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16 pages, 3227 KiB

Open AccessArticle

¹⁸F-FMISO-PET Hypoxia Monitoring for Head-and-Neck Cancer Patients: Radiomics Analyses Predict the Outcome of Chemo-Radiotherapy

by Montserrat Carles, Tobias Fechter, Anca L. Grosu, Arnd Sörensen, Benedikt Thomann, Raluca G. Stoian, Nicole Wiedenmann, Alexander Rühle, Constantinos Zamboglou, Juri Ruf, Luis Martí-Bonmatí, Dimos Baltas, Michael Mix and Nils H. Nicolay

Cancers 2021, 13(14), 3449; https://doi.org/10.3390/cancers13143449 - 9 Jul 2021

Cited by 23 | Viewed by 3522

Abstract

Tumor hypoxia is associated with radiation resistance and can be longitudinally monitored by ¹⁸F-fluoromisonidazole (¹⁸F-FMISO)-PET/CT. Our study aimed at evaluating radiomics dynamics of ¹⁸F-FMISO-hypoxia imaging during chemo-radiotherapy (CRT) as predictors for treatment outcome in head-and-neck squamous cell carcinoma (HNSCC) [...] Read more.

Tumor hypoxia is associated with radiation resistance and can be longitudinally monitored by ¹⁸F-fluoromisonidazole (¹⁸F-FMISO)-PET/CT. Our study aimed at evaluating radiomics dynamics of ¹⁸F-FMISO-hypoxia imaging during chemo-radiotherapy (CRT) as predictors for treatment outcome in head-and-neck squamous cell carcinoma (HNSCC) patients. We prospectively recruited 35 HNSCC patients undergoing definitive CRT and longitudinal ¹⁸F-FMISO-PET/CT scans at weeks 0, 2 and 5 (W0/W2/W5). Patients were classified based on peritherapeutic variations of the hypoxic sub-volume (HSV) size (increasing/stable/decreasing) and location (geographically-static/geographically-dynamic) by a new objective classification parameter (CP) accounting for spatial overlap. Additionally, 130 radiomic features (RF) were extracted from HSV at W0, and their variations during CRT were quantified by relative deviations (∆_RF). Prediction of treatment outcome was considered statistically relevant after being corrected for multiple testing and confirmed for the two ¹⁸F-FMISO-PET/CT time-points and for a validation cohort. HSV decreased in 64% of patients at W2 and in 80% at W5. CP distinguished earlier disease progression (geographically-dynamic) from later disease progression (geographically-static) in both time-points and cohorts. The texture feature low grey-level zone emphasis predicted local recurrence with AUC_W2 = 0.82 and AUC_W5 = 0.81 in initial cohort (N = 25) and AUC_W2 = 0.79 and AUC_W5 = 0.80 in validation cohort. Radiomics analysis of ¹⁸F-FMISO-derived hypoxia dynamics was able to predict outcome of HNSCC patients after CRT. Full article

(This article belongs to the Special Issue Novel Perspectives on Hypoxia in Cancer)

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17 pages, 15589 KiB

Open AccessArticle

Is Hypoxia a Factor Influencing PSMA-Directed Radioligand Therapy?—An In Silico Study on the Role of Chronic Hypoxia in Prostate Cancer

by Gabriele Birindelli, Milos Drobnjakovic, Volker Morath, Katja Steiger, Calogero D’Alessandria, Eleni Gourni, Ali Afshar-Oromieh, Wolfgang Weber, Axel Rominger, Matthias Eiber and Kuangyu Shi

Cancers 2021, 13(14), 3429; https://doi.org/10.3390/cancers13143429 - 8 Jul 2021

Cited by 10 | Viewed by 3629

Abstract

Radioligand therapy (RLT) targeting prostate specific-membrane antigen (PSMA) is an emerging treatment for metastatic castration-resistant prostate cancer (mCRPC). It administrates

^{225}

Ac- or

^{177}

Lu-labeled ligands for the targeted killing of tumor cells. Differently from X- or

γ

-ray, for the emitted

α

[...] Read more.

Radioligand therapy (RLT) targeting prostate specific-membrane antigen (PSMA) is an emerging treatment for metastatic castration-resistant prostate cancer (mCRPC). It administrates

^{225}

Ac- or

^{177}

Lu-labeled ligands for the targeted killing of tumor cells. Differently from X- or

γ

-ray, for the emitted

α

or

β

particles the ionization of the DNA molecule is less dependent on the tissue oxygenation status. Furthermore, the diffusion range of electrons in a tumor is much larger than the volume typically spanned by hypoxic regions. Therefore, hypoxia is less investigated as an influential factor for PSMA-directed RLT, in particular with

β

emitters. This study proposes an in silico approach to theoretically investigate the influence of tumor hypoxia on the PSMA-directed RLT. Based on mice histology images, the distribution of the radiopharmaceuticals was simulated with an in silico PBPK-based convection–reaction–diffusion model. Three anti-CD31 immunohistochemistry slices were used to simulate the tumor microenvironment. Ten regions of interest with varying hypoxia severity were analyzed. A kernel-based method was developed for dose calculation. The cell survival probability was calculated according to the linear-quadratic model. The statistical analysis performed on all the regions of interest (ROIs) shows more heterogeneous dose distributions obtained with

^{225}

Ac compared to

^{177}

Lu. The higher homogeneity of

^{177}

Lu-PSMA-ligand treatment is due to the larger range covered by the emitted

β

particles. The dose-to-tissue histogram (DTH) metric shows that in poorly vascularized ROIs only 10% of radiobiological hypoxic tissue receives the target dose using

^{177}

Lu-PSMA-ligand treatment. This percentage drops down to 5% using

^{225}

Ac. In highly vascularized ROIs, the percentage of hypoxic tissue receiving the target dose increases to more than 85% and 65% for the

^{177}

Lu and

^{225}

Ac-PSMA-ligands, respectively. The in silico study demonstrated that the reduced vascularization of the tumor strongly influences the dose delivered by PSMA-directed RLT, especially in hypoxic regions and consequently the treatment outcome. Full article

(This article belongs to the Special Issue Novel Perspectives on Hypoxia in Cancer)

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24 pages, 6332 KiB

Open AccessArticle

Connectivity Map Analysis Indicates PI3K/Akt/mTOR Inhibitors as Potential Anti-Hypoxia Drugs in Neuroblastoma

by Paolo Uva, Maria Carla Bosco, Alessandra Eva, Massimo Conte, Alberto Garaventa, Loredana Amoroso and Davide Cangelosi

Cancers 2021, 13(11), 2809; https://doi.org/10.3390/cancers13112809 - 4 Jun 2021

Cited by 11 | Viewed by 3926

Abstract

Neuroblastoma (NB) is one of the deadliest pediatric cancers, accounting for 15% of deaths in childhood. Hypoxia is a condition of low oxygen tension occurring in solid tumors and has an unfavorable prognostic factor for NB. In the present study, we aimed to [...] Read more.

Neuroblastoma (NB) is one of the deadliest pediatric cancers, accounting for 15% of deaths in childhood. Hypoxia is a condition of low oxygen tension occurring in solid tumors and has an unfavorable prognostic factor for NB. In the present study, we aimed to identify novel promising drugs for NB treatment. Connectivity Map (CMap), an online resource for drug repurposing, was used to identify connections between hypoxia-modulated genes in NB tumors and compounds. Two sets of 34 and 21 genes up- and down-regulated between hypoxic and normoxic primary NB tumors, respectively, were analyzed with CMap. The analysis reported a significant negative connectivity score across nine cell lines for 19 compounds mainly belonging to the class of PI3K/Akt/mTOR inhibitors. The gene expression profiles of NB cells cultured under hypoxic conditions and treated with the mTORC complex inhibitor PP242, referred to as the Mohlin dataset, was used to validate the CMap findings. A heat map representation of hypoxia-modulated genes in the Mohlin dataset and the gene set enrichment analysis (GSEA) showed an opposite regulation of these genes in the set of NB cells treated with the mTORC inhibitor PP242. In conclusion, our analysis identified inhibitors of the PI3K/Akt/mTOR signaling pathway as novel candidate compounds to treat NB patients with hypoxic tumors and a poor prognosis. Full article

(This article belongs to the Special Issue Novel Perspectives on Hypoxia in Cancer)

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15 pages, 1569 KiB

Open AccessArticle

Refinement of an Established Procedure and Its Application for Identification of Hypoxia in Prostate Cancer Xenografts

by Pernille B. Elming, Thomas R. Wittenborn, Morten Busk, Brita S. Sørensen, Mathilde Borg Houlberg Thomsen, Trine Strandgaard, Lars Dyrskjøt, Steffen Nielsen and Michael R. Horsman

Cancers 2021, 13(11), 2602; https://doi.org/10.3390/cancers13112602 - 26 May 2021

Cited by 3 | Viewed by 2730

Abstract

Background: This pre-clinical study was designed to refine a dissection method for validating the use of a 15-gene hypoxia classifier, which was previously established for head and neck squamous cell carcinoma (HNSCC) patients, to identify hypoxia in prostate cancer. Methods: PC3 and DU-145 [...] Read more.

Background: This pre-clinical study was designed to refine a dissection method for validating the use of a 15-gene hypoxia classifier, which was previously established for head and neck squamous cell carcinoma (HNSCC) patients, to identify hypoxia in prostate cancer. Methods: PC3 and DU-145 adenocarcinoma cells, in vitro, were gassed with various oxygen concentrations (0–21%) for 24 h, followed by real-time PCR. Xenografts were established in vivo, and the mice were injected with the hypoxic markers [18F]-FAZA and pimonidazole. Subsequently, tumors were excised, frozen, cryo-sectioned, and analyzed using autoradiography ([18F]-FAZA) and immunohistochemistry (pimonidazole); the autoradiograms used as templates for laser capture microdissection of hypoxic and non-hypoxic areas, which were lysed, and real-time PCR was performed. Results: In vitro, all 15 genes were increasingly up-regulated as oxygen concentrations decreased. With the xenografts, all 15 genes were up-regulated in the hypoxic compared to non-hypoxic areas for both cell lines, although this effect was greater in the DU-145. Conclusions: We have developed a combined autoradiographic/laser-guided microdissection method with broad applicability. Using this approach on fresh frozen tumor material, thereby minimizing the degree of RNA degradation, we showed that the 15-gene hypoxia gene classifier developed in HNSCC may be applicable for adenocarcinomas such as prostate cancer. Full article

(This article belongs to the Special Issue Novel Perspectives on Hypoxia in Cancer)

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12 pages, 1512 KiB

Open AccessArticle

Pharmacological Regulation of Tumor Hypoxia in Model Murine Tumors and Spontaneous Canine Tumors

by Martin Benej, Jinghai Wu, McKenzie Kreamer, Martin Kery, Sergio Corrales-Guerrero, Ioanna Papandreou, Terence M. Williams, Zihai Li, Edward E. Graves, Laura E. Selmic and Nicholas C. Denko

Cancers 2021, 13(7), 1696; https://doi.org/10.3390/cancers13071696 - 3 Apr 2021

Cited by 6 | Viewed by 3298

Abstract

Background: Hypoxia is found in many solid tumors and is associated with increased disease aggressiveness and resistance to therapy. Reducing oxygen demand by targeting mitochondrial oxidative metabolism is an emerging concept in translational cancer research aimed at reducing hypoxia. We have shown that [...] Read more.

Background: Hypoxia is found in many solid tumors and is associated with increased disease aggressiveness and resistance to therapy. Reducing oxygen demand by targeting mitochondrial oxidative metabolism is an emerging concept in translational cancer research aimed at reducing hypoxia. We have shown that the U.S. Food and Drug Administration (FDA)-approved drug papaverine and its novel derivative SMV-32 are potent mitochondrial complex I inhibitors. Methods: We used a dynamic in vivo luciferase reporter system, pODD-Luc, to evaluate the impact of pharmacological manipulation of mitochondrial metabolism on the levels of tumor hypoxia in transplanted mouse tumors. We also imaged canine patients with blood oxygen level-dependent (BOLD) MRI at baseline and one hour after a dose of 1 or 2 mg/kg papaverine. Results: We showed that the pharmacological suppression of mitochondrial oxygen consumption (OCR) in tumor-bearing mice increases tumor oxygenation, while the stimulation of mitochondrial OCR decreases tumor oxygenation. In parallel experiments in a small series of spontaneous canine sarcomas treated at The Ohio State University (OSU) Veterinary Medical Center, we observed a significant increase in BOLD signals indicative of an increase in tumor oxygenation of up to 10–50 mm HgO₂. Conclusion: In both transplanted murine tumors and spontaneous canine tumors we found that decreasing mitochondrial metabolism can decrease tumor hypoxia, potentially offering a therapeutic advantage. Full article

(This article belongs to the Special Issue Novel Perspectives on Hypoxia in Cancer)

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13 pages, 1273 KiB

Open AccessArticle

p38 MAPK Inhibition Mitigates Hypoxia-Induced AR Signaling in Castration-Resistant Prostate Cancer

by Serina Cheung, Pallavi Jain, Jonathan So, Saeid Shahidi, Stephen Chung and Marianne Koritzinsky

Cancers 2021, 13(4), 831; https://doi.org/10.3390/cancers13040831 - 17 Feb 2021

Cited by 19 | Viewed by 3928

Abstract

Background: Aberrant androgen receptor (AR) signaling is a major driver of castration-resistant prostate cancer (CRPC). Tumor hypoxia increases AR signaling and is associated with treatment resistance in prostate cancer. Heat shock protein 27 (Hsp27) is a molecular chaperone that is activated in response [...] Read more.

Background: Aberrant androgen receptor (AR) signaling is a major driver of castration-resistant prostate cancer (CRPC). Tumor hypoxia increases AR signaling and is associated with treatment resistance in prostate cancer. Heat shock protein 27 (Hsp27) is a molecular chaperone that is activated in response to heat shock and hypoxia. Hsp27 has previously been reported to facilitate AR nuclear translocation in a p38 mitogen-activated protein kinase (MAPK) dependent manner in castration-sensitive prostate cancer cell lines. Here, we evaluated the potential for inhibiting p38 MAPK/Hsp27 mediated AR signaling under normoxia and hypoxia in experimental models of CRPC. Methods: We inhibited p38 MAPK with SB203580 in prostate cancer cell lines and measured Hsp27 phosphorylation, AR activity, cell proliferation, and clonogenicity under normoxia and hypoxia. AR activity was measured using an androgen response element driven reporter assay and qPCR to measure expression of AR target genes. Xenograft-bearing mice were treated with SB203580 to measure tumor growth and serum prostate specific antigen (PSA). Results: Our results indicate that p38 MAPK and Hsp27 are activated under normoxia and hypoxia in response to androgens in CRPC cells. p38 MAPK inhibition diminished Hsp27 activation and the hypoxia-mediated increase in AR activity. Additionally, inhibition of p38 MAPK activity decreased proliferation and survival of CRPC cells in vitro and prolonged the survival of tumor-bearing mice. Conclusions: These results suggest that p38 MAPK inhibition may represent a therapeutic strategy to disrupt AR signaling in the heterogeneous CRPC tumor microenvironment. Full article

(This article belongs to the Special Issue Novel Perspectives on Hypoxia in Cancer)

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24 pages, 1813 KiB

Open AccessArticle

In Vitro and In Vivo Characterization of MCT1 Inhibitor AZD3965 Confirms Preclinical Safety Compatible with Breast Cancer Treatment

by Zohra Benyahia, Marine C. N. M. Blackman, Loïc Hamelin, Luca X. Zampieri, Tania Capeloa, Marie L. Bedin, Thibaut Vazeille, Olivier Schakman and Pierre Sonveaux

Cancers 2021, 13(3), 569; https://doi.org/10.3390/cancers13030569 - 2 Feb 2021

Cited by 17 | Viewed by 4775

Abstract

To survive and proliferate in solid tumors, cancer cells adapt and evolve rapidly in microenvironments where oxygen and substrate bioavailability fluctuates over time and space. This creates metabolic heterogeneity. Cancer cells can further cooperate metabolically, for example by swapping glycolytic end-product lactate for [...] Read more.

To survive and proliferate in solid tumors, cancer cells adapt and evolve rapidly in microenvironments where oxygen and substrate bioavailability fluctuates over time and space. This creates metabolic heterogeneity. Cancer cells can further cooperate metabolically, for example by swapping glycolytic end-product lactate for blood-borne glucose. This type of cooperation can be targeted therapeutically, since transmembrane lactate exchanges are facilitated by lactate-proton symporters of the monocarboxylate (MCT) family. Among new drugs, AZD3965 is a first-in-class selective MCT1 inhibitor currently tested in Phase I/II clinical trials for patients with different types of cancers. Because MCT1 can function bidirectionally, we tested here whether and how malignant and nonmalignant cells adapt their metabolism and MCT repertoire when AZD3965 inhibits either lactate import or export. Using breast-associated malignant and nonmalignant cell lines as models, we report that AZD3965 is not directly cytotoxic. In the presence of glucose and glutamine, oxidative cells can survive when lactate uptake is blocked, and proliferating cells compensate MCT1 inhibition by overexpressing MCT4, a specialized facilitator of lactate export. Phenotypic characterization of mice focusing on metabolism, muscle and brain physiology found partial and transient memory retention defect as sole consequence of MCT1 inhibition by AZD3965. We therefore conclude that AZD3965 is compatible with anticancer therapy. Full article

(This article belongs to the Special Issue Novel Perspectives on Hypoxia in Cancer)

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14 pages, 3884 KiB

Open AccessArticle

Photoacoustic and Magnetic Resonance Imaging of Hybrid Manganese Dioxide-Coated Ultra-Small NaGdF₄ Nanoparticles for Spatiotemporal Modulation of Hypoxia in Head and Neck Cancer

by Laurie J. Rich, Jossana A. Damasco, Julia C. Bulmahn, Hilliard L. Kutscher, Paras N. Prasad and Mukund Seshadri

Cancers 2020, 12(11), 3294; https://doi.org/10.3390/cancers12113294 - 6 Nov 2020

Cited by 21 | Viewed by 2751

Abstract

There is widespread interest in developing agents to modify tumor hypoxia in head and neck squamous cell carcinomas (HNSCC). Here, we report on the synthesis, characterization, and potential utility of ultra-small NaYF₄:Nd³⁺/NaGdF₄ nanocrystals coated with manganese dioxide (usNP-MnO [...] Read more.

There is widespread interest in developing agents to modify tumor hypoxia in head and neck squamous cell carcinomas (HNSCC). Here, we report on the synthesis, characterization, and potential utility of ultra-small NaYF₄:Nd³⁺/NaGdF₄ nanocrystals coated with manganese dioxide (usNP-MnO₂) for spatiotemporal modulation of hypoxia in HNSCC. Using a dual modality imaging approach, we first visualized the release of Mn²⁺ using T1-weighted magnetic resonance imaging (MRI) and modulation of oxygen saturation (%sO₂) using photoacoustic imaging (PAI) in vascular channel phantoms. Combined MRI and PAI performed in patient-derived HNSCC xenografts following local and systemic delivery of the hybrid nanoparticles enabled mapping of intratumoral nanoparticle accumulation (based on T1 contrast enhancement) and improvement in tumor oxygenation (increased %sO₂) within the tumor microenvironment. Our results demonstrate the potential of hybrid nanoparticles for the modulation of tumor hypoxia in head and neck cancer. Our findings also highlight the potential of combined MRI-PAI for simultaneous mapping nanoparticle delivery and oxygenation changes in tumors. Such imaging methods could be valuable in the precise selection of patients that are likely to benefit from hypoxia-modifying nanotherapies. Full article

(This article belongs to the Special Issue Novel Perspectives on Hypoxia in Cancer)

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Review

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40 pages, 3497 KiB

Open AccessReview

Hypoxia in Lung Cancer Management: A Translational Approach

by Julien Ancel, Jeanne-Marie Perotin, Maxime Dewolf, Claire Launois, Pauline Mulette, Béatrice Nawrocki-Raby, Véronique Dalstein, Christine Gilles, Gaëtan Deslée, Myriam Polette and Valérian Dormoy

Cancers 2021, 13(14), 3421; https://doi.org/10.3390/cancers13143421 - 8 Jul 2021

Cited by 20 | Viewed by 8834

Abstract

Lung cancer represents the first cause of death by cancer worldwide and remains a challenging public health issue. Hypoxia, as a relevant biomarker, has raised high expectations for clinical practice. Here, we review clinical and pathological features related to hypoxic lung tumours. Secondly, [...] Read more.

Lung cancer represents the first cause of death by cancer worldwide and remains a challenging public health issue. Hypoxia, as a relevant biomarker, has raised high expectations for clinical practice. Here, we review clinical and pathological features related to hypoxic lung tumours. Secondly, we expound on the main current techniques to evaluate hypoxic status in NSCLC focusing on positive emission tomography. We present existing alternative experimental approaches such as the examination of circulating markers and highlight the interest in non-invasive markers. Finally, we evaluate the relevance of investigating hypoxia in lung cancer management as a companion biomarker at various lung cancer stages. Hypoxia could support the identification of patients with higher risks of NSCLC. Moreover, the presence of hypoxia in treated tumours could help clinicians predict a worse prognosis for patients with resected NSCLC and may help identify patients who would benefit potentially from adjuvant therapies. Globally, the large quantity of translational data incites experimental and clinical studies to implement the characterisation of hypoxia in clinical NSCLC management. Full article

(This article belongs to the Special Issue Novel Perspectives on Hypoxia in Cancer)

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24 pages, 1071 KiB

Open AccessReview

Perspectives on Hypoxia Signaling in Tumor Stroma

by Yuqing Zhang, Morgan Coleman and Rolf A. Brekken

Cancers 2021, 13(12), 3070; https://doi.org/10.3390/cancers13123070 - 20 Jun 2021

Cited by 21 | Viewed by 4709

Abstract

Hypoxia is a well-known characteristic of solid tumors that contributes to tumor progression and metastasis. Oxygen deprivation due to high demand of proliferating cancer cells and standard of care therapies induce hypoxia. Hypoxia signaling, mainly mediated by the hypoxia-inducible transcription factor (HIF) family, [...] Read more.

Hypoxia is a well-known characteristic of solid tumors that contributes to tumor progression and metastasis. Oxygen deprivation due to high demand of proliferating cancer cells and standard of care therapies induce hypoxia. Hypoxia signaling, mainly mediated by the hypoxia-inducible transcription factor (HIF) family, results in tumor cell migration, proliferation, metabolic changes, and resistance to therapy. Additionally, the hypoxic tumor microenvironment impacts multiple cellular and non-cellular compartments in the tumor stroma, including disordered tumor vasculature, homeostasis of ECM. Hypoxia also has a multifaceted and often contradictory influence on immune cell function, which contributes to an immunosuppressive environment. Here, we review the important function of HIF in tumor stromal components and summarize current clinical trials targeting hypoxia. We provide an overview of hypoxia signaling in tumor stroma that might help address some of the challenges associated with hypoxia-targeted therapies. Full article

(This article belongs to the Special Issue Novel Perspectives on Hypoxia in Cancer)

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24 pages, 3450 KiB

Open AccessReview

Unveiling Cancer Metabolism through Spontaneous and Coherent Raman Spectroscopy and Stable Isotope Probing

by Jiabao Xu, Tong Yu, Christos E. Zois, Ji-Xin Cheng, Yuguo Tang, Adrian L. Harris and Wei E. Huang

Cancers 2021, 13(7), 1718; https://doi.org/10.3390/cancers13071718 - 5 Apr 2021

Cited by 46 | Viewed by 8474

Abstract

Metabolic reprogramming is a common hallmark in cancer. The high complexity and heterogeneity in cancer render it challenging for scientists to study cancer metabolism. Despite the recent advances in single-cell metabolomics based on mass spectrometry, the analysis of metabolites is still a destructive [...] Read more.

Metabolic reprogramming is a common hallmark in cancer. The high complexity and heterogeneity in cancer render it challenging for scientists to study cancer metabolism. Despite the recent advances in single-cell metabolomics based on mass spectrometry, the analysis of metabolites is still a destructive process, thus limiting in vivo investigations. Being label-free and nonperturbative, Raman spectroscopy offers intrinsic information for elucidating active biochemical processes at subcellular level. This review summarizes recent applications of Raman-based techniques, including spontaneous Raman spectroscopy and imaging, coherent Raman imaging, and Raman-stable isotope probing, in contribution to the molecular understanding of the complex biological processes in the disease. In addition, this review discusses possible future directions of Raman-based technologies in cancer research. Full article

(This article belongs to the Special Issue Novel Perspectives on Hypoxia in Cancer)

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52 pages, 2723 KiB

Open AccessEditor’s ChoiceReview

Hypoxia-Induced Cancer Cell Responses Driving Radioresistance of Hypoxic Tumors: Approaches to Targeting and Radiosensitizing

by Alexander E. Kabakov and Anna O. Yakimova

Cancers 2021, 13(5), 1102; https://doi.org/10.3390/cancers13051102 - 4 Mar 2021

Cited by 82 | Viewed by 11220

Abstract

Within aggressive malignancies, there usually are the “hypoxic zones”—poorly vascularized regions where tumor cells undergo oxygen deficiency through inadequate blood supply. Besides, hypoxia may arise in tumors as a result of antiangiogenic therapy or transarterial embolization. Adapting to hypoxia, tumor cells acquire a [...] Read more.

Within aggressive malignancies, there usually are the “hypoxic zones”—poorly vascularized regions where tumor cells undergo oxygen deficiency through inadequate blood supply. Besides, hypoxia may arise in tumors as a result of antiangiogenic therapy or transarterial embolization. Adapting to hypoxia, tumor cells acquire a hypoxia-resistant phenotype with the characteristic alterations in signaling, gene expression and metabolism. Both the lack of oxygen by itself and the hypoxia-responsive phenotypic modulations render tumor cells more radioresistant, so that hypoxic tumors are a serious challenge for radiotherapy. An understanding of causes of the radioresistance of hypoxic tumors would help to develop novel ways for overcoming this challenge. Molecular targets for and various approaches to radiosensitizing hypoxic tumors are considered in the present review. It is here analyzed how the hypoxia-induced cellular responses involving hypoxia-inducible factor-1, heat shock transcription factor 1, heat shock proteins, glucose-regulated proteins, epigenetic regulators, autophagy, energy metabolism reprogramming, epithelial–mesenchymal transition and exosome generation contribute to the radioresistance of hypoxic tumors or may be inhibited for attenuating this radioresistance. The pretreatments with a multitarget inhibition of the cancer cell adaptation to hypoxia seem to be a promising approach to sensitizing hypoxic carcinomas, gliomas, lymphomas, sarcomas to radiotherapy and, also, liver tumors to radioembolization. Full article

(This article belongs to the Special Issue Novel Perspectives on Hypoxia in Cancer)

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22 pages, 26963 KiB

Open AccessEditor’s ChoiceReview

Tumor Hypoxia as a Barrier in Cancer Therapy: Why Levels Matter

by Tord Hompland, Christina Sæten Fjeldbo and Heidi Lyng

Cancers 2021, 13(3), 499; https://doi.org/10.3390/cancers13030499 - 28 Jan 2021

Cited by 101 | Viewed by 10047

Abstract

Hypoxia arises in tumor regions with insufficient oxygen supply and is a major barrier in cancer treatment. The distribution of hypoxia levels is highly heterogeneous, ranging from mild, almost non-hypoxic, to severe and anoxic levels. The individual hypoxia levels induce a variety of [...] Read more.

Hypoxia arises in tumor regions with insufficient oxygen supply and is a major barrier in cancer treatment. The distribution of hypoxia levels is highly heterogeneous, ranging from mild, almost non-hypoxic, to severe and anoxic levels. The individual hypoxia levels induce a variety of biological responses that impair the treatment effect. A stronger focus on hypoxia levels rather than the absence or presence of hypoxia in our investigations will help development of improved strategies to treat patients with hypoxic tumors. Current knowledge on how hypoxia levels are sensed by cancer cells and mediate cellular responses that promote treatment resistance is comprehensive. Recently, it has become evident that hypoxia also has an important, more unexplored role in the interaction between cancer cells, stroma and immune cells, influencing the composition and structure of the tumor microenvironment. Establishment of how such processes depend on the hypoxia level requires more advanced tumor models and methodology. In this review, we describe promising model systems and tools for investigations of hypoxia levels in tumors. We further present current knowledge and emerging research on cellular responses to individual levels, and discuss their impact in novel therapeutic approaches to overcome the hypoxia barrier. Full article

(This article belongs to the Special Issue Novel Perspectives on Hypoxia in Cancer)

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31 pages, 2816 KiB

Open AccessReview

Roles of HIF and 2-Oxoglutarate-Dependent Dioxygenases in Controlling Gene Expression in Hypoxia

by Julianty Frost, Mark Frost, Michael Batie, Hao Jiang and Sonia Rocha

Cancers 2021, 13(2), 350; https://doi.org/10.3390/cancers13020350 - 19 Jan 2021

Cited by 24 | Viewed by 6423

Abstract

Hypoxia—reduction in oxygen availability—plays key roles in both physiological and pathological processes. Given the importance of oxygen for cell and organism viability, mechanisms to sense and respond to hypoxia are in place. A variety of enzymes utilise molecular oxygen, but of particular importance [...] Read more.

Hypoxia—reduction in oxygen availability—plays key roles in both physiological and pathological processes. Given the importance of oxygen for cell and organism viability, mechanisms to sense and respond to hypoxia are in place. A variety of enzymes utilise molecular oxygen, but of particular importance to oxygen sensing are the 2-oxoglutarate (2-OG) dependent dioxygenases (2-OGDs). Of these, Prolyl-hydroxylases have long been recognised to control the levels and function of Hypoxia Inducible Factor (HIF), a master transcriptional regulator in hypoxia, via their hydroxylase activity. However, recent studies are revealing that dioxygenases are involved in almost all aspects of gene regulation, including chromatin organisation, transcription and translation. We highlight the relevance of HIF and 2-OGDs in the control of gene expression in response to hypoxia and their relevance to human biology and health. Full article

(This article belongs to the Special Issue Novel Perspectives on Hypoxia in Cancer)

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20 pages, 1282 KiB

Open AccessReview

Cyclic Hypoxia: An Update on Its Characteristics, Methods to Measure It and Biological Implications in Cancer

by Samuel B. Bader, Mark W. Dewhirst and Ester M. Hammond

Cancers 2021, 13(1), 23; https://doi.org/10.3390/cancers13010023 - 23 Dec 2020

Cited by 70 | Viewed by 5154

Abstract

Regions of hypoxia occur in most if not all solid cancers. Although the presence of tumor hypoxia is a common occurrence, the levels of hypoxia and proportion of the tumor that are hypoxic vary significantly. Importantly, even within tumors, oxygen levels fluctuate due [...] Read more.

Regions of hypoxia occur in most if not all solid cancers. Although the presence of tumor hypoxia is a common occurrence, the levels of hypoxia and proportion of the tumor that are hypoxic vary significantly. Importantly, even within tumors, oxygen levels fluctuate due to changes in red blood cell flux, vascular remodeling and thermoregulation. Together, this leads to cyclic or intermittent hypoxia. Tumor hypoxia predicts for poor patient outcome, in part due to increased resistance to all standard therapies. However, it is less clear how cyclic hypoxia impacts therapy response. Here, we discuss the causes of cyclic hypoxia and, importantly, which imaging modalities are best suited to detecting cyclic vs. chronic hypoxia. In addition, we provide a comparison of the biological response to chronic and cyclic hypoxia, including how the levels of reactive oxygen species and HIF-1 are likely impacted. Together, we highlight the importance of remembering that tumor hypoxia is not a static condition and that the fluctuations in oxygen levels have significant biological consequences. Full article

(This article belongs to the Special Issue Novel Perspectives on Hypoxia in Cancer)

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