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Cancers
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The Development of Effective Therapy Targeting the Microenvironment of Cancer
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The Development of Effective Therapy Targeting the Microenvironment of Cancer

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

Deadline for manuscript submissions: closed (25 October 2023) | Viewed by 14292

Special Issue Editors

Prof. Dr. Moriaki Kusakabe

E-Mail Website
Guest Editor
Graduate School of Agricultural and Life Science, University of Tokyo, Tokyo 113-8657, Japan
Interests: cancer treatment; experimental pathology; regenerative medicine
Special Issues, Collections and Topics in MDPI journals
Dr. Sasagu Kurozumi

E-Mail Website
Guest Editor
Department of Breast Surgery, International University of Health and Walfare, Narita 286-8686, Chiba, Japan
Interests: breast cancer; artificial intelligence; biomarker research; pathology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

For many years, cancer medications have primarily targeted the inhibition of cancer cell growth. However, over the past 20 years, the mechanisms that form the tumor microenvironment through interactions with the stromal cells surrounding cancer cells have been elucidated. These cancer stromal cells are involved in the proliferation, invasion, and metastasis of cancer cells, even though they are normal cells. Therefore, therapeutic approaches targeting the tumor microenvironment have recently attracted much attention. In this Special Issue, we are seeking papers on innovative therapies targeting the tumor microenvironment. Proposals for any type of therapy, e.g., chemotherapy, antibody therapy, radiation therapy, etc., will be accepted. However, it is preferable that the results be proven to be effective at the animal level, rather than in a culture system.

Prof. Dr. Moriaki Kusakabe
Dr. Sasagu Kurozumi
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

  • cancer
  • tumor microenvironment
  • cancer therapy
  • cancer cell
  • animal level

Published Papers (7 papers)

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Research

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14 pages, 1806 KiB  
Article
High Tumoral STMN1 Expression Is Associated with Malignant Potential and Poor Prognosis in Patients with Neuroblastoma
by Kenjiro Ogushi, Takehiko Yokobori, Sumihito Nobusawa, Takahiro Shirakura, Junko Hirato, Bilguun Erkhem-Ochir, Haruka Okami, Gendensuren Dorjkhorloo, Akira Nishi, Makoto Suzuki, Sayaka Otake, Hiroshi Saeki and Ken Shirabe
Cancers 2023, 15(18), 4482; https://doi.org/10.3390/cancers15184482 - 08 Sep 2023
Viewed by 1025
Abstract
Background. Stathmin 1 (STMN1), a marker for immature neurons and tumors, controls microtubule dynamics by destabilizing tubulin. It plays an essential role in cancer progression and indicates poor prognosis in several cancers. This potential protein has not been clarified in clinical patients with [...] Read more.
Background. Stathmin 1 (STMN1), a marker for immature neurons and tumors, controls microtubule dynamics by destabilizing tubulin. It plays an essential role in cancer progression and indicates poor prognosis in several cancers. This potential protein has not been clarified in clinical patients with neuroblastoma. Therefore, this study aimed to assess the clinical significance and STMN1 function in neuroblastoma with and without MYCN amplification. Methods. Using immunohistochemical staining, STMN1 expression was examined in 81 neuroblastoma samples. Functional analysis revealed the association among STMN1 suppression, cellular viability, and endogenous or exogenous MYCN expression in neuroblastoma cell lines. Result. High levels of STMN1 expression were associated with malignant potential, proliferation potency, and poor prognosis in neuroblastoma. STMN1 expression was an independent prognostic factor in patients with neuroblastoma. Furthermore, STMN1 knockdown inhibited neuroblastoma cell growth regardless of endogenous and exogenous MYCN overexpression. Conclusion. Our data suggest that assessing STMN1 expression in neuroblastoma could be a powerful indicator of prognosis and that STMN1 might be a promising therapeutic candidate against refractory neuroblastoma with and without MYCN amplification. Full article
(This article belongs to the Special Issue The Development of Effective Therapy Targeting the Microenvironment of Cancer)
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14 pages, 2788 KiB  
Article
Development of a Smart Portable Hypoxic Chamber with Accurate Sensing, Control and Visualization of In Vitro Cell Culture for Replication of Cancer Microenvironment
by Harish Ramachandramoorthy, Tuan Dang, Ankitha Srinivasa, Kytai Truong Nguyen and Phuc Nguyen
Cancers 2023, 15(14), 3645; https://doi.org/10.3390/cancers15143645 - 16 Jul 2023
Viewed by 1497
Abstract
Clinical resistance towards treatment is a major concern in cancer therapy. This is due to in vitro studies lacking essential microenvironmental aspects. Tumor-hypoxia is an important pathophysiological phenomenon in numerous malignant tumors. Various studies have shown the importance of a hypoxic microenvironment (HME) [...] Read more.
Clinical resistance towards treatment is a major concern in cancer therapy. This is due to in vitro studies lacking essential microenvironmental aspects. Tumor-hypoxia is an important pathophysiological phenomenon in numerous malignant tumors. Various studies have shown the importance of a hypoxic microenvironment (HME) in cancer drug resistance and its effects on cellular signaling and metabolism pathways. Most drugs fail in transition from a laboratory to clinical trials because of the variability in the testing microenvironment conditions. It is, thus, very crucial that research work needs to replicate these conditions in vitro to test the drugs and/or drug carriers for cancer therapy. Previous works have used a portable hypoxia chamber to reduce the cell microenvironment to hypoxic conditions. These techniques lack reliability and consistency due to a lack of control and visualization. In this research, we developed a smart portable hypoxia chamber that could accurately control the oxygen inside the portable chamber and have a global visualization. The proposed hypoxia chamber provided ease of use with the ranges of 1% to 20% oxygen with increments of 0.5%, as well as reproducibility and accuracy. The chamber displayed great precision on reaching the set oxygen limit and a high stability in maintaining that set level of oxygen compared to the uncontrolled setup for extended durations (24 h). For instance, at a 2% oxygen level, our automated system maintained this level over 1400 min, whereas the oxygen level fluctuated up to 4.5% in the conventional hypoxic chamber. We have also demonstrated the pitfalls of uncontrolled and non-visualized hypoxia chamber setup and the dire need for our system. The hypoxia-induced factor (HIF-1α) expression in cancer cell lines was tested and compared between the conventional hypoxia setup and our automated hypoxia chamber. We observed that there was a twofold increase in HIF-1α expression in the automated controlled chamber compared to the conventional device. The device also provided real-time sensing, visualization and control of the chamber conditions, which could aid in complex in vitro studies. Full article
(This article belongs to the Special Issue The Development of Effective Therapy Targeting the Microenvironment of Cancer)
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17 pages, 3582 KiB  
Article
Regression and Eradication of Triple-Negative Breast Carcinoma in 4T1 Mouse Model by Combination Immunotherapies
by Saifun Nahar, Yue Huang, Bethany A. Nagy, John A. Zebala, Dean Y. Maeda, Udo Rudloff, Joost J. Oppenheim and De Yang
Cancers 2023, 15(8), 2366; https://doi.org/10.3390/cancers15082366 - 19 Apr 2023
Cited by 2 | Viewed by 2467
Abstract
Triple-negative breast carcinoma (TNBC) is one of the most aggressive types of solid-organ cancers. While immune checkpoint blockade (ICB) therapy has significantly improved outcomes in certain types of solid-organ cancers, patients with immunologically cold TNBC are afforded only a modest gain in survival [...] Read more.
Triple-negative breast carcinoma (TNBC) is one of the most aggressive types of solid-organ cancers. While immune checkpoint blockade (ICB) therapy has significantly improved outcomes in certain types of solid-organ cancers, patients with immunologically cold TNBC are afforded only a modest gain in survival by the addition of ICB to systemic chemotherapy. Thus, it is urgently needed to develop novel effective therapeutic approaches for TNBC. Utilizing the 4T1 murine model of TNBC, we developed a novel combination immunotherapeutic regimen consisting of intratumoral delivery of high-mobility group nucleosome binding protein 1 (HMGN1), TLR2/6 ligand fibroblast-stimulating lipopeptide (FSL-1), TLR7/8 agonist (R848/resiquimod), and CTLA-4 blockade. We also investigated the effect of adding SX682, a small-molecule inhibitor of CXCR1/2 known to reduce MDSC trafficking to tumor microenvironment, to our therapeutic approach. 4T1-bearing mice responded with significant tumor regression and tumor elimination to our therapeutic combination regimen. Mice with complete tumor regressions did not recur and became long-term survivors. Treatment with HMGN1, FSL-1, R848, and anti-CTLA4 antibody increased the number of infiltrating CD4+ and CD8+ effector/memory T cells in both tumors and draining lymph nodes and triggered the generation of 4T1-specific cytotoxic T lymphocytes (CTLs) in the draining lymph nodes. Thus, we developed a potentially curative immunotherapeutic regimen consisting of HMGN1, FSL-1, R848, plus a checkpoint inhibitor for TNBC, which does not rely on the administration of chemotherapy, radiation, or exogenous tumor-associated antigen(s). Full article
(This article belongs to the Special Issue The Development of Effective Therapy Targeting the Microenvironment of Cancer)
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13 pages, 1698 KiB  
Article
Association between Tumor Mutational Burden, Stromal CD8+ Tumor-Infiltrating Lymphocytes, and Clinical Factors in Cervical Cancers Treated with Radiotherapy
by Hanguang Ruan, Takahiro Oike, Hiro Sato, Ken Ando and Tatsuya Ohno
Cancers 2023, 15(4), 1210; https://doi.org/10.3390/cancers15041210 - 14 Feb 2023
Cited by 3 | Viewed by 1460
Abstract
Background: Tumor mutational burden (TMB) and stromal CD8-positive tumor-infiltrating lymphocytes (CD8+TILs) serve important roles in antitumor immune responses to radiotherapy. This study aimed to elucidate the association between TMB, CD8+TILs, and clinical factors in patients with cervical cancer treated [...] Read more.
Background: Tumor mutational burden (TMB) and stromal CD8-positive tumor-infiltrating lymphocytes (CD8+TILs) serve important roles in antitumor immune responses to radiotherapy. This study aimed to elucidate the association between TMB, CD8+TILs, and clinical factors in patients with cervical cancer treated with radiotherapy. Methods: Patients with squamous cell carcinoma of the uterine cervix treated with definitive radiotherapy, and with available somatic mutation data and immunohistochemical staining data from identical tumor tissues, were enrolled retrospectively. The association between TMB and/or CD8+TIL density and patient characteristics, mutation profiles, and treatment outcome was analyzed. Results: The study analyzed 44 patients (median follow-up period, 61 months). There was no significant correlation between TMB and CD8+TIL density, or between TMB or CD8+TIL density and patient characteristics. TMB-high or CD8+TIL density-low status was associated with worse overall survival and distant metastasis-free survival; the predictive value of these factors became greater when used in combination. TMB-high or CD8+TIL density-high status was associated with ARID1A mutations. Conclusions: These data indicate independence of TMB and CD8+TIL density and the involvement of ARID1A alterations in antitumor immune responses in patients with cervical cancers treated with radiotherapy, warranting further mechanistic research and prospective validation. Full article
(This article belongs to the Special Issue The Development of Effective Therapy Targeting the Microenvironment of Cancer)
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Review

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25 pages, 2048 KiB  
Review
Interdependencies of the Neuronal, Immune and Tumor Microenvironment in Gliomas
by Alexander Yuile, Joe Q. Wei, Aditya A. Mohan, Kelly M. Hotchkiss and Mustafa Khasraw
Cancers 2023, 15(10), 2856; https://doi.org/10.3390/cancers15102856 - 21 May 2023
Cited by 1 | Viewed by 2702
Abstract
Gliomas are the most common primary brain malignancy and are universally fatal. Despite significant breakthrough in understanding tumor biology, treatment breakthroughs have been limited. There is a growing appreciation that major limitations on effective treatment are related to the unique and highly complex [...] Read more.
Gliomas are the most common primary brain malignancy and are universally fatal. Despite significant breakthrough in understanding tumor biology, treatment breakthroughs have been limited. There is a growing appreciation that major limitations on effective treatment are related to the unique and highly complex glioma tumor microenvironment (TME). The TME consists of multiple different cell types, broadly categorized into tumoral, immune and non-tumoral, non-immune cells. Each group provides significant influence on the others, generating a pro-tumor dynamic with significant immunosuppression. In addition, glioma cells are highly heterogenous with various molecular distinctions on the cellular level. These variations, in turn, lead to their own unique influence on the TME. To develop future treatments, an understanding of this complex TME interplay is needed. To this end, we describe the TME in adult gliomas through interactions between its various components and through various glioma molecular phenotypes. Full article
(This article belongs to the Special Issue The Development of Effective Therapy Targeting the Microenvironment of Cancer)
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30 pages, 1692 KiB  
Review
The Glioma Immune Landscape: A Double-Edged Sword for Treatment Regimens
by Sukrit Mahajan, Mirko H. H. Schmidt and Ulrike Schumann
Cancers 2023, 15(7), 2024; https://doi.org/10.3390/cancers15072024 - 28 Mar 2023
Cited by 9 | Viewed by 2991
Abstract
Immune cells constitute a major part of the tumor microenvironment, thereby playing an important role in regulating tumor development. They interact with tumor cells, resulting in the suppression or promotion of glioma development. Therefore, in recent years, scientists have focused on immunotherapy that [...] Read more.
Immune cells constitute a major part of the tumor microenvironment, thereby playing an important role in regulating tumor development. They interact with tumor cells, resulting in the suppression or promotion of glioma development. Therefore, in recent years, scientists have focused on immunotherapy that involves enhancing the immune response to fight the battle against cancer more effectively. While it has shown success against different cancer types, immunotherapy faces major roadblocks in glioma treatment. These involve the blood brain barrier, tumor heterogeneity and an immunosuppressive glioma microenvironment, among other factors. Additionally, the interaction of the peripheral immune system with the central nervous system provides another challenge for immunotherapeutic regimens. For modulating different immune cell populations to counter glioma cells, it is important to expand our knowledge about their role within the glioma microenvironment; therefore, herein, we review the different immune cell populations found in the glioma microenvironment and navigate through the various shortcomings of current immunotherapies for glioma. We conclude by providing an insight into ongoing pre-clinical and clinical trials for glioma therapies. Full article
(This article belongs to the Special Issue The Development of Effective Therapy Targeting the Microenvironment of Cancer)
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14 pages, 432 KiB  
Review
Small Tweaks, Major Changes: Post-Translational Modifications That Occur within M2 Macrophages in the Tumor Microenvironment
by Shutao Zheng, Yan Liang, Yiyi Tan, Lu Li, Qing Liu, Tao Liu and Xiaomei Lu
Cancers 2022, 14(22), 5532; https://doi.org/10.3390/cancers14225532 - 10 Nov 2022
Cited by 1 | Viewed by 1027
Abstract
The majority of proteins are subjected to post-translational modifications (PTMs), regardless of whether they occur in or after biosynthesis of the protein. Capable of altering the physical and chemical properties and functions of proteins, PTMs are thus crucial. By fostering the proliferation, migration, [...] Read more.
The majority of proteins are subjected to post-translational modifications (PTMs), regardless of whether they occur in or after biosynthesis of the protein. Capable of altering the physical and chemical properties and functions of proteins, PTMs are thus crucial. By fostering the proliferation, migration, and invasion of cancer cells with which they communicate in the tumor microenvironment (TME), M2 macrophages have emerged as key cellular players in the TME. Furthermore, growing evidence illustrates that PTMs can occur in M2 macrophages as well, possibly participating in molding the multifaceted characteristics and physiological behaviors in the TME. Hence, there is a need to review the PTMs that have been reported to occur within M2 macrophages. Although there are several reviews available regarding the roles of M2 macrophages, the majority of these reviews overlooked PTMs occurring within M2 macrophages. Considering this, in this review, we provide a review focusing on the advancement of PTMs that have been reported to take place within M2 macrophages, mainly in the TME, to better understand the performance of M2 macrophages in the tumor microenvironment. Incidentally, we also briefly cover the advances in developing inhibitors that target PTMs and the application of artificial intelligence (AI) in the prediction and analysis of PTMs at the end of the review. Full article
(This article belongs to the Special Issue The Development of Effective Therapy Targeting the Microenvironment of Cancer)
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