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The Role of Tumor Microenvironment in Solid Tumors: The New...
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The Role of Tumor Microenvironment in Solid Tumors: The New Frontier of Cancer Research

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Tumor Microenvironment".

Deadline for manuscript submissions: closed (30 April 2023) | Viewed by 40572

Special Issue Editors

Prof. Dr. Antonio Giuseppe Naccarato

E-Mail Website
Guest Editor
Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy
Interests: breast Cancer; neuropathology; molecular pathology
Special Issues, Collections and Topics in MDPI journals
Dr. Andres Martin Acosta

E-Mail Website
Guest Editor
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
Interests: urology; genitourinary pathology; prostate cancer; molecular pathology; soft tissue tumors; translational research
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Groundbreaking insights and cutting-edge technologies have shed light on the tumors’ complex and heterogeneous composition, highlighting the pivotal role of the tumor microenvironment (TME) in cancer initiation, progression, metastasization, and immune escape. The investigation of the multifaceted bidirectional interactions between these two aspects represents the new frontier in cancer research. However, several aspects still remain unclear. Innovative studies with unique approaches could revolutionize the understanding of cancer mechanisms, laying the foundations for novel therapeutic strategies targeted against TME components.

This Special Issue in Cancers, entitled “The Role of Tumor Microenvironment in Solid Tumors: The New Frontier of Cancer Research”, will try to draw a complete portrait of the current state of knowledge on TME, highlighting the pioneering findings that could have a promising translational application. We especially welcome original research articles, reviews (either systematic or discursive), and short communications of significant preliminary results.

Prof. Dr. Antonio Giuseppe Naccarato
Dr. Andres Martin Acosta
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. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • tumor microenvironment
  • immune microenvironment
  • solid tumors
  • prognostic biomarkers
  • predictive biomarkers
  • translational research

Published Papers (14 papers)

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Research

Jump to: Review

23 pages, 3473 KiB  
Article
Matrix Metalloproteinase 9 Induced in Esophageal Squamous Cell Carcinoma Cells via Close Contact with Tumor-Associated Macrophages Contributes to Cancer Progression and Poor Prognosis
by Shuichi Tsukamoto, Yu-ichiro Koma, Yu Kitamura, Kohei Tanigawa, Yuki Azumi, Shoji Miyako, Satoshi Urakami, Masayoshi Hosono, Takayuki Kodama, Mari Nishio, Manabu Shigeoka and Hiroshi Yokozaki
Cancers 2023, 15(11), 2987; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15112987 - 30 May 2023
Cited by 3 | Viewed by 1521
Abstract
Tumor-associated macrophages (TAMs) contribute to disease progression in various cancers, including esophageal squamous cell carcinoma (ESCC). We have previously used an indirect co-culture system between ESCC cell lines and macrophages to analyze their interactions. Recently, we established a direct co-culture system to closely [...] Read more.
Tumor-associated macrophages (TAMs) contribute to disease progression in various cancers, including esophageal squamous cell carcinoma (ESCC). We have previously used an indirect co-culture system between ESCC cell lines and macrophages to analyze their interactions. Recently, we established a direct co-culture system to closely simulate actual ESCC cell-TAM contact. We found that matrix metalloproteinase 9 (MMP9) was induced in ESCC cells by direct co-culture with TAMs, not by indirect co-culture. MMP9 was associated with ESCC cell migration and invasion, and its expression was controlled by the Stat3 signaling pathway in vitro. Immunohistochemical analyses revealed that MMP9 expression in cancer cells at the invasive front (“cancer cell MMP9”) was related to high infiltration of CD204 positive M2-like TAMs (p < 0.001) and was associated with worse overall and disease-free survival of patients (p = 0.036 and p = 0.038, respectively). Furthermore, cancer cell MMP9 was an independent prognostic factor for disease-free survival. Notably, MMP9 expression in cancer stroma was not associated with any clinicopathological factors or patient prognoses. Our results suggest that close interaction with TAMs infiltrating in cancer stroma or cancer nests induces MMP9 expression in ESCC cells, equipping them with more malignant features. Full article
(This article belongs to the Special Issue The Role of Tumor Microenvironment in Solid Tumors: The New Frontier of Cancer Research)
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15 pages, 8368 KiB  
Article
E. coli Phagelysate: A Primer to Enhance Nanoparticles and Drug Deliveries in Tumor
by Ketevan Ghambashidze, Ramaz Chikhladze, Tamar Saladze, P. Jack Hoopes and Fridon Shubitidze
Cancers 2023, 15(8), 2315; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15082315 - 15 Apr 2023
Cited by 1 | Viewed by 1537
Abstract
The tumor microenvironment (TME), where cancer cells reside, plays a crucial role in cancer progression and metastasis. It maintains an immunosuppressive state in many tumors and regulates the differentiation of precursor monocytes into M1 (anti-tumor)- and M2 (pro-tumor)-polarized macrophages, and greatly reduces anticancer [...] Read more.
The tumor microenvironment (TME), where cancer cells reside, plays a crucial role in cancer progression and metastasis. It maintains an immunosuppressive state in many tumors and regulates the differentiation of precursor monocytes into M1 (anti-tumor)- and M2 (pro-tumor)-polarized macrophages, and greatly reduces anticancer drug and nanoparticle delivery. As a result, the effectiveness of recently developed chemo- and/or nanotechnology-mediated immune and magnetic nanoparticle hyperthermia (mNPH) therapies is inhibited significantly. One of the ways to overcome this limitation is to use E. coli phagelysate as a primer to modify the tumor microenvironment by switching tumor-associated M2 macrophages to anti-tumor M1 macrophages, and initiate the infiltration of tumor-associated macrophages (TAMs). Recently, bacteriophages and phage-induced lysed bacteria (bacterial phagelysates—BPLs) have been shown to be capable of modifying the tumor-associated environment. Phage/BPL-coated proteins tend to elicit strong anti-tumor responses from the innate immune system, prompting phagocytosis and cytokine release. It has also been reported that the microenvironments of bacteriophage- and BPL-treated tumors facilitate the conversion of M2-polarized TAMS to a more M1-polarized (tumoricidal) environment post-phage treatment. This paper demonstrates the feasibility and enhanced efficacy of combining E. coli phagelysate (EcPHL) and mNPH, a promising technology for treating cancers, in a rodent model. Specifically, we illustrate the EcPHL vaccination effect on the TME and mNP distribution in Ehrlich adenocarcinoma tumors by providing the tumor growth dynamics and histology (H&E and Prussian blue) distribution of mNP in tumor and normal tissue. Full article
(This article belongs to the Special Issue The Role of Tumor Microenvironment in Solid Tumors: The New Frontier of Cancer Research)
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19 pages, 3483 KiB  
Article
Roles of IL-7R Induced by Interactions between Cancer Cells and Macrophages in the Progression of Esophageal Squamous Cell Carcinoma
by Yu Kitamura, Yu-ichiro Koma, Kohei Tanigawa, Shuichi Tsukamoto, Yuki Azumi, Shoji Miyako, Satoshi Urakami, Takayuki Kodama, Mari Nishio, Manabu Shigeoka, Yoshihiro Kakeji and Hiroshi Yokozaki
Cancers 2023, 15(2), 394; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15020394 - 06 Jan 2023
Cited by 5 | Viewed by 2393
Abstract
High infiltration of tumor-associated macrophages (TAMs), which contribute to the progression of several cancer types, is correlated with poor prognosis of esophageal squamous cell carcinoma (ESCC). In addition to the previously reported increase in migration and invasion, ESCC cells co-cultured directly with macrophages [...] Read more.
High infiltration of tumor-associated macrophages (TAMs), which contribute to the progression of several cancer types, is correlated with poor prognosis of esophageal squamous cell carcinoma (ESCC). In addition to the previously reported increase in migration and invasion, ESCC cells co-cultured directly with macrophages exhibited enhanced survival and growth. Furthermore, interleukin-related molecules are associated with ESCC; however, the precise mechanism underlying this association is unclear. Therefore, we explored the role of interleukin-related molecules in ESCC progression. A cDNA microarray analysis of monocultured and co-cultured ESCC cells revealed that the interleukin 7 receptor (IL-7R) was upregulated in ESCC cells co-cultured with macrophages. Overexpression of IL-7R promoted the survival and growth of ESCC cells by activating the Akt and Erk1/2 signaling pathways. The IL-7/IL-7R axis also contributed to the promotion of ESCC cell migration via the Akt and Erk1/2 signaling pathways. Furthermore, immunohistochemistry showed that ESCC patients with high IL-7R expression in cancer nests exhibited a trend toward poor prognosis in terms of disease-free survival, and showed significant correlation with increased numbers of infiltrating macrophages and cancer-associated fibroblasts. Therefore, IL-7R, which is upregulated when directly co-cultured with macrophages, may contribute to ESCC progression by promoting the development of various malignant phenotypes in cancer cells. Full article
(This article belongs to the Special Issue The Role of Tumor Microenvironment in Solid Tumors: The New Frontier of Cancer Research)
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16 pages, 5416 KiB  
Article
Construction of an Immune Escape-Related Signature in Clear Cell Renal Cell Carcinoma and Identification of the Relationship between IFNAR1 and Immune Infiltration by Multiple Immunohistochemistry
by Kun Chang, Fujiang Xu, Xuanzhi Zhang, Bohan Zeng, Wei Zhang, Guohai Shi and Dingwei Ye
Cancers 2023, 15(1), 169; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15010169 - 28 Dec 2022
Cited by 1 | Viewed by 1827
Abstract
Background: In the past decade, immunotherapy has been widely used in the treatment of various tumors, such as PD-1/PD-L1 inhibitors. Although clear cell renal cell carcinoma (ccRCC) has been shown to be sensitive to immunotherapy, it is effective only in several cases, which [...] Read more.
Background: In the past decade, immunotherapy has been widely used in the treatment of various tumors, such as PD-1/PD-L1 inhibitors. Although clear cell renal cell carcinoma (ccRCC) has been shown to be sensitive to immunotherapy, it is effective only in several cases, which brings great obstacles to anti-tumor therapy for patients. Lawson et al. have successfully identified 182 “core cancer innate immune escape genes” whose deletion makes cancer cells more sensitive or resistant to T-cell attack. Methods: In this research, we sought to explore genes closely associated with ccRCC among the 182 core cancer innate immune escape genes. We used online databases to screen mutated genes in ccRCC, and then used ConsensusClusterPlus to cluster clinical samples to analyze differences in clinical prognosis and immune components between the two subgroups. In addition, the immune escape score was calculated using lasso cox regression, and a stable tumor immune escape-related nomogram was established to predict the overall survival of patients. Results: Higher immune escape score was significantly correlated with shorter survival time. Meanwhile, through the validation of the external cohort and the correlation analysis of the immune microenvironment, we proved that IFNAR1 is the key gene regulating immune escape in ccRCC, and we also found that the function of IFNAR1 in promoting immune activation is achieved by facilitating the infiltration of CD4+ T cells and CD8+ T cells. IFNAR1 regulates the malignant behavior of ccRCC by inhibiting the proliferation and migration properties. Conclusions: IFNAR1 may become a key biomarker for evaluating the efficacy of ccRCC immunotherapy and may also be a potential target for immunotherapy. Full article
(This article belongs to the Special Issue The Role of Tumor Microenvironment in Solid Tumors: The New Frontier of Cancer Research)
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17 pages, 3681 KiB  
Article
Sodium New Houttuyfonate Inhibits Cancer-Promoting Fusobacterium nucleatum (Fn) to Reduce Colorectal Cancer Progression
by Fengjing Jia, Qun Yu, Ling Zhao, Yunhui Shen, Haidong Guo and Feng He
Cancers 2022, 14(24), 6111; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14246111 - 12 Dec 2022
Cited by 6 | Viewed by 1546
Abstract
Colorectal cancer (CRC) is a major cause of morbidity and mortality worldwide. Recent studies showed that the common anaerobe Fusobacterium nucleatum (Fn) is closely associated with a higher risk for carcinogenesis, metastasis, and chemoresistance of CRC. However, there is no specific [...] Read more.
Colorectal cancer (CRC) is a major cause of morbidity and mortality worldwide. Recent studies showed that the common anaerobe Fusobacterium nucleatum (Fn) is closely associated with a higher risk for carcinogenesis, metastasis, and chemoresistance of CRC. However, there is no specific antimicrobial therapy for CRC treatment. Herbal medicine has a long history of treating diseases with remarkable effects and is attracting extensive attention. In this study, we tested six common phytochemicals for their antimicrobial activities against Fn and whether anti-Fn phytochemicals can modulate CRC development associated with Fn. Among these antimicrobials, we found that SNH showed the highest antimicrobial activity and little cytotoxicity toward cancer cells and normal cells in vitro and in vivo. Mechanistically, SNH may target membrane-associated FadA, leading to FadA oligomerization, membrane fragmentation and permeabilization. More importantly, SNH blocked the tumor-promoting activity of Fn and Fn-associated cancer-driven inflammation, thus improving the intestinal barrier damaged by Fn. SNH reduced Fn load in the CRC-cells-derived mice xenografts with Fn inoculation and significantly inhibited CRC progression. Our data suggest that SNH could be used for an antimicrobial therapy that inhibits Fn and cancer-driven inflammation of CRC. Our results provide an important foundation for future gut microbiota-targeted clinical treatment of CRC. Full article
(This article belongs to the Special Issue The Role of Tumor Microenvironment in Solid Tumors: The New Frontier of Cancer Research)
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20 pages, 5536 KiB  
Article
Tumor-Associated Macrophages Promote Metastasis of Oral Squamous Cell Carcinoma via CCL13 Regulated by Stress Granule
by Zhixin Liu, Tao Rui, Zhaoyu Lin, Shule Xie, Bin Zhou, Min Fu, Lianxi Mai, Chuandong Zhu, Guotao Wu and Youyuan Wang
Cancers 2022, 14(20), 5081; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14205081 - 17 Oct 2022
Cited by 6 | Viewed by 1925
Abstract
M2 tumor-associated macrophages (TAMs) have been a well-established promoter of oral squamous cell carcinoma (OSCC) progression. However, the mechanisms of M2 TAMs promoting OSCC metastasis have not been elucidated clearly. This study illustrated the regulatory mechanisms in which M2 TAMs enhance OSCC malignancy [...] Read more.
M2 tumor-associated macrophages (TAMs) have been a well-established promoter of oral squamous cell carcinoma (OSCC) progression. However, the mechanisms of M2 TAMs promoting OSCC metastasis have not been elucidated clearly. This study illustrated the regulatory mechanisms in which M2 TAMs enhance OSCC malignancy in a novel point of view. In this study, mass spectrometry was utilized to analyze the proteins expression profile of M2 type monocyte-derived macrophages (MDMs-M2), whose results revealed the high expression of G3BP1 in M2 macrophages. RNA sequencing analyzed the genome-wide changes upon G3BP1 knockdown in MDMs-M2 and identified that CCL13 was the most significantly downregulated inflammatory cytokines in MDMs-M2. Co-immunoprecipitation and qualitative mass spectrometry were used to identify the proteins that directly interacted with endogenous G3BP1 in MDMs-M2. Elevated stress granule (SG) formation in stressed M2 TAMs enhanced the expression of CCL13, which promoted OSCC metastasis both in vitro and in vivo. For mechanisms, we demonstrated SG formation improved DDX3Y/hnRNPF-mediated CCL13 mRNA stability, thus enhancing CCL13 expression and promoting OSCC metastasis. Collectively, our findings demonstrated for the first time the roles of CCL13 in improving OSCC metastasis and illustrated the molecular mechanisms of CCL13 expression regulated by SG, indicating that the SG-CCL13 axis can be the potential targets for TAM-navigated tumor therapy. Full article
(This article belongs to the Special Issue The Role of Tumor Microenvironment in Solid Tumors: The New Frontier of Cancer Research)
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17 pages, 2124 KiB  
Article
Circulating and Tumor-Infiltrating Immune Checkpoint-Expressing CD8+ Treg/T Cell Subsets and Their Associations with Disease-Free Survival in Colorectal Cancer Patients
by Alhasan Alsalman, Mohammad A. Al-Mterin, Khaled Murshed, Ferial Alloush, Samia T. Al-Shouli, Salman M. Toor and Eyad Elkord
Cancers 2022, 14(13), 3194; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14133194 - 29 Jun 2022
Cited by 8 | Viewed by 2262
Abstract
T cells in the tumor microenvironment (TME) have diverse roles in anti-tumor immunity, including orchestration of immune responses and anti-tumor cytotoxic attack. However, different T cell subsets may have opposing roles in tumor progression, especially in inflammation-related cancers such as colorectal cancer (CRC). [...] Read more.
T cells in the tumor microenvironment (TME) have diverse roles in anti-tumor immunity, including orchestration of immune responses and anti-tumor cytotoxic attack. However, different T cell subsets may have opposing roles in tumor progression, especially in inflammation-related cancers such as colorectal cancer (CRC). In this study, we phenotypically characterized CD3+CD4- (CD8+) T cells in colorectal tumor tissues (TT), normal colon tissues (NT) and in circulation of CRC patients. We investigated the expression levels of key immune checkpoints (ICs) and Treg-related markers in CD8+ T cells. Importantly, we investigated associations between different tumor-infiltrating CD8+ T cell subpopulations and disease-free survival (DFS) in CRC patients. We found that FoxP3 expression and ICs including PD-1, CTLA-4, TIM-3, and LAG-3 were significantly increased in tumor-infiltrating CD8+ T cells compared with NT and peripheral blood. In the TME, we found that TIM-3 expression was significantly increased in patients with early stages and absent lymphovascular invasion (LVI) compared to patients with advanced stages and LVI. Importantly, we report that high levels of certain circulating CD8+ T cell subsets (TIM-3-expressing, FoxP3−Helios−TIM-3+ and FoxP3−Helios+TIM-3+ cells) in CRC patients were associated with better DFS. Moreover, in the TME, we report that elevated levels of CD25+ and TIM-3+ T cells, and FoxP3+Helios−TIM-3+ Tregs were associated with better DFS. Full article
(This article belongs to the Special Issue The Role of Tumor Microenvironment in Solid Tumors: The New Frontier of Cancer Research)
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19 pages, 2303 KiB  
Article
A Small Molecule–Drug Conjugate (SMDC) Consisting of a Modified Camptothecin Payload Linked to an αVß3 Binder for the Treatment of Multiple Cancer Types
by Hans-Georg Lerchen, Beatrix Stelte-Ludwig, Charlotte Kopitz, Melanie Heroult, Dmitry Zubov, Joerg Willuda, Thomas Schlange, Antje Kahnert, Harvey Wong, Raquel Izumi and Ahmed Hamdy
Cancers 2022, 14(2), 391; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14020391 - 13 Jan 2022
Cited by 13 | Viewed by 4529
Abstract
To improve tumor selectivity of cytotoxic agents, we designed VIP236, a small molecule–drug conjugate consisting of an αVβ3 integrin binder linked to a modified camptothecin payload (VIP126), which is released by the enzyme neutrophil elastase (NE) in the tumor microenvironment [...] Read more.
To improve tumor selectivity of cytotoxic agents, we designed VIP236, a small molecule–drug conjugate consisting of an αVβ3 integrin binder linked to a modified camptothecin payload (VIP126), which is released by the enzyme neutrophil elastase (NE) in the tumor microenvironment (TME). The tumor targeting and pharmacokinetics of VIP236 were studied in tumor-bearing mice by in vivo near-infrared imaging and by analyzing tumor and plasma samples. The efficacy of VIP236 was investigated in a panel of cancer cell lines in vitro, and in MX-1, NCI-H69, and SW480 murine xenograft models. Imaging studies with the αVβ3 binder demonstrated efficient tumor targeting. Administration of VIP126 via VIP236 resulted in a 10-fold improvement in the tumor/plasma ratio of VIP126 compared with VIP126 administered alone. Unlike SN38, VIP126 is not a substrate of P-gp and BCRP drug transporters. VIP236 presented strong cytotoxic activity in the presence of NE. VIP236 treatment resulted in tumor regressions and very good tolerability in all in vivo models tested. VIP236 represents a novel approach for delivering a potent cytotoxic agent by utilizing αVβ3 as a targeting moiety and NE in the TME to release the VIP126 payload—designed for high permeability and low efflux—directly into the tumor stroma. Full article
(This article belongs to the Special Issue The Role of Tumor Microenvironment in Solid Tumors: The New Frontier of Cancer Research)
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15 pages, 3288 KiB  
Article
Tumor-Associated Regulatory T Cell Expression of LAIR2 Is Prognostic in Lung Adenocarcinoma
by Dalam Ly, Quan Li, Roya Navab, Cédric Zeltz, Linan Fang, Michael Cabanero, Chang-Qi Zhu, Ming-Sound Tsao and Li Zhang
Cancers 2022, 14(1), 205; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14010205 - 31 Dec 2021
Cited by 16 | Viewed by 2784
Abstract
Cancer development requires a permissive microenvironment that is shaped by interactions between tumor cells, stroma, and the surrounding matrix. As collagen receptors, the leukocyte-associated immunoglobulin-like receptor (LAIR) family allows the immune system to interact with the extracellular matrix. However, little is known about [...] Read more.
Cancer development requires a permissive microenvironment that is shaped by interactions between tumor cells, stroma, and the surrounding matrix. As collagen receptors, the leukocyte-associated immunoglobulin-like receptor (LAIR) family allows the immune system to interact with the extracellular matrix. However, little is known about their role in regulating tumor immunity and cancer progression. Methods: Genetic analysis of resected human lung adenocarcinoma was correlated to clinical-pathological characteristics, gene ontologies, and single cell RNA sequencing (scRNASeq). LAIR2 production was determined in subsets of immune cells isolated from blood leukocytes and lung adenocarcinoma tumor. Functional assays were used to determine the role of LAIR2 in tumorigenesis. Results: LAIR2 expression was adversely prognostic in lung adenocarcinoma. LAIR2 was preferentially produced by activated CD4+ T cells and enhanced in vitro tumor invasion into collagen. scRNASeq analysis of tumor infiltrating T cells revealed that LAIR2 expression co-localized with FOXP3 expressing cells and shared a transcriptional signature with tumor-associated regulatory T (Treg) cells. A CD4+ LAIR2+ Treg gene signature was prognostically significant in the TCGA dataset (n = 439; hazard ratio (HR) = 1.37; 95% confidence interval (CI), 1.05–1.77, p = 0.018) and validated in NCI Director’s Challenge lung adenocarcinoma dataset (n = 488; HR = 1.54; 95% CI, 1.14–2.09, p = 0.0045). Conclusions: Our data support a role for LAIR2 in lung adenocarcinoma tumorigenesis and identify a CD4+ LAIR2+ Treg gene signature in lung adenocarcinoma prognosis. LAIR2 provides a novel target for development of immunotherapies. Full article
(This article belongs to the Special Issue The Role of Tumor Microenvironment in Solid Tumors: The New Frontier of Cancer Research)
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20 pages, 4604 KiB  
Article
Metallothionein 2A Expression in Cancer-Associated Fibroblasts and Cancer Cells Promotes Esophageal Squamous Cell Carcinoma Progression
by Masaki Shimizu, Yu-ichiro Koma, Hiroki Sakamoto, Shuichi Tsukamoto, Yu Kitamura, Satoshi Urakami, Kohei Tanigawa, Takayuki Kodama, Nobuhide Higashino, Mari Nishio, Manabu Shigeoka, Yoshihiro Kakeji and Hiroshi Yokozaki
Cancers 2021, 13(18), 4552; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13184552 - 10 Sep 2021
Cited by 19 | Viewed by 3345
Abstract
Esophageal cancer has the sixth highest mortality rate worldwide. Cancer-associated fibroblasts (CAFs) are involved in the progression of various cancers. Previously, we demonstrated an association between high expression of the CAF marker, fibroblast activation protein, and poor prognosis of esophageal squamous cell carcinoma [...] Read more.
Esophageal cancer has the sixth highest mortality rate worldwide. Cancer-associated fibroblasts (CAFs) are involved in the progression of various cancers. Previously, we demonstrated an association between high expression of the CAF marker, fibroblast activation protein, and poor prognosis of esophageal squamous cell carcinoma (ESCC). We also established CAF-like cells by indirect co-culture of bone marrow-derived mesenchymal stem cells with ESCC cell lines and found metallothionein 2A (MT2A) to be highly expressed in them. Here, to explore the function of MT2A in CAFs, we silenced MT2A in the CAF-like cells and ESCC cell lines using small interfering RNA. MT2A knockdown in the CAF-like cells suppressed expression and secretion of insulin-like growth factor binding protein 2 (IGFBP2); recombinant IGFBP2 promoted migration and invasiveness of ESCC cells via NFκB, Akt, and Erk signaling pathways. Furthermore, MT2A knockdown in the ESCC cell lines inhibited their growth, migration, and invasiveness. Immunohistochemistry demonstrated that high MT2A expression in the cancer stroma and cancer nest of ESCC tissues correlated with poor prognosis of ESCC patients. Hence, we report that MT2A in CAFs and cancer cells contributes to ESCC progression. MT2A and IGFBP2 are potential novel therapeutic targets in ESCC. Full article
(This article belongs to the Special Issue The Role of Tumor Microenvironment in Solid Tumors: The New Frontier of Cancer Research)
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Review

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20 pages, 5429 KiB  
Review
Modelling the Tumour Microenvironment, but What Exactly Do We Mean by “Model”?
by Constantino Carlos Reyes-Aldasoro
Cancers 2023, 15(15), 3796; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15153796 - 26 Jul 2023
Viewed by 1601
Abstract
The Oxford English Dictionary includes 17 definitions for the word “model” as a noun and another 11 as a verb. Therefore, context is necessary to understand the meaning of the word model. For instance, “model railways” refer to replicas of railways and trains [...] Read more.
The Oxford English Dictionary includes 17 definitions for the word “model” as a noun and another 11 as a verb. Therefore, context is necessary to understand the meaning of the word model. For instance, “model railways” refer to replicas of railways and trains at a smaller scale and a “model student” refers to an exemplary individual. In some cases, a specific context, like cancer research, may not be sufficient to provide one specific meaning for model. Even if the context is narrowed, specifically, to research related to the tumour microenvironment, “model” can be understood in a wide variety of ways, from an animal model to a mathematical expression. This paper presents a review of different “models” of the tumour microenvironment, as grouped by different definitions of the word into four categories: model organisms, in vitro models, mathematical models and computational models. Then, the frequencies of different meanings of the word “model” related to the tumour microenvironment are measured from numbers of entries in the MEDLINE database of the United States National Library of Medicine at the National Institutes of Health. The frequencies of the main components of the microenvironment and the organ-related cancers modelled are also assessed quantitatively with specific keywords. Whilst animal models, particularly xenografts and mouse models, are the most commonly used “models”, the number of these entries has been slowly decreasing. Mathematical models, as well as prognostic and risk models, follow in frequency, and these have been growing in use. Full article
(This article belongs to the Special Issue The Role of Tumor Microenvironment in Solid Tumors: The New Frontier of Cancer Research)
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25 pages, 1677 KiB  
Review
A Quick Guide to CAF Subtypes in Pancreatic Cancer
by Anna Brichkina, Pierfrancesco Polo, Shrey Dharamvir Sharma, Nico Visestamkul and Matthias Lauth
Cancers 2023, 15(9), 2614; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15092614 - 04 May 2023
Cited by 3 | Viewed by 3252
Abstract
Pancreatic cancer represents one of the most desmoplastic malignancies and is characterized by an extensive deposition of extracellular matrix. The latter is provided by activated cancer-associated fibroblasts (CAFs), which are abundant cells in the pancreatic tumor microenvironment. Many recent studies have made it [...] Read more.
Pancreatic cancer represents one of the most desmoplastic malignancies and is characterized by an extensive deposition of extracellular matrix. The latter is provided by activated cancer-associated fibroblasts (CAFs), which are abundant cells in the pancreatic tumor microenvironment. Many recent studies have made it clear that CAFs are not a singular cellular entity but represent a multitude of potentially dynamic subgroups that affect tumor biology at several levels. As mentioned before, CAFs significantly contribute to the fibrotic reaction and the biomechanical properties of the tumor, but they can also modulate the local immune environment and the response to targeted, chemo or radiotherapy. As the number of known and emerging CAF subgroups is steadily increasing, it is becoming increasingly difficult to keep up with these developments and to clearly discriminate the cellular subsets identified so far. This review aims to provide a helpful overview that enables readers to quickly familiarize themselves with field of CAF heterogeneity and to grasp the phenotypic, functional and therapeutic distinctions of the various stromal subpopulations. Full article
(This article belongs to the Special Issue The Role of Tumor Microenvironment in Solid Tumors: The New Frontier of Cancer Research)
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21 pages, 1683 KiB  
Review
Proteoglycans in Cancer: Friends or Enemies? A Special Focus on Hepatocellular Carcinoma
by Francesco Dituri, Gianluigi Gigante, Rosanna Scialpi, Serena Mancarella, Isabel Fabregat and Gianluigi Giannelli
Cancers 2022, 14(8), 1902; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14081902 - 09 Apr 2022
Cited by 11 | Viewed by 5359
Abstract
Proteoglycans are a class of highly glycosylated proteins expressed in virtually all tissues, which are localized within membranes, but more often in the pericellular space and extracellular matrix (ECM), and are involved in tissue homeostasis and remodeling of the stromal microenvironment during physiological [...] Read more.
Proteoglycans are a class of highly glycosylated proteins expressed in virtually all tissues, which are localized within membranes, but more often in the pericellular space and extracellular matrix (ECM), and are involved in tissue homeostasis and remodeling of the stromal microenvironment during physiological and pathological processes, such as tissue regeneration, angiogenesis, and cancer. In general, proteoglycans can perform signaling activities and influence a range of physical, chemical, and biological tissue properties, including the diffusivity of small electrolytes and nutrients and the bioavailability of growth factors. While the dysregulated expression of some proteoglycans is observed in many cancers, whether they act as supporters or limiters of neoplastic progression is still a matter of controversy, as the tumor promoting or suppressive function of some proteoglycans is context dependent. The participation of multiple proteoglycans in organ regeneration (as demonstrated for the liver in hepatectomy mouse models) and in cancer suggests that these molecules actively influence cell growth and motility, thus contributing to key events that characterize neoplastic progression. In this review, we outline the main roles of proteoglycans in the physiology and pathology of cancers, with a special mention to hepatocellular carcinoma (HCC), highlighting the translational potential of proteoglycans as targets or therapeutic agents for the treatment of this disease. Full article
(This article belongs to the Special Issue The Role of Tumor Microenvironment in Solid Tumors: The New Frontier of Cancer Research)
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38 pages, 2155 KiB  
Review
Extracellular Matrices and Cancer-Associated Fibroblasts: Targets for Cancer Diagnosis and Therapy?
by Ismahane Belhabib, Sonia Zaghdoudi, Claire Lac, Corinne Bousquet and Christine Jean
Cancers 2021, 13(14), 3466; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13143466 - 11 Jul 2021
Cited by 52 | Viewed by 4664
Abstract
Solid cancer progression is dictated by neoplastic cell features and pro-tumoral crosstalks with their microenvironment. Stroma modifications, such as fibroblast activation into cancer-associated fibroblasts (CAFs) and extracellular matrix (ECM) remodeling, are now recognized as critical events for cancer progression and as potential therapeutic [...] Read more.
Solid cancer progression is dictated by neoplastic cell features and pro-tumoral crosstalks with their microenvironment. Stroma modifications, such as fibroblast activation into cancer-associated fibroblasts (CAFs) and extracellular matrix (ECM) remodeling, are now recognized as critical events for cancer progression and as potential therapeutic or diagnostic targets. The recent appreciation of the key, complex and multiple roles of the ECM in cancer and of the CAF diversity, has revolutionized the field and raised innovative but challenging questions. Here, we rapidly present CAF heterogeneity in link with their specific ECM remodeling features observed in cancer, before developing each of the impacts of such ECM modifications on tumor progression (survival, angiogenesis, pre-metastatic niche, chemoresistance, etc.), and on patient prognosis. Finally, based on preclinical studies and recent results obtained from clinical trials, we highlight key mechanisms or proteins that are, or may be, used as potential therapeutic or diagnostic targets, and we report and discuss benefits, disappointments, or even failures, of recently reported stroma-targeting strategies. Full article
(This article belongs to the Special Issue The Role of Tumor Microenvironment in Solid Tumors: The New Frontier of Cancer Research)
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