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Signal Transduction and Targeted Therapy Feb 2023Having a hypoxic microenvironment is a common and salient feature of most solid tumors. Hypoxia has a profound effect on the biological behavior and malignant phenotype... (Review)
Review
Having a hypoxic microenvironment is a common and salient feature of most solid tumors. Hypoxia has a profound effect on the biological behavior and malignant phenotype of cancer cells, mediates the effects of cancer chemotherapy, radiotherapy, and immunotherapy through complex mechanisms, and is closely associated with poor prognosis in various cancer patients. Accumulating studies have demonstrated that through normalization of the tumor vasculature, nanoparticle carriers and biocarriers can effectively increase the oxygen concentration in the tumor microenvironment, improve drug delivery and the efficacy of radiotherapy. They also increase infiltration of innate and adaptive anti-tumor immune cells to enhance the efficacy of immunotherapy. Furthermore, drugs targeting key genes associated with hypoxia, including hypoxia tracers, hypoxia-activated prodrugs, and drugs targeting hypoxia-inducible factors and downstream targets, can be used for visualization and quantitative analysis of tumor hypoxia and antitumor activity. However, the relationship between hypoxia and cancer is an area of research that requires further exploration. Here, we investigated the potential factors in the development of hypoxia in cancer, changes in signaling pathways that occur in cancer cells to adapt to hypoxic environments, the mechanisms of hypoxia-induced cancer immune tolerance, chemotherapeutic tolerance, and enhanced radiation tolerance, as well as the insights and applications of hypoxia in cancer therapy.
Topics: Humans; Cell Hypoxia; Neoplasms; Hypoxia; Immunotherapy; Radiation Tolerance; Tumor Microenvironment
PubMed: 36797231
DOI: 10.1038/s41392-023-01332-8 -
International Journal of Radiation... May 2021Spinal cord tolerance data for stereotactic body radiation therapy (SBRT) were extracted from published reports, reviewed, and modelled. For de novo SBRT delivered in 1... (Review)
Review
Spinal cord tolerance data for stereotactic body radiation therapy (SBRT) were extracted from published reports, reviewed, and modelled. For de novo SBRT delivered in 1 to 5 fractions, the following spinal cord point maximum doses (D) are estimated to be associated with a 1% to 5% risk of radiation myelopathy (RM): 12.4 to 14.0 Gy in 1 fraction, 17.0 Gy in 2 fractions, 20.3 Gy in 3 fractions, 23.0 Gy in 4 fractions, and 25.3 Gy in 5 fractions. For reirradiation SBRT delivered in 1 to 5 fractions, reported factors associated with a lower risk of RM include cumulative thecal sac equivalent dose in 2 Gy fractions with an alpha/beta of 2 (EQD2) D ≤70 Gy; SBRT thecal sac EQD2 D ≤25 Gy, thecal sac SBRT EQD2 D to cumulative EQD2 D ratio ≤0.5, and a minimum time interval to reirradiation of ≥5 months. Larger studies containing complete institutional cohorts with dosimetric data of patients treated with spine SBRT, with and without RM, are required to refine RM risk estimates.
Topics: Dose-Response Relationship, Radiation; Humans; Models, Biological; Models, Theoretical; Organs at Risk; Radiation Dose Hypofractionation; Radiation Tolerance; Radiosurgery; Radiotherapy Dosage; Re-Irradiation; Spinal Cord; Spinal Cord Diseases
PubMed: 31606528
DOI: 10.1016/j.ijrobp.2019.09.038 -
Journal of Translational Medicine Mar 2023Radiotherapy resistance is the main cause of low tumor regression for locally advanced rectum adenocarcinoma (READ). The biomarkers correlated to radiotherapy...
BACKGROUND
Radiotherapy resistance is the main cause of low tumor regression for locally advanced rectum adenocarcinoma (READ). The biomarkers correlated to radiotherapy sensitivity and potential molecular mechanisms have not been completely elucidated.
METHODS
A mRNA expression profile and a gene expression dataset of READ (GSE35452) were acquired from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Differentially expressed genes (DEGs) between radiotherapy responder and non-responder of READ were screened out. Gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis for DEGs were performed. Random survival forest analysis was used to identified hub genes by randomForestSRC package. Based on CIBERSORT algorithm, Genomics of Drug Sensitivity in Cancer (GDSC) database, Gene set variation analysis (GSVA), enrichment analysis (GSEA), nomogram, motif enrichment and non-coding RNA network analyses, the associations between hub genes and immune cell infiltration, drug sensitivity, specific signaling pathways, prognosis prediction and TF - miRNA regulatory and ceRNA network were investigated. The expressions of hub genes in clinical samples were displayed with the online Human Protein Atlas (HPA).
RESULTS
In total, 544 up-regulated and 575 down-regulated DEGs in READ were enrolled. Among that, three hubs including PLAGL2, ZNF337 and ALG10 were identified. These three hub genes were significantly associated with tumor immune infiltration, different immune-related genes and sensitivity of chemotherapeutic drugs. Also, they were correlated with the expression of various disease-related genes. In addition, GSVA and GSEA analysis revealed that different expression levels of PLAGL2, ZNF337 and ALG10 affected various signaling pathways related to disease progression. A nomogram and calibration curves based on three hub genes showed excellent prognosis predictive performance. And then, a regulatory network of transcription factor (ZBTB6) - mRNA (PLAGL2) and a ceRNA network of miRNA (has-miR-133b) - lncRNA were established. Finally, the results from HPA online database demonstrated the protein expression levels of PLAGL2, ZNF337 and ALG10 varied widely in READ patients.
CONCLUSION
These findings indicated that up-regulation of PLAGL2, ZNF337 and ALG10 in READ associated with radiotherapy response and involved in multiple process of cellular biology in tumor. They might be potential predictive biomarkers for radiotherapy sensitivity and prognosis for READ.
Topics: Humans; Rectal Neoplasms; MicroRNAs; Radiation Tolerance; Nomograms; Adenocarcinoma; Databases, Protein; DNA-Binding Proteins; Transcription Factors; RNA-Binding Proteins
PubMed: 36879254
DOI: 10.1186/s12967-023-04029-2 -
Nature Reviews. Clinical Oncology Feb 2023Owing to advances in radiotherapy, the physical properties of radiation can be optimized to enable individualized treatment; however, optimization is rarely based on... (Review)
Review
Owing to advances in radiotherapy, the physical properties of radiation can be optimized to enable individualized treatment; however, optimization is rarely based on biological properties and, therefore, treatments are generally planned with the assumption that all tumours respond similarly to radiation. Radiation affects multiple cellular pathways, including DNA damage, hypoxia, proliferation, stem cell phenotype and immune response. In this Review, we summarize the effect of these pathways on tumour responses to radiotherapy and the current state of research on genomic classifiers designed to exploit these variations to inform treatment decisions. We also discuss whether advances in genomics have generated evidence that could be practice changing and whether advances in genomics are now ready to be used to guide the delivery of radiotherapy alone or in combination.
Topics: Humans; Radiation Tolerance; Neoplasms; Radiation Oncology; Genomics; Radiotherapy
PubMed: 36477705
DOI: 10.1038/s41571-022-00709-y -
The Journal of Clinical Investigation Mar 2021Glioblastoma (GBM) is composed of heterogeneous tumor cell populations, including those with stem cell properties, termed glioma stem cells (GSCs). GSCs are innately...
Glioblastoma (GBM) is composed of heterogeneous tumor cell populations, including those with stem cell properties, termed glioma stem cells (GSCs). GSCs are innately less radiation sensitive than the tumor bulk and are believed to drive GBM formation and recurrence after repeated irradiation. However, it is unclear how GSCs adapt to escape the toxicity of repeated irradiation used in clinical practice. To identify important mediators of adaptive radioresistance in GBM, we generated radioresistant human and mouse GSCs by exposing them to repeat cycles of irradiation. Surviving subpopulations acquired strong radioresistance in vivo, which was accompanied by a reduction in cell proliferation and an increase in cell-cell adhesion and N-cadherin expression. Increasing N-cadherin expression rendered parental GSCs radioresistant, reduced their proliferation, and increased their stemness and intercellular adhesive properties. Conversely, radioresistant GSCs lost their acquired phenotypes upon CRISPR/Cas9-mediated knockout of N-cadherin. Mechanistically, elevated N-cadherin expression resulted in the accumulation of β-catenin at the cell surface, which suppressed Wnt/β-catenin proliferative signaling, reduced neural differentiation, and protected against apoptosis through Clusterin secretion. N-cadherin upregulation was induced by radiation-induced IGF1 secretion, and the radiation resistance phenotype could be reverted with picropodophyllin, a clinically applicable blood-brain-barrier permeable IGF1 receptor inhibitor, supporting clinical translation.
Topics: Adaptation, Physiological; Animals; Antigens, CD; Apoptosis; Brain Neoplasms; Cadherins; Cell Adhesion; Cell Line, Tumor; Cell Proliferation; Clusterin; Female; Gene Knockout Techniques; Glioblastoma; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Nude; Neoplastic Stem Cells; Radiation Tolerance; Up-Regulation; Wnt Signaling Pathway; Xenograft Model Antitumor Assays
PubMed: 33720050
DOI: 10.1172/JCI136098 -
Journal of Translational Medicine Jun 2023Tumor cells with the capability of radiation resistance can escape the fate of cell death after radiotherapy, serving as the main cause of treatment failure....
BACKGROUND
Tumor cells with the capability of radiation resistance can escape the fate of cell death after radiotherapy, serving as the main cause of treatment failure. Repopulation of tumors after radiotherapy is dominated by this group of residual cells, which greatly reduce the sensitivity of recurrent tumors to the therapy, resulting in poor clinical outcomes. Therefore, revealing the mechanism of radiation resistant cells participating in tumor repopulation is of vital importance for cancer patients to obtain a better prognosis.
METHODS
Co-expressed genes were searched by using genetic data of radiation resistant cells (from GEO database) and TCGA colorectal cancer. Univariate and multivariate Cox regression analysis were performed to define the most significant co-expressed genes for establishing prognostic indicator. Logistic analysis, WGCNA analysis, and other types of tumors were included to verify the predictive ability of the indicator. RT-qPCR was carried out to test expression level of key genes in colorectal cancer cell lines. Colongenic assay was utilized to test the radio-sensitivity and repopulation ability of key gene knockdown cells.
RESULTS
Prognostic indicator based on TCGA colorectal cancer patients containing four key radiation resistance genes (LGR5, KCNN4, TNS4, CENPH) was established. The indicator was shown to be significantly correlated with the prognosis of colorectal cancer patients undergoing radiotherapy, and also had an acceptable predictive effect in the other five types of cancer. RT-qPCR showed that expression level of key genes was basically consistent with the radiation resistance level of colorectal cancer cells. The clonogenic ability of all key gene knockdown cells decreased after radiation treatment compared with the control groups.
CONCLUSIONS
Our data suggest that LGR5, KCNN4, TNS4 and CENPH are correlated with radiation sensitivity of colorectal cancer cells, and the indicator composed by them can reflect the prognosis of colorectal cancer patients undergoing radiation therapy. Our data provide an evidence of radiation resistant tumor cells involved in tumor repopulation, and give patients undergoing radiotherapy an approving prognostic indicator with regard to tumor progression.
Topics: Humans; Prognosis; Radiation Tolerance; Cell Line, Tumor; Cell Death; Colorectal Neoplasms
PubMed: 37328854
DOI: 10.1186/s12967-023-04260-x -
Journal of Thoracic Oncology : Official... May 2021
Topics: Genomics; Humans; Lung Neoplasms; Prescriptions; Radiation Tolerance
PubMed: 33896574
DOI: 10.1016/j.jtho.2021.02.027 -
The Journal of Pathology Apr 2020Normal tissue responses to ionizing radiation have been a major subject for study since the discovery of X-rays at the end of the 19th century. Shortly thereafter,... (Review)
Review
Normal tissue responses to ionizing radiation have been a major subject for study since the discovery of X-rays at the end of the 19th century. Shortly thereafter, time-dose relationships were established for some normal tissue endpoints that led to investigations into how the size of dose per fraction and the quality of radiation affected outcome. The assessment of the radiosensitivity of bone marrow stem cells using colony-forming assays by Till and McCulloch prompted the establishment of in situ clonogenic assays for other tissues that added to the radiobiology toolbox. These clonogenic and functional endpoints enabled mathematical modeling to be performed that elucidated how tissue structure, and in particular turnover time, impacted clinically relevant fractionated radiation schedules. More recently, lineage tracing technology, advanced imaging and single cell sequencing have shed further light on the behavior of cells within stem, and other, cellular compartments, both in homeostasis and after radiation damage. The discovery of heterogeneity within the stem cell compartment and plasticity in response to injury have added new dimensions to the consideration of radiation-induced tissue damage. Clinically, radiobiology of the 20th century garnered wisdom relevant to photon treatments delivered to a fairly wide field at around 2 Gy per fraction, 5 days per week, for 5-7 weeks. Recently, the scope of radiobiology has been extended by advances in technology, imaging and computing, as well as by the use of charged particles. These allow radiation to be delivered more precisely to tumors while minimizing the amount of normal tissue receiving high doses. One result has been an increase in the use of schedules with higher doses per fraction given in a shorter time frame (hypofractionation). We are unable to cover these new technologies in detail in this review, just as we must omit low-dose stochastic effects, and many aspects of dose, dose rate and radiation quality. We argue that structural diversity and plasticity within tissue compartments provides a general context for discussion of most radiation responses, while acknowledging many omissions. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Topics: Acute Radiation Syndrome; DNA Damage; Dose-Response Relationship, Radiation; Humans; Neoplasms; Radiation Tolerance; Time Factors
PubMed: 31990369
DOI: 10.1002/path.5389 -
Food & Function Jul 2023High-fat diet (HFD) increases the risk of developing malignant tumors. Ionizing radiation (IR) is used as an adjuvant treatment in oncology. In this study, we...
High-fat diet (HFD) increases the risk of developing malignant tumors. Ionizing radiation (IR) is used as an adjuvant treatment in oncology. In this study, we investigated the effects of an 8-week 35% fat HFD on the tolerance to IR and the modulatory effect of melatonin (MLT). The results of lethal dose irradiation survival experiments revealed that the 8-week HFD altered the radiation tolerance of female mice and increased their radiosensitivity, whereas it had no comparable effects on males. Pre-treatment with MLT was, however, found to attenuate the radiation-induced hematopoietic damage in mice, promote intestinal structural repair after whole abdominal irradiation (WAI), and enhance the regeneration of Lgr5 intestinal stem cells. 16S rRNA high-throughput sequencing and untargeted metabolome analyses revealed that HFD consumption and WAI sex-specifically altered the composition of intestinal microbiota and fecal metabolites and that MLT supplementation differentially modulated the composition of the intestinal microflora in mice. However, in both males and females, different bacteria were associated with the modulation of the metabolite 5-methoxytryptamine. Collectively, the findings indicate that MLT ameliorates the radiation-induced damage and sex-specifically shapes the composition of the gut microbiota and metabolites, protecting mice from the adverse side effects associated with HFD and IR.
Topics: Male; Mice; Female; Animals; Melatonin; Diet, High-Fat; RNA, Ribosomal, 16S; Intestines; Radiation Tolerance; Mice, Inbred C57BL
PubMed: 37401725
DOI: 10.1039/d3fo01831h -
Radiotherapy and Oncology : Journal of... Dec 2023Radiotherapy is a widely used treatment modality against cancer, and although survival rates are increasing, radioresistant properties of tumours remain a significant... (Review)
Review
Radiotherapy is a widely used treatment modality against cancer, and although survival rates are increasing, radioresistant properties of tumours remain a significant barrier for curative treatment. Tumour hypoxia is one of the main contributors to radioresistance and is common in most solid tumours. Hypoxia is responsible for many molecular changes within the cell which helps tumours to survive under such challenging conditions. These hypoxia-induced molecular changes are predominantly coordinated by the hypoxia inducible factor (HIF) and have been linked with the ability to confer resistance to radiation-induced cell death. To overcome this obstacle research has been directed towards autophagy, a cellular process involved in self degradation and recycling of macromolecules, as HIF plays a large role in its coordination under hypoxic conditions. The role that autophagy has following radiotherapy treatment is conflicted with evidence of both cytoprotective and cytotoxic effects. This literature review aims to explore the intricate relationship between radiotherapy, hypoxia, and autophagy in the context of cancer treatment. It provides valuable insights into the potential of targeting autophagy as a therapeutic strategy to improve the response of hypoxic tumours to radiotherapy.
Topics: Humans; Radiation Tolerance; Neoplasms; Hypoxia; Cell Hypoxia; Autophagy; Cell Line, Tumor; Hypoxia-Inducible Factor 1, alpha Subunit
PubMed: 37838322
DOI: 10.1016/j.radonc.2023.109951