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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 -
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 -
Biochimica Et Biophysica Acta. Reviews... Aug 2017Despite recent advances in radiotherapy, a majority of patients diagnosed with pancreatic cancer (PC) do not achieve objective responses due to the existence of... (Review)
Review
Despite recent advances in radiotherapy, a majority of patients diagnosed with pancreatic cancer (PC) do not achieve objective responses due to the existence of intrinsic and acquired radioresistance. Identification of molecular mechanisms that compromise the efficacy of radiation therapy and targeting these pathways is paramount for improving radiation response in PC patients. In this review, we have summarized molecular mechanisms associated with the radio-resistant phenotype of PC. Briefly, we discuss the reversible and irreversible biological consequences of radiotherapy, such as DNA damage and DNA repair, mechanisms of cancer cell survival and radiation-induced apoptosis following radiotherapy. We further describe various small molecule inhibitors and molecular targeting agents currently being tested in preclinical and clinical studies as potential radiosensitizers for PC. Notably, we draw attention towards the confounding effects of cancer stem cells, immune system, and the tumor microenvironment in the context of PC radioresistance and radiosensitization. Finally, we discuss the need for examining selective radioprotectors in light of the emerging evidence on radiation toxicity to non-target tissue associated with PC radiotherapy.
Topics: Animals; Apoptosis; DNA Damage; DNA Repair; Humans; Pancreatic Neoplasms; Radiation Tolerance; Tumor Microenvironment
PubMed: 28249796
DOI: 10.1016/j.bbcan.2017.02.003 -
Cancer Gene Therapy Mar 2015Radiation therapy is a critical component of cancer treatment with over half of patients receiving radiation during their treatment. Despite advances in image-guided... (Review)
Review
Radiation therapy is a critical component of cancer treatment with over half of patients receiving radiation during their treatment. Despite advances in image-guided therapy and dose fractionation, patients receiving radiation therapy are still at risk for side effects due to off-target radiation damage of normal tissues. To reduce normal tissue damage, researchers have sought radioprotectors, which are agents capable of protecting tissue against radiation by preventing radiation damage from occurring or by decreasing cell death in the presence of radiation damage. Although much early research focused on small-molecule radioprotectors, there has been a growing interest in gene therapy for radioprotection. The amenability of gene therapy vectors to targeting, as well as the flexibility of gene therapy to accomplish ablation or augmentation of biologically relevant genes, makes gene therapy an excellent strategy for radioprotection. Future improvements to vector targeting and delivery should greatly enhance radioprotection through gene therapy.
Topics: Animals; Gene Expression; Genetic Therapy; Humans; Neoplasms; Radiation Injuries; Radiation Tolerance; Transgenes
PubMed: 25721205
DOI: 10.1038/cgt.2015.8 -
Molecular Cancer Research : MCR Jan 2013Radiation oncology modalities such as intensity-modulated and image-guided radiation therapy can reduce the high dose to normal tissue and deliver a heterogeneous dose... (Review)
Review
Radiation oncology modalities such as intensity-modulated and image-guided radiation therapy can reduce the high dose to normal tissue and deliver a heterogeneous dose to tumors, focusing on areas deemed at highest risk for tumor persistence. Clinical radiation oncology produces daily doses ranging from 1 to 20 Gy, with tissues being exposed to 30 or more daily fractions. Hypothesizing the cells that survive fractionated radiation therapy have a substantially different phenotype than the untreated cells, which might be exploitable for targeting with molecular therapeutics or immunotherapy, three prostate cancer cell lines (PC3, DU145, and LNCaP) and normal endothelial cells were studied to understand the biology of differential effects of multifraction (MF) radiation of 0.5, 1, and/or 2 Gy fraction to 10 Gy total dose, and a single dose of 5 and 10 Gy. The resulting changes in mRNA, miRNA, and phosphoproteome were analyzed. Significant differences were observed in the MF radiation exposures including those from the 0.5 Gy MF that produces little cell killing. As expected, p53 function played a major role in response. Pathways modified by MF include immune response, DNA damage, cell-cycle arrest, TGF-β, survival, and apoptotic signal transduction. The radiation-induced stress response will set forth a unique platform for exploiting the effects of radiation therapy as "focused biology" for cancer treatment in conjunction with molecular targeted or immunologically directed therapy. Given that more normal tissue is treated, albeit to lower doses with these newer techniques, the response of the normal tissue may also influence long-term treatment outcome.
Topics: Cell Line, Tumor; Dose-Response Relationship, Radiation; Humans; Neoplasms; Radiation Tolerance; Radiotherapy, Image-Guided; Survivors
PubMed: 23175523
DOI: 10.1158/1541-7786.MCR-12-0492 -
Bioscience Reports Oct 2023Radiotherapy is utilised in the treatment of ∼50% of all human cancers, which predominantly employs photon radiation. However, particle radiotherapy elicits... (Review)
Review
Radiotherapy is utilised in the treatment of ∼50% of all human cancers, which predominantly employs photon radiation. However, particle radiotherapy elicits significant benefits over conventional photons due to more precise dose deposition and increased linear energy transfer (LET) that generates an enhanced therapeutic response. Specifically, proton beam therapy (PBT) and carbon ion radiotherapy (CIRT) are characterised by a Bragg peak, which generates a low entrance radiation dose, with the majority of the energy deposition being defined within a small region which can be specifically targeted to the tumour, followed by a low exit dose. PBT is deemed relatively low-LET whereas CIRT is more densely ionising and therefore high LET. Despite the radiotherapy type, tumour cell killing relies heavily on the introduction of DNA damage that overwhelms the repair capacity of the tumour cells. It is known that DNA damage complexity increases with LET that leads to enhanced biological effectiveness, although the specific DNA repair pathways that are activated following the different radiation sources is unclear. This knowledge is required to determine whether specific proteins and enzymes within these pathways can be targeted to further increase the efficacy of the radiation. In this review, we provide an overview of the different radiation modalities and the DNA repair pathways that are responsive to these. We also provide up-to-date knowledge of studies examining the impact of LET and DNA damage complexity on DNA repair pathway choice, followed by evidence on how enzymes within these pathways could potentially be therapeutically exploited to further increase tumour radiosensitivity, and therefore radiotherapy efficacy.
Topics: Humans; DNA Damage; Radiation, Ionizing; Neoplasms; Photons; Radiation Tolerance
PubMed: 37695845
DOI: 10.1042/BSR20222586 -
Journal of Experimental & Clinical... Feb 2019S-phase kinase-associated protein 2 (SKP2) is an oncogene and cell cycle regulator that specifically recognizes phosphorylated cell cycle regulator proteins and mediates...
BACKGROUND
S-phase kinase-associated protein 2 (SKP2) is an oncogene and cell cycle regulator that specifically recognizes phosphorylated cell cycle regulator proteins and mediates their ubiquitination. Programmed cell death protein 4 (PDCD4) is a tumor suppressor gene that plays a role in cell apoptosis and DNA-damage response via interacting with eukaryotic initiation factor-4A (eIF4A) and P53. Previous research showed SKP2 may interact with PDCD4, however the relationship between SKP2 and PDCD4 is unclear.
METHODS
To validate the interaction between SKP2 and PDCD4, mass spectrometric analysis and reciprocal co-immunoprecipitation (Co-IP) experiments were performed. SKP2 stably overexpressed or knockdown breast cancer cell lines were established and western blot was used to detect proteins changes before and after radiation. In vitro and in vivo experiments were performed to verify whether SKP2 inhibits cell apoptosis and promotes DNA-damage response via PDCD4 suppression. SMIP004 was used to test the effect of radiotherapy combined with SKP2 inhibitor.
RESULTS
We found that SKP2 remarkably promoted PDCD4 phosphorylation, ubiquitination and degradation. SKP2 promoted cell proliferation, inhibited cell apoptosis and enhanced the response to DNA-damage via PDCD4 suppression in breast cancer. SKP2 and PDCD4 showed negative correlation in human breast cancer tissues. Radiotherapy combine with SKP2 inhibitor SMIP004 showed significant inhibitory effects on breast cancer cells in vitro and in vivo.
CONCLUSIONS
We identify PDCD4 as an important ubiquitination substrate of SKP2. SKP2 promotes breast cancer tumorigenesis and radiation tolerance via PDCD4 degradation. Radiotherapy combine with SKP2-targeted adjuvant therapy may improve breast cancer patient survival in clinical medicine.
Topics: Animals; Apoptosis Regulatory Proteins; Breast Neoplasms; Carcinogenesis; Female; Humans; Radiation Tolerance; S-Phase Kinase-Associated Proteins; Ubiquitination
PubMed: 30760284
DOI: 10.1186/s13046-019-1069-3 -
Clinical Cancer Research : An Official... Mar 2019The clinical success of immune checkpoint inhibitors in treating metastatic and refractory cancers has generated significant interest in investigating their role in... (Review)
Review
The clinical success of immune checkpoint inhibitors in treating metastatic and refractory cancers has generated significant interest in investigating their role in treating locally advanced diseases, thus requiring them to be combined with standard treatments in the hope of producing synergistic antitumor responses. Radiotherapy, in particular, has long been hypothesized to have actions complementary to those of immune checkpoint blockade, and a growing body of evidence indicates that cancer immunotherapy may also have radiosensitizing effects, which would provide unique benefit for locoregional treatments. Recent studies have demonstrated that when immune cells are activated by immunotherapeutics, they can reprogram the tumor microenvironment in ways that may potentially increase the radiosensitivity of the tumor. In this review, we highlight the evidence that supports reciprocal interactions between cancer immunotherapy and radiotherapy, where in addition to the traditional notion that radiation serves to enhance the activation of antitumor immunity, an alternative scenario also exists in which T-cell activation by cancer immunotherapy may sensitize tumors to radiation treatment through mechanisms that include normalization of the tumor vasculature and tissue hypoxia. We describe the empirical observations from preclinical models that support such effects and discuss their implications for future research and trial design.
Topics: Animals; Antineoplastic Agents, Immunological; Cell Line, Tumor; Clinical Trials as Topic; Combined Modality Therapy; Costimulatory and Inhibitory T-Cell Receptors; Disease Models, Animal; Humans; Immunotherapy; Neoplasms; Radiation Tolerance; Radiotherapy; Research Design; T-Lymphocytes; Tumor Escape; Tumor Microenvironment
PubMed: 30413527
DOI: 10.1158/1078-0432.CCR-18-2581 -
Oncotarget Mar 2016Radiation therapy (RT) is one of the most important strategies in cancer treatment. Radioresistance (the failure to RT) results in locoregional recurrence and... (Review)
Review
Radiation therapy (RT) is one of the most important strategies in cancer treatment. Radioresistance (the failure to RT) results in locoregional recurrence and metastasis. Therefore, it is critically important to investigate the mechanisms leading to cancer radioresistance to overcome this problem and increase patients' survival. Currently, the majority of the radioresistance-associated researches have focused on preclinical studies. Although the exact mechanisms of cancer radioresistance have not been fully uncovered, accumulating evidence supports that cancer stem cells (CSCs) and different signaling pathways play important roles in regulating radiation response and radioresistance. Therefore, targeting CSCs or signaling pathway proteins may hold promise for developing novel combination modalities and overcoming radioresistance. The present review focuses on the key evidence of CSC markers and several important signaling pathways in cancer radioresistance and explores innovative approaches for future radiation treatment.
Topics: Animals; Humans; Neoplasms; Neoplastic Stem Cells; Radiation Tolerance; Signal Transduction
PubMed: 26716904
DOI: 10.18632/oncotarget.6760 -
Frontiers in Endocrinology 2021Iodine-resistant cancers account for the vast majority of thyroid related mortality and, until recently, there were limited therapeutic options. However, over the last... (Review)
Review
Iodine-resistant cancers account for the vast majority of thyroid related mortality and, until recently, there were limited therapeutic options. However, over the last decade our understanding of the molecular foundation of thyroid function and carcinogenesis has driven the development of many novel therapeutics. These include FDA approved tyrosine kinase inhibitors and small molecular inhibitors of VEGFR, BRAF, MEK, NTRK and RET, which collectively have significantly changed the prognostic outlook for this patient population. Some therapeutics can re-sensitize de-differentiated cancers to iodine, allowing for radioactive iodine treatment and improved disease control. Remarkably, there is now an FDA approved treatment for BRAF-mutated patients with anaplastic thyroid cancer, previously considered invariably and rapidly fatal. The treatment landscape for iodine-resistant thyroid cancer is changing rapidly with many new targets, therapeutics, clinical trials, and approved treatments. We provide an up-to-date review of novel therapeutic options in the treatment of iodine-resistant thyroid cancer.
Topics: Humans; Iodine Radioisotopes; Radiation Tolerance; Therapies, Investigational; Thyroid Neoplasms; Treatment Failure
PubMed: 34335481
DOI: 10.3389/fendo.2021.720723