysis showed no resemblance between the groups. The variance of the difference of the recurrence rates analysis using the surgical date as the starting point showed similarities in the age subgroup. Conclusion: Our clinical analysis shows different metastatic behavior in different analysis and treatment regimes. These findings justify further investigations on a larger database. These results may possibly identify an improved follow-up setting depending on tumor stage, biology, treatment, and patient factors (i.e., age, …). Full article
(This article belongs to the Topic Advances in Tumor Microenvironment)
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