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Cancers
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Cancer Microenvironment–Hypoxia
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Cancer Microenvironment–Hypoxia

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

Deadline for manuscript submissions: closed (30 September 2022) | Viewed by 25089

Special Issue Editor

Dr. María Dolores Chiara Romero

E-Mail Website
Guest Editor
Institute of Sanitary Research of the Principality of Asturias, 33006 Oviedo, Spain
Interests: hypoxia; oncometabolites; cancer; metastasis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

Cancer cells cohabit and interact with non-cancerous cells and molecular components of their environment, conforming to a highly dynamic and diverse ecosystem. While the specific interactions and compositions of tumor ecosystems are highly variable, there are significant overlaps of processes that significantly impact on shaping tumor invasion and metastasis and compromise patient survival and response to targeted therapies.

Oxygen deprivation (hypoxia), occurring as tumor cells’ proliferation expands beyond the capacity of the tumor to increase the formation of new blood vessels, is one of the most relevant disturbances affecting the functioning of the tumoral ecosystem. Tumor hypoxia causes reduced sensitivity to radiotherapy and chemotherapy, immunosuppression, and an increased likelihood of metastasis via the induction of extracellular matrix (ECM) remodeling, metabolic re-programming, genetic instability, resistance to apoptosis, sustained proliferation, and angiogenesis. The major hub where hypoxia signaling converges is represented by the hypoxia inducible transcription factors HIF1a, HIF2a, and HIF3a. A role for HIFa proteins, particularly HIF1a and HIF2a, in the initiation of tumor formation has also been proposed based on studies on diverse hereditary cancer syndromes. Thus, tremendous interest in targeting HIF has been raised as a novel opportunity for cancer therapy. Notably, HIF-2α inhibitors are currently being evaluated in ongoing phase I/II clinical trials in clear cell renal cell carcinoma and glioblastoma.

Despite extensive research efforts on the understanding of the pathological role of HIFa subunits in cancer, there are still gaps of knowledge required for the successful use of drugs targeting the hypoxic tumor environment and for the proper design of future clinical trials. Specifically, little is known about the functional significance of the interactions between multiple cell types in hypoxic microenvironments, about the specific role of each HIFa subunit in different cancer types, or about the impact of long-term hypoxia in the epigenome, noncoding RNAs, and the metabolome of cancer cells. This Special Issue will cover these aspects aimed at understanding the value of targeting the hypoxic ecosystem of tumors for improvement of cancer patient survival.

Dr. María Dolores Chiara Romero
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 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

  • hypoxia
  • cancer
  • cancer microenvironment
  • neuroendocrine tumors
  • pseudohypoxic tumors

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Published Papers (7 papers)

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Research

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17 pages, 5744 KiB  
Article
Preservation of the Hypoxic Transcriptome in Glioblastoma Patient-Derived Cell Lines Maintained at Lowered Oxygen Tension
by Agata Gozdz, Bartosz Wojtaś, Patrycja Szpak, Paulina Szadkowska, Tomasz Czernicki, Andrzej Marchel, Katarzyna Wójtowicz, Wojciech Kaspera, Piotr Ladzinski, Wojciech Szopa, Marcin Niedbala, Sergiusz Nawrocki, Bozena Kaminska and Ilona Kalaszczynska
Cancers 2022, 14(19), 4852; https://doi.org/10.3390/cancers14194852 - 4 Oct 2022
Cited by 2 | Viewed by 2252
Abstract
Despite numerous efforts aiming to characterise glioblastoma pathology (GBM) and discover new therapeutic strategies, GBM remains one of the most challenging tumours to treat. Here we propose the optimisation of in vitro culturing of GBM patient-derived cells, namely the establishment of GBM-derived cultures [...] Read more.
Despite numerous efforts aiming to characterise glioblastoma pathology (GBM) and discover new therapeutic strategies, GBM remains one of the most challenging tumours to treat. Here we propose the optimisation of in vitro culturing of GBM patient-derived cells, namely the establishment of GBM-derived cultures and their maintenance at oxygen tension mimicking oxygenation conditions occurring within the tumour. To globally analyse cell states, we performed the transcriptome analysis of GBM patient-derived cells kept as spheroids in serum-free conditions at the reduced oxygen tension (5% O2), cells cultured at atmospheric oxygen (20% O2), and parental tumour. Immune cells present in the tumour were depleted, resulting in the decreased expression of the immune system and inflammation-related genes. The expression of genes promoting cell proliferation and DNA repair was higher in GBM cell cultures when compared to the relevant tumour sample. However, lowering oxygen tension to 5% did not affect the proliferation rate and expression of cell cycle and DNA repair genes in GBM cell cultures. Culturing GBM cells at 5% oxygen was sufficient to increase the expression of specific stemness markers, particularly the PROM1 gene, without affecting neural cell differentiation markers. GBM spheroids cultured at 5% oxygen expressed higher levels of hypoxia-inducible genes, including those encoding glycolytic enzymes and pro-angiogenic factors. The genes up-regulated in cells cultured at 5% oxygen had higher expression in parental GBMs compared to that observed in 20% cell cultures, suggesting the preservation of the hypoxic component of GBM transcriptome at 5% oxygen and its loss in standard culture conditions. Evaluation of expression of those genes in The Cancer Genome Atlas dataset comprising samples of normal brain tissue, lower-grade gliomas and GBMs indicated the expression pattern of the indicated genes was specific for GBM. Moreover, GBM cells cultured at 5% oxygen were more resistant to temozolomide, the chemotherapeutic used in GBM therapy. The presented comparison of GBM cultures maintained at high and low oxygen tension together with analysis of tumour transcriptome indicates that lowering oxygen tension during cell culture may more allegedly reproduce tumour cell behaviour within GBM than standard culture conditions (e.g., atmospheric oxygen tension). Low oxygen culture conditions should be considered as a more appropriate model for further studies on glioblastoma pathology and therapy. Full article
(This article belongs to the Special Issue Cancer Microenvironment–Hypoxia)
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22 pages, 7281 KiB  
Article
Differential HIF2α Protein Expression in Human Carotid Body and Adrenal Medulla under Physiologic and Tumorigenic Conditions
by Lucía Celada, Tamara Cubiella, Jaime San-Juan-Guardado, Andrés San José Martínez, Nuria Valdés, Paula Jiménez-Fonseca, Ignacio Díaz, Jose María Enguita, Aurora Astudillo, Enol Álvarez-González, Luisa María Sierra and María-Dolores Chiara
Cancers 2022, 14(12), 2986; https://doi.org/10.3390/cancers14122986 - 17 Jun 2022
Cited by 7 | Viewed by 3191
Abstract
Hypoxia-inducible factors (HIF) 2α and 1α are the major oxygen-sensing molecules in eukaryotic cells. HIF2α has been pathogenically linked to paraganglioma and pheochromocytoma (PPGL) arising in sympathetic paraganglia or the adrenal medulla (AM), respectively. However, its involvement in the pathogenesis of paraganglioma arising [...] Read more.
Hypoxia-inducible factors (HIF) 2α and 1α are the major oxygen-sensing molecules in eukaryotic cells. HIF2α has been pathogenically linked to paraganglioma and pheochromocytoma (PPGL) arising in sympathetic paraganglia or the adrenal medulla (AM), respectively. However, its involvement in the pathogenesis of paraganglioma arising in the carotid body (CB) or other parasympathetic ganglia in the head and neck (HNPGL) remains to be defined. Here, we retrospectively analyzed HIF2α by immunohistochemistry in 62 PPGL/HNPGL and human CB and AM, and comprehensively evaluated the HIF-related transcriptome of 202 published PPGL/HNPGL. We report that HIF2α is barely detected in the AM, but accumulates at high levels in PPGL, mostly (but not exclusively) in those with loss-of-function mutations in VHL and genes encoding components of the succinate dehydrogenase (SDH) complex. This is associated with upregulation of EPAS1 and the HIF2α-regulated genes COX4I2 and ADORA2A. In contrast, HIF2α and HIF2α-regulated genes are highly expressed in CB and HNPGL, irrespective of VHL and SDH dysfunctions. We also found that HIF2α and HIF1α protein expressions are not correlated in PPGL nor HNPGL. In addition, HIF1α-target genes are almost exclusively overexpressed in VHL-mutated HNPGL/PPGL. Collectively, the data suggest that involvement of HIF2α in the physiology and tumor pathology of human paraganglia is organ-of-origin-dependent and HIF1α-independent. Full article
(This article belongs to the Special Issue Cancer Microenvironment–Hypoxia)
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20 pages, 5016 KiB  
Article
miR-150-5p-Containing Extracellular Vesicles Are a New Immunoregulator That Favor the Progression of Lung Cancer in Hypoxic Microenvironments by Altering the Phenotype of NK Cells
by Wei-An Chang, Ming-Ju Tsai, Jen-Yu Hung, Kuan-Li Wu, Ying-Ming Tsai, Yung-Chi Huang, Chao-Yuan Chang, Pei-Hsun Tsai and Ya-Ling Hsu
Cancers 2021, 13(24), 6252; https://doi.org/10.3390/cancers13246252 - 13 Dec 2021
Cited by 18 | Viewed by 2888
Abstract
Natural killer (NKs) cells are cytotoxic effector cells, which can modulate tumor metastasis according to their function; however, the role of NK cells in lung cancer has not been extensively investigated. In this study, we determined the functional profiles of NK cells in [...] Read more.
Natural killer (NKs) cells are cytotoxic effector cells, which can modulate tumor metastasis according to their function; however, the role of NK cells in lung cancer has not been extensively investigated. In this study, we determined the functional profiles of NK cells in a hypoxic tumor microenvironment (TME) of lung cancer. We revealed CD226 downregulation and functional repression of NK cells after hypoxic lung cancer priming and we then investigated their interaction with extracellular vesicles (EVs) and miR-150-5p. We also found that NK cells from lung cancer patients had lower expression of CD226 on their surface and exhibited a pro-inflammatory, pro-angiogenic and tumorigenesis phenotype by expressing VEGF, CXCL1, CXCL8, S100A8 and MMPs. Moreover, inhibition of miR-150 improved tumor surveillance by reversing CD226 expression and subsequently reinstating cytotoxic NK cell activity in an animal model. Our study introduces a new scenario for the pro-inflammatory and pro-angiogenic activities of NK cells in the hypoxic TME in lung cancer. Full article
(This article belongs to the Special Issue Cancer Microenvironment–Hypoxia)
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Review

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28 pages, 1636 KiB  
Review
Role of the Hypoxic-Secretome in Seed and Soil Metastatic Preparation
by Cynthia Clemente-González and Amancio Carnero
Cancers 2022, 14(23), 5930; https://doi.org/10.3390/cancers14235930 - 30 Nov 2022
Cited by 3 | Viewed by 2339
Abstract
During tumor growth, the delivery of oxygen to cells is impaired due to aberrant or absent vasculature. This causes an adaptative response that activates the expression of genes that control several essential processes, such as glycolysis, neovascularization, immune suppression, and the cancer stemness [...] Read more.
During tumor growth, the delivery of oxygen to cells is impaired due to aberrant or absent vasculature. This causes an adaptative response that activates the expression of genes that control several essential processes, such as glycolysis, neovascularization, immune suppression, and the cancer stemness phenotype, leading to increased metastasis and resistance to therapy. Hypoxic tumor cells also respond to an altered hypoxic microenvironment by secreting vesicles, factors, cytokines and nucleic acids that modify not only the immediate microenvironment but also organs at distant sites, allowing or facilitating the attachment and growth of tumor cells and contributing to metastasis. Hypoxia induces the release of molecules of different biochemical natures, either secreted or inside extracellular vesicles, and both tumor cells and stromal cells are involved in this process. The mechanisms by which these signals that can modify the premetastatic niche are sent from the primary tumor site include changes in the extracellular matrix, recruitment and activation of different stromal cells and immune or nonimmune cells, metabolic reprogramming, and molecular signaling network rewiring. In this review, we will discuss how hypoxia might alter the premetastatic niche through different signaling molecules. Full article
(This article belongs to the Special Issue Cancer Microenvironment–Hypoxia)
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17 pages, 1321 KiB  
Review
Cancer-Associated Fibroblasts in the Hypoxic Tumor Microenvironment
by Iljin Kim, Sanga Choi, Seongkyeong Yoo, Mingyu Lee and In-San Kim
Cancers 2022, 14(14), 3321; https://doi.org/10.3390/cancers14143321 - 7 Jul 2022
Cited by 35 | Viewed by 6499
Abstract
Solid cancers are composed of malignant cells and their surrounding matrix components. Hypoxia plays a critical role in shaping the tumor microenvironment that contributes to cancer progression and treatment failure. Cancer-associated fibroblasts (CAFs) are one of the most prominent components of the tumor [...] Read more.
Solid cancers are composed of malignant cells and their surrounding matrix components. Hypoxia plays a critical role in shaping the tumor microenvironment that contributes to cancer progression and treatment failure. Cancer-associated fibroblasts (CAFs) are one of the most prominent components of the tumor microenvironment. CAFs are highly sensitive to hypoxia and participates in the crosstalk with cancer cells. Hypoxic CAFs modulate several mechanisms that induce cancer malignancy, such as extracellular matrix (ECM) remodeling, immune evasion, metabolic reprogramming, angiogenesis, metastasis, and drug resistance. Key signaling molecules regulating CAFs in hypoxia include transforming growth factor (TGF-β) and hypoxia-inducible factors (HIFs). In this article, we summarize the mechanisms underlying the hypoxic regulation of CAFs and how hypoxic CAFs affect cancer development and progression. We also discuss the potential therapeutic strategies focused on targeting CAFs in the hypoxic tumor microenvironment. Full article
(This article belongs to the Special Issue Cancer Microenvironment–Hypoxia)
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17 pages, 2366 KiB  
Review
Implications of Hyperoxia over the Tumor Microenvironment: An Overview Highlighting the Importance of the Immune System
by Ana Belén Herrera-Campos, Esteban Zamudio-Martinez, Daniel Delgado-Bellido, Mónica Fernández-Cortés, Luis M. Montuenga, F. Javier Oliver and Angel Garcia-Diaz
Cancers 2022, 14(11), 2740; https://doi.org/10.3390/cancers14112740 - 31 May 2022
Cited by 10 | Viewed by 3597
Abstract
Hyperoxia is used in order to counteract hypoxia effects in the TME (tumor microenvironment), which are described to boost the malignant tumor phenotype and poor prognosis. The reduction of tumor hypoxic state through the formation of a non-aberrant vasculature or an increase in [...] Read more.
Hyperoxia is used in order to counteract hypoxia effects in the TME (tumor microenvironment), which are described to boost the malignant tumor phenotype and poor prognosis. The reduction of tumor hypoxic state through the formation of a non-aberrant vasculature or an increase in the toxicity of the therapeutic agent improves the efficacy of therapies such as chemotherapy. Radiotherapy efficacy has also improved, where apoptotic mechanisms seem to be implicated. Moreover, hyperoxia increases the antitumor immunity through diverse pathways, leading to an immunopermissive TME. Although hyperoxia is an approved treatment for preventing and treating hypoxemia, it has harmful side-effects. Prolonged exposure to high oxygen levels may cause acute lung injury, characterized by an exacerbated immune response, and the destruction of the alveolar–capillary barrier. Furthermore, under this situation, the high concentration of ROS may cause toxicity that will lead not only to cell death but also to an increase in chemoattractant and proinflammatory cytokine secretion. This would end in a lung leukocyte recruitment and, therefore, lung damage. Moreover, unregulated inflammation causes different consequences promoting tumor development and metastasis. This process is known as protumor inflammation, where different cell types and molecules are implicated; for instance, IL-1β has been described as a key cytokine. Although current results show benefits over cancer therapies using hyperoxia, further studies need to be conducted, not only to improve tumor regression, but also to prevent its collateral damage. Full article
(This article belongs to the Special Issue Cancer Microenvironment–Hypoxia)
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Other

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16 pages, 3347 KiB  
Perspective
HIF-1α Inhibition Improves Anti-Tumor Immunity and Promotes the Efficacy of Stereotactic Ablative Radiotherapy (SABR)
by Chang W. Song, Hyunkyung Kim, Haeun Cho, Mi-Sook Kim, Sun-Ha Paek, Heon-Joo Park, Robert J. Griffin, Stephanie Terezakis and Lawrence Chinsoo Cho
Cancers 2022, 14(13), 3273; https://doi.org/10.3390/cancers14133273 - 4 Jul 2022
Cited by 18 | Viewed by 3343
Abstract
High-dose hypofractionated radiation such as SABR (stereotactic ablative radiotherapy) evokes an anti-tumor immune response by promoting a series of immune-stimulating processes, including the release of tumor-specific antigens from damaged tumor cells and the final effector phase of immune-mediated lysis of target tumor cells. [...] Read more.
High-dose hypofractionated radiation such as SABR (stereotactic ablative radiotherapy) evokes an anti-tumor immune response by promoting a series of immune-stimulating processes, including the release of tumor-specific antigens from damaged tumor cells and the final effector phase of immune-mediated lysis of target tumor cells. High-dose hypofractionated radiation also causes vascular damage in tumors, thereby increasing tumor hypoxia and upregulation of hypoxia-inducible factors HIF-1α and HIF-2α, the master transcription factors for the cellular response to hypoxia. HIF-1α and HIF-2α are critical factors in the upregulation of immune suppression and are the master regulators of immune evasion of tumors. Consequently, SABR-induced increase in anti-tumor immunity is counterbalanced by the increase in immune suppression mediated by HIFα. Inhibition of HIF-1α with small molecules such as metformin downregulates immunosuppressive pathways, including the expression of immune checkpoints, and it improves or restores the anti-tumor immunity stimulated by irradiation. Combinations of HIFα inhibitors, particularly HIF-1α inhibitors, with immune checkpoint blocking antibodies may represent a novel approach to boost the overall anti-tumor immune profile in patients and thus enhance outcomes after SABR. Full article
(This article belongs to the Special Issue Cancer Microenvironment–Hypoxia)
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