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Tumor Microenvironment 3.0
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Tumor Microenvironment 3.0

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

Deadline for manuscript submissions: closed (22 June 2020) | Viewed by 25130

Special Issue Editor

Prof. Dr. Naofumi Mukaida

E-Mail Website1 Website2
Guest Editor
Kanazawa University, Division of Molecular Bioregulation, Kanazawa, Japan
Interests: chemokine; tumor microenvironment; metastasis; invasion; Immunology; Laboratory medicine; Experimental Pathology; Pathological Medical Biochemistry
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The accumulation of gene mutations can transform normal cells into cancer cells, which are required, but not sufficient, to induce cancer tissues. Cancer development and its malignant progression unexceptionally proceeds under the influence of tumor microenvironments, which are governed by the communication between cancer cells and normal resident cells present in tumor tissues, such as leukocytes, endothelial cells, and fibroblasts. Moreover, normal cells present in tumor tissues frequently support the survival of cancer stem cells by providing them with niche, thereby inducing resistance to chemotherapy and radiotherapy. Thus, in order to identify druggable targets for exploiting efficient anti-cancer strategies, it is mandatory to clarify the interplay of cancer cells with intratumoral normal cells at molecular levels. Here, in this Special Issue “Tumor Microenvironments”, we will discuss various types of mediators including cytokines, chemokines, extracellular vesicles, and lipid mediators, which are deeply involved in the interaction between cancer cells and normal cells in cancer tissues.

Prof. Dr. Naofumi Mukaida
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • angiogenesis
  • chemokine
  • cytokine
  • endothelial cell
  • fibroblast
  • invasion
  • lipid mediator
  • leukocyte
  • metastasis
  • niche

Related Special Issues

Published Papers (5 papers)

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Research

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17 pages, 3161 KiB  
Article
Interferon-Induced Transmembrane Protein 1 (IFITM1) Promotes Distant Metastasis of Small Cell Lung Cancer
by Shuichi Sakamoto, Hiroyuki Inoue, Yasuko Kohda, Shun-ichi Ohba, Taketoshi Mizutani and Manabu Kawada
Int. J. Mol. Sci. 2020, 21(14), 4934; https://doi.org/10.3390/ijms21144934 - 13 Jul 2020
Cited by 12 | Viewed by 3282
Abstract
Small cell lung cancer (SCLC) is a severe malignancy associated with early and widespread metastasis. To study SCLC metastasis, we previously developed an orthotopic transplantation model using the human SCLC cell line DMS273. In the model, metastatic foci were found in distant tissues [...] Read more.
Small cell lung cancer (SCLC) is a severe malignancy associated with early and widespread metastasis. To study SCLC metastasis, we previously developed an orthotopic transplantation model using the human SCLC cell line DMS273. In the model, metastatic foci were found in distant tissues such as bone and the adrenal gland, similarly as observed in patients with SCLC. In this study, we evaluated the differentially expressed genes between orthotopic and metastatic tumors in the model. We isolated tumor cells from orthotopic and metastatic sites, and the tumor cell RNA was analyzed using DNA microarray analysis. We found that 19 genes in metastatic tumors were upregulated by more than 4-fold compared with their expression in orthotopic tumors. One of these genes encodes a transmembrane protein, interferon (IFN)-induced transmembrane protein 1 (IFITM1), and immunohistochemical analysis confirmed the higher expression of the protein in metastatic sites than in orthotopic sites. IFITM1 was also detected in some SCLC cell lines and lung tumors from patients with SCLC. The overexpression of IFITM1 in DMS273 cells increased their metastatic formation in the orthotopic model and in an experimental metastasis model. Conversely, the silencing of IFITM1 suppressed metastatic formation by DMS273 cells. We also found that IFITM1 overexpression promoted the metastatic formation of NCI-H69 human SCLC cells. These results demonstrate that IFITM1 promotes distant metastasis in xenograft models of human SCLC. Full article
(This article belongs to the Special Issue Tumor Microenvironment 3.0)
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12 pages, 38701 KiB  
Article
Brachytherapy in a Single Dose of 10Gy as an “in situ” Vaccination
by Magdalena Jarosz-Biej, Ryszard Smolarczyk, Tomasz Cichoń, Alina Drzyzga, Justyna Czapla, Zbigniew Urbaś, Ewelina Pilny, Sybilla Matuszczak and Piotr Wojcieszek
Int. J. Mol. Sci. 2020, 21(13), 4585; https://doi.org/10.3390/ijms21134585 - 28 Jun 2020
Cited by 9 | Viewed by 2276
Abstract
Radiotherapy (RT) is one of the major methods of cancer treatment. RT destroys cancer cells, but also affects the tumor microenvironment (TME). The delicate balance between immunomodulation processes in TME is dependent, among other things, on a specific radiation dose. Despite many studies, [...] Read more.
Radiotherapy (RT) is one of the major methods of cancer treatment. RT destroys cancer cells, but also affects the tumor microenvironment (TME). The delicate balance between immunomodulation processes in TME is dependent, among other things, on a specific radiation dose. Despite many studies, the optimal dose has not been clearly determined. Here, we demonstrate that brachytherapy (contact radiotherapy) inhibits melanoma tumor growth in a dose-dependent manner. Doses of 10Gy and 15Gy cause the most effective tumor growth inhibition compared to the control group. Brachytherapy, at a single dose of ≥ 5Gy, resulted in reduced tumor blood vessel density. Only a dose of 10Gy had the greatest impact on changes in the levels of tumor-infiltrating immune cells. It most effectively reduced the accumulation of protumorogenic M2 tumor-associated macrophages and increased the infiltration of cytotoxic CD8+ T lymphocytes. To summarize, more knowledge about the effects of irradiation doses in anticancer therapy is needed. It may help in the optimization of RT treatment. Our results indicate that a single dose of 10Gy leads to the development of a robust immune response. It seems that it is able to convert a tumor microenvironment into an “in situ” vaccine and lead to a significant inhibition of tumor growth. Full article
(This article belongs to the Special Issue Tumor Microenvironment 3.0)
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13 pages, 5925 KiB  
Article
Cancer Cell-Derived Granulocyte-Macrophage Colony-Stimulating Factor Is Dispensable for the Progression of 4T1 Murine Breast Cancer
by Teizo Yoshimura, Kaoru Nakamura, Chunning Li, Masayoshi Fujisawa, Tsuyoshi Shiina, Mayu Imamura, Tiantian Li, Naofumi Mukaida and Akihiro Matsukawa
Int. J. Mol. Sci. 2019, 20(24), 6342; https://doi.org/10.3390/ijms20246342 - 16 Dec 2019
Cited by 9 | Viewed by 4300
Abstract
We previously reported that 4T1 murine breast cancer cells produce GM-CSF that up-regulates macrophage expression of several cancer promoting genes, including Mcp-1/Ccl2, Ccl17 and Rankl, suggesting a critical role of cancer cell-derived GM-CSF in cancer progression. Here, we attempted to define [...] Read more.
We previously reported that 4T1 murine breast cancer cells produce GM-CSF that up-regulates macrophage expression of several cancer promoting genes, including Mcp-1/Ccl2, Ccl17 and Rankl, suggesting a critical role of cancer cell-derived GM-CSF in cancer progression. Here, we attempted to define whether 4T1 cell-derived GM-CSF contributes to the expression of these genes by 4T1tumors, and their subsequent progression. Intraperitoneal injection of anti-GM-CSF neutralizing antibody did not decrease the expression of Mcp-1, Ccl17 or Rankl mRNA by 4T1 tumors. To further examine the role of cancer cell-derived GM-CSF, we generated GM-CSF-deficient 4T1 cells by using the Crisper-Cas9 system. As previously demonstrated, 4T1 cells are a mixture of cells and cloning of cells by itself significantly reduced tumor growth and lung metastasis. By contrast, GM-CSF-deficiency did not affect tumor growth, lung metastasis or the expression of these chemokine and cytokine genes in tumor tissues. By in-situ hybridization, the expression of Mcp-1 mRNA was detected in both F4/80-expressing and non-expressing cells in tumors of GM-CSF-deficient cells. These results indicate that cancer cell-derived GM-CSF is dispensable for the tuning of the 4T1 tumor microenvironment and the production of MCP-1, CCL17 or RANKL in the 4T1 tumor microenvironment is likely regulated by redundant mechanisms. Full article
(This article belongs to the Special Issue Tumor Microenvironment 3.0)
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Review

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22 pages, 1370 KiB  
Review
Two-Faced Roles of Tumor-Associated Neutrophils in Cancer Development and Progression
by Naofumi Mukaida, So-ichiro Sasaki and Tomohisa Baba
Int. J. Mol. Sci. 2020, 21(10), 3457; https://doi.org/10.3390/ijms21103457 - 14 May 2020
Cited by 55 | Viewed by 6223
Abstract
Neutrophils are the most abundant circulating leukocytes in humans. Neutrophil infiltration into tumor tissues has long been observed but its roles have been ignored due to the presumed short life cycle and metabolic incompetence of neutrophils. Recent advances in neutrophil biology research have [...] Read more.
Neutrophils are the most abundant circulating leukocytes in humans. Neutrophil infiltration into tumor tissues has long been observed but its roles have been ignored due to the presumed short life cycle and metabolic incompetence of neutrophils. Recent advances in neutrophil biology research have revealed that neutrophils have a longer life cycle with a potential to express various bioactive molecules. Clinical studies have simultaneously unraveled an increase in the neutrophil–lymphocyte ratio (NLR), a ratio of absolute neutrophil to absolute lymphocyte numbers in cancer patient peripheral blood and an association of higher NLR with more advanced or aggressive disease. As a consequence, tumor-associated neutrophils (TANs) have emerged as important players in tumor microenvironment. The elucidation of the roles of TANs, however, has been hampered by their multitude of plasticity in terms of phenotypes and functionality. Difficulties are further enhanced by the presence of a related cell population—polymorphonuclear leukocyte (PMN)-myeloid-derived suppressor cells (MDSCs)—and various dissimilar aspects of neutrophil biology between humans and mice. Here, we discuss TAN biology in various tumorigenesis processes, and particularly focus on the context-dependent functional heterogeneity of TANs. Full article
(This article belongs to the Special Issue Tumor Microenvironment 3.0)
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16 pages, 1493 KiB  
Review
Tumor Milieu Controlled by RB Tumor Suppressor
by Shunsuke Kitajima, Fengkai Li and Chiaki Takahashi
Int. J. Mol. Sci. 2020, 21(7), 2450; https://doi.org/10.3390/ijms21072450 - 01 Apr 2020
Cited by 16 | Viewed by 8551
Abstract
The RB gene is one of the most frequently mutated genes in human cancers. Canonically, RB exerts its tumor suppressive activity through the regulation of the G1/S transition during cell cycle progression by modulating the activity of E2F transcription factors. However, aberration of [...] Read more.
The RB gene is one of the most frequently mutated genes in human cancers. Canonically, RB exerts its tumor suppressive activity through the regulation of the G1/S transition during cell cycle progression by modulating the activity of E2F transcription factors. However, aberration of the RB gene is most commonly detected in tumors when they gain more aggressive phenotypes, including metastatic activity or drug resistance, rather than accelerated proliferation. This implicates RB controls’ malignant progression to a considerable extent in a cell cycle-independent manner. In this review, we highlight the multifaceted functions of the RB protein in controlling tumor lineage plasticity, metabolism, and the tumor microenvironment (TME), with a focus on the mechanism whereby RB controls the TME. In brief, RB inactivation in several types of cancer cells enhances production of pro-inflammatory cytokines, including CCL2, through upregulation of mitochondrial reactive oxygen species (ROS) production. These factors not only accelerate the growth of cancer cells in a cell-autonomous manner, but also stimulate non-malignant cells in the TME to generate a pro-tumorigenic niche in a non-cell-autonomous manner. Here, we discuss the biological and pathological significance of the non-cell-autonomous functions of RB and attempt to predict their potential clinical relevance to cancer immunotherapy. Full article
(This article belongs to the Special Issue Tumor Microenvironment 3.0)
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