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Tumor Microenvironment

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

Deadline for manuscript submissions: closed (31 March 2018) | Viewed by 139368

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 contribute to the development of resistance to chemotherapeutic drugs. 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, 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.

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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

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Published Papers (15 papers)

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Research

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12 pages, 8225 KiB  
Article
Hedgehog Signals Mediate Anti-Cancer Drug Resistance in Three-Dimensional Primary Colorectal Cancer Organoid Culture
by Tatsuya Usui, Masashi Sakurai, Koji Umata, Mohamed Elbadawy, Takashi Ohama, Hideyuki Yamawaki, Shoichi Hazama, Hiroko Takenouchi, Masao Nakajima, Ryouichi Tsunedomi, Nobuaki Suzuki, Hiroaki Nagano, Koichi Sato, Masahiro Kaneda and Kazuaki Sasaki
Int. J. Mol. Sci. 2018, 19(4), 1098; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19041098 - 06 Apr 2018
Cited by 68 | Viewed by 8675
Abstract
Colorectal cancer is one of the most common causes of cancer death worldwide. In patients with metastatic colorectal cancer, combination treatment with several anti-cancer drugs is employed and improves overall survival in some patients. Nevertheless, most patients with metastatic disease are not cured [...] Read more.
Colorectal cancer is one of the most common causes of cancer death worldwide. In patients with metastatic colorectal cancer, combination treatment with several anti-cancer drugs is employed and improves overall survival in some patients. Nevertheless, most patients with metastatic disease are not cured owing to the drug resistance. Cancer stem cells are known to regulate resistance to chemotherapy. In the previous study, we established a novel three-dimensional organoid culture model from tumor colorectal tissues of human patients using an air–liquid interface (ALI) method, which contained numerous cancer stem cells and showed resistance to 5-fluorouracil (5-FU) and Irinotecan. Here, we investigate which inhibitor for stem cell-related signal improves the sensitivity for anti-cancer drug treatment in tumor ALI organoids. Treatment with Hedgehog signal inhibitors (AY9944, GANT61) decreases the cell viability of organoids compared with Notch (YO-01027, DAPT) and Wnt (WAV939, Wnt-C59) signal inhibitors. Combination treatment of AY9944 or GANT61 with 5-FU, Irinotecan or Oxaliplatin decreases the cell viability of tumor organoids compared with each anti-cancer drug alone treatment. Treatment with AY9944 or GANT61 inhibits expression of stem cell markers c-Myc, CD44 and Nanog, likely through the decrease of their transcription factor, GLI-1 expression. Combination treatment of AY9944 or GANT61 with 5-FU or Irinotecan also prevents colony formation of colorectal cancer cell lines HCT116 and SW480. These findings suggest that Hedgehog signals mediate anti-cancer drug resistance in colorectal tumor patient-derived ALI organoids and that the inhibitors are useful as a combinational therapeutic strategy against colorectal cancer. Full article
(This article belongs to the Special Issue Tumor Microenvironment)
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20 pages, 11775 KiB  
Article
Microenvironment Stimuli HGF and Hypoxia Differently Affected miR-125b and Ets-1 Function with Opposite Effects on the Invasiveness of Bone Metastatic Cells: A Comparison with Breast Carcinoma Cells
by Emanuela Matteucci, Paola Maroni, Francesco Nicassio, Francesco Ghini, Paola Bendinelli and Maria Alfonsina Desiderio
Int. J. Mol. Sci. 2018, 19(1), 258; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19010258 - 16 Jan 2018
Cited by 5 | Viewed by 4623 | Retraction
Abstract
We examined the influence of microenvironment stimuli on molecular events relevant to the biological functions of 1833-bone metastatic clone and the parental MDA-MB231 cells. (i) In both the cell lines, hepatocyte growth factor (HGF) and the osteoblasts’ biological products down regulated nuclear Ets-1-protein [...] Read more.
We examined the influence of microenvironment stimuli on molecular events relevant to the biological functions of 1833-bone metastatic clone and the parental MDA-MB231 cells. (i) In both the cell lines, hepatocyte growth factor (HGF) and the osteoblasts’ biological products down regulated nuclear Ets-1-protein level in concomitance with endogenous miR-125b accumulation. In contrast, under hypoxia nuclear Ets-1 was unchanged, notwithstanding the miR-125b increase. (ii) Also, the 1833-cell invasiveness and the expression of Endothelin-1, the target gene of Ets-1/HIF-1, showed opposite patterns under HGF and hypoxia. We clarified the molecular mechanism(s) reproducing the high miR-125b levels with the mimic in 1833 cells. Under hypoxia, the miR-125b mimic maintained a basal level and functional Ets-1 protein, as testified by the elevated cell invasiveness. However, under HGF ectopic miR-125b downregulated Ets-1 protein and cell motility, likely involving an Ets-1-dominant negative form sensible to serum conditions; Ets-1-activity inhibition by HGF implicated HIF-1α accumulation, which drugged Ets-1 in the complex bound to the Endothelin-1 promoter. Altogether, 1833-cell exposure to HGF would decrease Endothelin-1 transactivation and protein expression, with the possible impairment of Endothelin-1-dependent induction of E-cadherin, and the reversion towards an invasive phenotype: this was favoured by Ets-1 overexpression, which inhibited HIF-1α expression and HIF-1 activity. (iii) In MDA-MB231 cells, HGF strongly and rapidly decreased Ets-1, hampering invasiveness and reducing Ets-1-binding to Endothelin-1 promoter; HIF-1α did not form a complex with Ets-1 and Endothelin-1-luciferase activity was unchanged. Overall, depending on the microenvironment conditions and endogenous miR-125b levels, bone-metastatic cells might switch from Ets-1-dependent motility towards colonization/growth, regulated by the balance between Ets-1 and HIF-1. Full article
(This article belongs to the Special Issue Tumor Microenvironment)
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11 pages, 825 KiB  
Article
Dissecting Time- from Tumor-Related Gene Expression Variability in Bilateral Breast Cancer
by Maurizio Callari, Matteo Dugo, Patrizia Miodini, Silvia Veneroni, Giampaolo Bianchini, Maria Grazia Daidone and Vera Cappelletti
Int. J. Mol. Sci. 2018, 19(1), 196; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19010196 - 09 Jan 2018
Cited by 1 | Viewed by 3585
Abstract
Metachronous (MBC) and synchronous bilateral breast tumors (SBC) are mostly distinct primaries, whereas paired primaries and their local recurrences (LRC) share a common origin. Intra-pair gene expression variability in MBC, SBC, and LRC derives from time/tumor microenvironment-related and tumor genetic background-related factors and [...] Read more.
Metachronous (MBC) and synchronous bilateral breast tumors (SBC) are mostly distinct primaries, whereas paired primaries and their local recurrences (LRC) share a common origin. Intra-pair gene expression variability in MBC, SBC, and LRC derives from time/tumor microenvironment-related and tumor genetic background-related factors and pairs represents an ideal model for trying to dissect tumor-related from microenvironment-related variability. Pairs of tumors derived from women with SBC (n = 18), MBC (n = 11), and LRC (n = 10) undergoing local-regional treatment were profiled for gene expression; similarity between pairs was measured using an intraclass correlation coefficient (ICC) computed for each gene and compared using analysis of variance (ANOVA). When considering biologically unselected genes, the highest correlations were found for primaries and paired LRC, and the lowest for MBC pairs. By instead limiting the analysis to the breast cancer intrinsic genes, correlations between primaries and paired LRC were enhanced, while lower similarities were observed for SBC and MBC. Focusing on stromal-related genes, the ICC values decreased for MBC and were significantly different from SBC. These findings indicate that it is possible to dissect intra-pair gene expression variability into components that are associated with genetic origin or with time and microenvironment by using specific gene subsets. Full article
(This article belongs to the Special Issue Tumor Microenvironment)
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Review

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28 pages, 1968 KiB  
Review
The Role of IL-33/ST2 Pathway in Tumorigenesis
by Kristen M. Larsen, Maydelis Karla Minaya, Vivek Vaish and Maria Marjorette O. Peña
Int. J. Mol. Sci. 2018, 19(9), 2676; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19092676 - 09 Sep 2018
Cited by 81 | Viewed by 14123
Abstract
Cancer is initiated by mutations in critical regulatory genes; however, its progression to malignancy is aided by non-neoplastic cells and molecules that create a permissive environment known as the tumor stroma or microenvironment (TME). Interleukin 33 (IL-33) is a dual function cytokine that [...] Read more.
Cancer is initiated by mutations in critical regulatory genes; however, its progression to malignancy is aided by non-neoplastic cells and molecules that create a permissive environment known as the tumor stroma or microenvironment (TME). Interleukin 33 (IL-33) is a dual function cytokine that also acts as a nuclear factor. IL-33 typically resides in the nucleus of the cells where it is expressed. However, upon tissue damage, necrosis, or injury, it is quickly released into extracellular space where it binds to its cognate receptor suppression of tumorigenicity 2 (ST2)L found on the membrane of target cells to potently activate a T Helper 2 (Th2) immune response, thus, it is classified as an alarmin. While its role in immunity and immune-related disorders has been extensively studied, its role in tumorigenesis is only beginning to be elucidated and has revealed opposing roles in tumor development. The IL-33/ST2 axis is emerging as a potent modulator of the TME. By recruiting a cohort of immune cells, it can remodel the TME to promote malignancy or impose tumor regression. Here, we review its multiple functions in various cancers to better understand its potential as a therapeutic target to block tumor progression or as adjuvant therapy to enhance the efficacy of anticancer immunotherapies. Full article
(This article belongs to the Special Issue Tumor Microenvironment)
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21 pages, 3174 KiB  
Review
Fibroblasts in the Tumor Microenvironment: Shield or Spear?
by Twana Alkasalias, Lidia Moyano-Galceran, Marie Arsenian-Henriksson and Kaisa Lehti
Int. J. Mol. Sci. 2018, 19(5), 1532; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19051532 - 21 May 2018
Cited by 179 | Viewed by 10807
Abstract
Tumorigenesis is a complex process involving dynamic interactions between malignant cells and their surrounding stroma, including both the cellular and acellular components. Within the stroma, fibroblasts represent not only a predominant cell type, but also a major source of the acellular tissue microenvironment [...] Read more.
Tumorigenesis is a complex process involving dynamic interactions between malignant cells and their surrounding stroma, including both the cellular and acellular components. Within the stroma, fibroblasts represent not only a predominant cell type, but also a major source of the acellular tissue microenvironment comprising the extracellular matrix (ECM) and soluble factors. Normal fibroblasts can exert diverse suppressive functions against cancer initiating and metastatic cells via direct cell-cell contact, paracrine signaling by soluble factors, and ECM integrity. The loss of such suppressive functions is an inherent step in tumor progression. A tumor cell-induced switch of normal fibroblasts into cancer-associated fibroblasts (CAFs), in turn, triggers a range of pro-tumorigenic signals accompanied by distraction of the normal tissue architecture, thus creating an optimal niche for cancer cells to grow extensively. To further support tumor progression and metastasis, CAFs secrete factors such as ECM remodeling enzymes that further modify the tumor microenvironment in combination with the altered adhesive forces and cell-cell interactions. These paradoxical tumor suppressive and promoting actions of fibroblasts are the focus of this review, highlighting the heterogenic molecular properties of both normal and cancer-associated fibroblasts, as well as their main mechanisms of action, including the emerging impact on immunomodulation and different therapy responses. Full article
(This article belongs to the Special Issue Tumor Microenvironment)
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12 pages, 1211 KiB  
Review
Contribution of Tumor Endothelial Cells in Cancer Progression
by Kyoko Hida, Nako Maishi, Dorcas A. Annan and Yasuhiro Hida
Int. J. Mol. Sci. 2018, 19(5), 1272; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19051272 - 24 Apr 2018
Cited by 177 | Viewed by 9623
Abstract
Tumor progression depends on the process of angiogenesis, which is the formation of new blood vessels. These newly formed blood vessels supply oxygen and nutrients to the tumor, supporting its progression and providing a gateway for tumor metastasis. Tumor angiogenesis is regulated by [...] Read more.
Tumor progression depends on the process of angiogenesis, which is the formation of new blood vessels. These newly formed blood vessels supply oxygen and nutrients to the tumor, supporting its progression and providing a gateway for tumor metastasis. Tumor angiogenesis is regulated by the balance between angiogenic activators and inhibitors within the tumor microenvironment. Because the newly formed tumor blood vessels originate from preexisting normal vessels, tumor blood vessels, and tumor endothelial cells (TECs) have historically been considered to be the same as normal blood vessels and endothelial cells; however, evidence of TECs’ distinctive abnormal phenotypes has increased. In addition, it has been revealed that TECs constitute a heterogeneous population. Thus, TECs that line tumor blood vessels are important targets in cancer therapy. We have previously reported that TECs induce cancer metastasis. In this review, we describe recent studies on TEC abnormalities related to cancer progression to provide insight into new anticancer therapies. Full article
(This article belongs to the Special Issue Tumor Microenvironment)
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16 pages, 714 KiB  
Review
A Metabolomic Approach to Predict Breast Cancer Behavior and Chemotherapy Response
by Marcella Regina Cardoso, Juliana Carvalho Santos, Marcelo Lima Ribeiro, Maria Cecília Ramiro Talarico, Lais Rosa Viana and Sophie Françoise Mauricette Derchain
Int. J. Mol. Sci. 2018, 19(2), 617; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19020617 - 21 Feb 2018
Cited by 30 | Viewed by 6431
Abstract
Although the classification of breast carcinomas into molecular or immunohistochemical subtypes has contributed to a better categorization of women into different therapeutic regimens, breast cancer nevertheless still progresses or recurs in a remarkable number of patients. Identifying women who would benefit from chemotherapy [...] Read more.
Although the classification of breast carcinomas into molecular or immunohistochemical subtypes has contributed to a better categorization of women into different therapeutic regimens, breast cancer nevertheless still progresses or recurs in a remarkable number of patients. Identifying women who would benefit from chemotherapy could potentially increase treatment effectiveness, which has important implications for long-term survival. Metabolomic analyses of fluids and tissues from cancer patients improve our knowledge of the reprogramming of metabolic pathways involved in resistance to chemotherapy. This review evaluates how recent metabolomic approaches have contributed to understanding the relationship between breast cancer and the acquisition of resistance. We focus on the advantages and challenges of cancer treatment and the use of new strategies in clinical care, which helps us comprehend drug resistance and predict responses to treatment. Full article
(This article belongs to the Special Issue Tumor Microenvironment)
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13 pages, 1158 KiB  
Review
New Insights into the Tumor Microenvironment Utilizing Protein Array Technology
by Wei Huang, Shuhong Luo, Rob Burgess, Yu-Hua Yi, Gordon F. Huang and Ruo-Pan Huang
Int. J. Mol. Sci. 2018, 19(2), 559; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19020559 - 13 Feb 2018
Cited by 27 | Viewed by 5940
Abstract
The tumor microenvironment (TME) is a considerably heterogeneous niche, which is created by tumor cells, the surrounding tumor stroma, blood vessels, infiltrating immune cells, and a variety of associated stromal cells. Intercellular communication within this niche is driven by soluble proteins synthesized by [...] Read more.
The tumor microenvironment (TME) is a considerably heterogeneous niche, which is created by tumor cells, the surrounding tumor stroma, blood vessels, infiltrating immune cells, and a variety of associated stromal cells. Intercellular communication within this niche is driven by soluble proteins synthesized by local tumor and stromal cells and include chemokines, growth factors, interferons, interleukins, and angiogenic factors. The interaction of tumor cells with their microenvironment is essential for tumorigenesis, tumor progression, growth, and metastasis, and resistance to drug therapy. Protein arrays enable the parallel detection of hundreds of proteins in a small amount of biological sample. Recent data have demonstrated that the application of protein arrays may yield valuable information regarding the structure and functional mechanisms of the TME. In this review, we will discuss protein array technologies and their applications in TME analysis to discern pathways involved in promoting the tumorigenic phenotype. Full article
(This article belongs to the Special Issue Tumor Microenvironment)
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33 pages, 4759 KiB  
Review
The Many Facets of Metzincins and Their Endogenous Inhibitors: Perspectives on Ovarian Cancer Progression
by Ruth M. Escalona, Emily Chan, George Kannourakis, Jock K. Findlay and Nuzhat Ahmed
Int. J. Mol. Sci. 2018, 19(2), 450; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19020450 - 02 Feb 2018
Cited by 12 | Viewed by 5554
Abstract
Approximately sixty per cent of ovarian cancer patients die within the first five years of diagnosis due to recurrence associated with chemoresistance. The metzincin family of metalloproteinases is enzymes involved in matrix remodeling in response to normal physiological changes and diseased states. Recently, [...] Read more.
Approximately sixty per cent of ovarian cancer patients die within the first five years of diagnosis due to recurrence associated with chemoresistance. The metzincin family of metalloproteinases is enzymes involved in matrix remodeling in response to normal physiological changes and diseased states. Recently, there has been a mounting awareness of these proteinases and their endogenous inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), as superb modulators of cellular communication and signaling regulating key biological processes in cancer progression. This review investigates the role of metzincins and their inhibitors in ovarian cancer. We propose that understanding the metzincins and TIMP biology in ovarian cancer may provide valuable insights in combating ovarian cancer progression and chemoresistance-mediated recurrence in patients. Full article
(This article belongs to the Special Issue Tumor Microenvironment)
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24 pages, 2555 KiB  
Review
Halfway between 2D and Animal Models: Are 3D Cultures the Ideal Tool to Study Cancer-Microenvironment Interactions?
by Jessica Hoarau-Véchot, Arash Rafii, Cyril Touboul and Jennifer Pasquier
Int. J. Mol. Sci. 2018, 19(1), 181; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19010181 - 18 Jan 2018
Cited by 304 | Viewed by 13075
Abstract
An area that has come to be of tremendous interest in tumor research in the last decade is the role of the microenvironment in the biology of neoplastic diseases. The tumor microenvironment (TME) comprises various cells that are collectively important for normal tissue [...] Read more.
An area that has come to be of tremendous interest in tumor research in the last decade is the role of the microenvironment in the biology of neoplastic diseases. The tumor microenvironment (TME) comprises various cells that are collectively important for normal tissue homeostasis as well as tumor progression or regression. Seminal studies have demonstrated the role of the dialogue between cancer cells (at many sites) and the cellular component of the microenvironment in tumor progression, metastasis, and resistance to treatment. Using an appropriate system of microenvironment and tumor culture is the first step towards a better understanding of the complex interaction between cancer cells and their surroundings. Three-dimensional (3D) models have been widely described recently. However, while it is claimed that they can bridge the gap between in vitro and in vivo, it is sometimes hard to decipher their advantage or limitation compared to classical two-dimensional (2D) cultures, especially given the broad number of techniques used. We present here a comprehensive review of the different 3D methods developed recently, and, secondly, we discuss the pros and cons of 3D culture compared to 2D when studying interactions between cancer cells and their microenvironment. Full article
(This article belongs to the Special Issue Tumor Microenvironment)
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516 KiB  
Review
Fibrocytes: A Novel Stromal Cells to Regulate Resistance to Anti-Angiogenic Therapy and Cancer Progression
by Hisatsugu Goto and Yasuhiko Nishioka
Int. J. Mol. Sci. 2018, 19(1), 98; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19010098 - 29 Dec 2017
Cited by 13 | Viewed by 4966
Abstract
An adequate blood supply is essential for cancer cells to survive and grow; thus, the concept of inhibiting tumor angiogenesis has been applied to cancer therapy, and several drugs are already in clinical use. It has been shown that treatment with those anti-angiogenic [...] Read more.
An adequate blood supply is essential for cancer cells to survive and grow; thus, the concept of inhibiting tumor angiogenesis has been applied to cancer therapy, and several drugs are already in clinical use. It has been shown that treatment with those anti-angiogenic drugs improved the response rate and prolonged the survival of patients with various types of cancer; however, it is also true that the effect was mostly limited. Currently, the disappointing clinical results are explained by the existence of intrinsic or acquired resistance to the therapy mediated by both tumor cells and stromal cells. This article reviews the mechanisms of resistance mediated by stromal cells such as endothelial cells, pericytes, fibroblasts and myeloid cells, with an emphasis on fibrocytes, which were recently identified as the cell type responsible for regulating acquired resistance to anti-angiogenic therapy. In addition, the other emerging role of fibrocytes as mediator-producing cells in tumor progression is discussed. Full article
(This article belongs to the Special Issue Tumor Microenvironment)
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654 KiB  
Review
The Dark Side of IFN-γ: Its Role in Promoting Cancer Immunoevasion
by Marija Mojic, Kazuyoshi Takeda and Yoshihiro Hayakawa
Int. J. Mol. Sci. 2018, 19(1), 89; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19010089 - 28 Dec 2017
Cited by 212 | Viewed by 23823
Abstract
Interferon-γ (IFN-γ) is a pleiotropic cytokine that has long been praised as an important effector molecule of anti-tumor immunity, capable of suppressing tumor growth through various mechanisms. On the contrary to such a bright side of IFN-γ, it has also been involved in [...] Read more.
Interferon-γ (IFN-γ) is a pleiotropic cytokine that has long been praised as an important effector molecule of anti-tumor immunity, capable of suppressing tumor growth through various mechanisms. On the contrary to such a bright side of IFN-γ, it has also been involved in promoting an outgrowth of tumor cells with immunoevasive phenotype suggesting an existence of a dark “tumor-promoting” side effect of IFN-γ. In this review, we will summarize this multi-functional role of IFN-γ in tumor context, how it promotes changes in tumor phenotype towards increased fitness for growth in immunocompetent host. Furthermore, we summarize how IFN-γ is involved in homeostatic or cancer-triggered mechanisms to establish an immunosuppressive tumor microenvironment. Full article
(This article belongs to the Special Issue Tumor Microenvironment)
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897 KiB  
Review
Major Challenges and Potential Microenvironment-Targeted Therapies in Glioblastoma
by Ali S. Arbab, Mohammad H. Rashid, Kartik Angara, Thaiz F. Borin, Ping-Chang Lin, Meenu Jain and Bhagelu R. Achyut
Int. J. Mol. Sci. 2017, 18(12), 2732; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18122732 - 16 Dec 2017
Cited by 22 | Viewed by 5191
Abstract
Glioblastoma (GBM) is considered one of the most malignant, genetically heterogeneous, and therapy-resistant solid tumor. Therapeutic options are limited in GBM and involve surgical resection followed by chemotherapy and/or radiotherapy. Adjuvant therapies, including antiangiogenic treatments (AATs) targeting the VEGF–VEGFR pathway, have witnessed enhanced [...] Read more.
Glioblastoma (GBM) is considered one of the most malignant, genetically heterogeneous, and therapy-resistant solid tumor. Therapeutic options are limited in GBM and involve surgical resection followed by chemotherapy and/or radiotherapy. Adjuvant therapies, including antiangiogenic treatments (AATs) targeting the VEGF–VEGFR pathway, have witnessed enhanced infiltration of bone marrow-derived myeloid cells, causing therapy resistance and tumor relapse in clinics and in preclinical models of GBM. This review article is focused on gathering previous clinical and preclinical reports featuring major challenges and lessons in GBM. Potential combination therapies targeting the tumor microenvironment (TME) to overcome the myeloid cell-mediated resistance problem in GBM are discussed. Future directions are focused on the use of TME-directed therapies in combination with standard therapy in clinical trials, and the exploration of novel therapies and GBM models for preclinical studies. We believe this review will guide the future of GBM research and therapy. Full article
(This article belongs to the Special Issue Tumor Microenvironment)
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1361 KiB  
Review
Chemokines as a Conductor of Bone Marrow Microenvironment in Chronic Myeloid Leukemia
by Naofumi Mukaida, Yamato Tanabe and Tomohisa Baba
Int. J. Mol. Sci. 2017, 18(8), 1824; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18081824 - 22 Aug 2017
Cited by 27 | Viewed by 7962
Abstract
All blood lineage cells are generated from hematopoietic stem cells (HSCs), which reside in bone marrow after birth. HSCs self-renew, proliferate, and differentiate into mature progeny under the control of local microenvironments including hematopoietic niche, which can deliver regulatory signals in the form [...] Read more.
All blood lineage cells are generated from hematopoietic stem cells (HSCs), which reside in bone marrow after birth. HSCs self-renew, proliferate, and differentiate into mature progeny under the control of local microenvironments including hematopoietic niche, which can deliver regulatory signals in the form of bound or secreted molecules and from physical cues such as oxygen tension and shear stress. Among these mediators, accumulating evidence indicates the potential involvement of several chemokines, particularly CXCL12, in the interaction between HSCs and bone marrow microenvironments. Fusion between breakpoint cluster region (BCR) and Abelson murine leukemia viral oncogene homolog (ABL)-1 gene gives rise to BCR-ABL protein with a constitutive tyrosine kinase activity and transforms HSCs and/or hematopoietic progenitor cells (HPCs) into disease-propagating leukemia stem cells (LSCs) in chronic myeloid leukemia (CML). LSCs can self-renew, proliferate, and differentiate under the influence of the signals delivered by bone marrow microenvironments including niche, as HSCs can. Thus, the interaction with bone marrow microenvironments is indispensable for the initiation, maintenance, and progression of CML. Moreover, the crosstalk between LSCs and bone marrow microenvironments can contribute to some instances of therapeutic resistance. Furthermore, evidence is accumulating to indicate the important roles of bone marrow microenvironment-derived chemokines. Hence, we will herein discuss the roles of chemokines in CML with a focus on bone marrow microenvironments. Full article
(This article belongs to the Special Issue Tumor Microenvironment)
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3385 KiB  
Review
The Role of Tumor Microenvironment in Chemoresistance: To Survive, Keep Your Enemies Closer
by Dimakatso Alice Senthebane, Arielle Rowe, Nicholas Ekow Thomford, Hendrina Shipanga, Daniella Munro, Mohammad A. M. Al Mazeedi, Hashim A. M. Almazyadi, Karlien Kallmeyer, Collet Dandara, Michael S. Pepper, M. Iqbal Parker and Kevin Dzobo
Int. J. Mol. Sci. 2017, 18(7), 1586; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18071586 - 21 Jul 2017
Cited by 291 | Viewed by 13180
Abstract
Chemoresistance is a leading cause of morbidity and mortality in cancer and it continues to be a challenge in cancer treatment. Chemoresistance is influenced by genetic and epigenetic alterations which affect drug uptake, metabolism and export of drugs at the cellular levels. While [...] Read more.
Chemoresistance is a leading cause of morbidity and mortality in cancer and it continues to be a challenge in cancer treatment. Chemoresistance is influenced by genetic and epigenetic alterations which affect drug uptake, metabolism and export of drugs at the cellular levels. While most research has focused on tumor cell autonomous mechanisms of chemoresistance, the tumor microenvironment has emerged as a key player in the development of chemoresistance and in malignant progression, thereby influencing the development of novel therapies in clinical oncology. It is not surprising that the study of the tumor microenvironment is now considered to be as important as the study of tumor cells. Recent advances in technological and analytical methods, especially ‘omics’ technologies, has made it possible to identify specific targets in tumor cells and within the tumor microenvironment to eradicate cancer. Tumors need constant support from previously ‘unsupportive’ microenvironments. Novel therapeutic strategies that inhibit such microenvironmental support to tumor cells would reduce chemoresistance and tumor relapse. Such strategies can target stromal cells, proteins released by stromal cells and non-cellular components such as the extracellular matrix (ECM) within the tumor microenvironment. Novel in vitro tumor biology models that recapitulate the in vivo tumor microenvironment such as multicellular tumor spheroids, biomimetic scaffolds and tumor organoids are being developed and are increasing our understanding of cancer cell-microenvironment interactions. This review offers an analysis of recent developments on the role of the tumor microenvironment in the development of chemoresistance and the strategies to overcome microenvironment-mediated chemoresistance. We propose a systematic analysis of the relationship between tumor cells and their respective tumor microenvironments and our data show that, to survive, cancer cells interact closely with tumor microenvironment components such as mesenchymal stem cells and the extracellular matrix. Full article
(This article belongs to the Special Issue Tumor Microenvironment)
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