Effective radiotherapy for cancer has relied on the promise of maximally eradicating tumor cells while minimally killing normal cells. Technological advancement has provided state-of-the-art ...instrumentation that enables delivery of radiotherapy with great precision to tumor lesions with substantial reduced injury to normal tissues. Moreover, better understanding of radiobiology, particularly the mechanisms of radiation sensitivity and resistance in tumor lesions and toxicity in normal tissues, has improved the treatment efficacy of radiotherapy. Previous mechanism-based studies have identified many cellular targets that can affect radiation sensitivity, notably reactive oxygen species, DNA-damaging response signals, and tumor microenvironments. Several radiation sensitizers and protectors have been developed and clinically evaluated; however, many of these results are inconclusive, indicating that improvement remains needed. In this era of personalized medicine in which patients' genetic variations, transcriptome and proteomics, tumor metabolism and microenvironment, and tumor immunity are available. These new developments have provided opportunity for new target discovery. Several radiotherapy sensitivity-associated "gene signatures" have been reported although clinical validations are needed. Recently, several immune modifiers have been shown to associate with improved radiotherapy in preclinical models and in early clinical trials. Combination of radiotherapy and immunocheckpoint blockade has shown promising results especially in targeting metastatic tumors through abscopal response. In this article, we succinctly review recent advancements in the areas of mechanism-driven targets and exploitation of new targets from current radio-oncogenomic and radiation-immunotherapeutic approaches that bear clinical implications for improving the treatment efficacy of radiotherapy.
To determine whether whole-body total lesion glycolysis (TLG), which combines volumetric and metabolic information from fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography ...(PET)/computed tomography (CT), can provide a better evaluation of the prognosis for non-small cell lung cancer (NSCLC).
The institutional review board approved this retrospective study, and the requirement to obtain informed consent was waived. The authors identified 105 consecutive patients with NSCLC who underwent staging FDG PET/CT before any therapy. These patients were free of brain metastasis and underwent standard treatment and subsequent clinical follow-up. Metabolic tumor volume (MTV), mean standardized uptake value (SUV), and maximum SUV of each tumor over the whole body were determined. Whole-body MTV and whole-body TLG are the summation of all the MTVs and summation of individual tumor volume multiplied by its mean SUV, respectively. Univariate and multivariate analyses were performed to assess the prognostic significance of whole-body TLG and other factors, including whole-body MTV, lung TLG, lung MTV, maximum SUV, sex, age, performance status, histologic subtype, T stage, N stage, clinical stage, and treatment method.
The median follow-up time was 3.1 years. The estimated median progression-free survival (PFS) and overall survival (OS) for the cohort was 10.8 months and 2.8 years, respectively. The 1-year PFS was 0.0% for patients with high whole-body TLG (>655) and 50.0% for those with low whole-body TLG (≤655). The 1-year OS was 58.8% for patients with high whole-body TLG and 84.1% for those with low whole-body TLG. Univariate analysis showed that whole-body TLG, whole-body MTV, lung TLG, lung MTV, maximum SUV, performance status, T stage, N stage, clinical stage, and treatment type (surgery vs other) were significant prognostic factors for PFS (P < .01 for all). With use of the forward stepwise multivariate Cox proportional hazards model, whole-body TLG (hazard ratio = 2.92; 95% confidence interval: 1.62, 5.26; P < .01) and surgical treatment (hazard ratio = 4.24; 95% confidence interval: 2.54, 7.07; P < .01) remained significant in PFS.
Whole-body TLG is of prognostic value for NSCLC. It may be a promising tool for stratifying patients with NSCLC for risk-adapted therapies.
The intrauterine environment provides a key interface between the mother and the developing fetus during pregnancy, and is a target for investigating mechanisms of fetal programming. Studies have ...demonstrated an association between prenatal stress and neurodevelopmental disorders. The role of the intrauterine environment in mediating this effect is still being elucidated. In this review, we discuss emerging preclinical and clinical evidence suggesting the existence of microbial communities in utero. We also outline possible mechanisms of bacterial translocation to the intrauterine environment and immune responses to the presence of microbes or microbial components. Lastly, we overview the effects of intrauterine inflammation on neurodevelopment. We hypothesize that maternal gestational stress leads to disruptions in the maternal oral, gut, and vaginal microbiome that may lead to the translocation of bacteria to the intrauterine environment, eliciting an inflammatory response and resulting in deficits in neurodevelopment.
The existence of an intrauterine microbiome in a healthy pregnancy is highly controversial. While several recent experiments have identified bacterial communities within the placenta and uterus, others indicate that such findings could be due to contamination.There is emerging evidence that the microbiota within the intrauterine environment may originate from the oral cavity, gut, or vagina.Maternal gestational stress has been associated with inflammation in utero.Intrauterine inflammation has been linked to detrimental neurodevelopmental outcomes, both structurally and functionally.
Radiation therapy remains an important treatment modality in cancer therapy, however, resistance is a major problem for treatment failure. Elevated expression of glutathione is known to associate ...with radiation resistance. We used glutathione overexpressing small cell lung cancer cell lines, SR3A-13 and SR3A-14, established by transfection with γ-glutamylcysteine synthetase (γ-GCS) cDNA, as a model for investigating strategies of overcoming radiation resistance. These radiation-resistant cells exhibit upregulated human copper transporter 1 (hCtr1), which also transports cisplatin. This study was initiated to investigate the effect and the underlying mechanism of iron-platinum nanoparticles (FePt NPs) on radiation sensitization in cancer cells.
Uptakes of FePt NPs in these cells were studied by plasma optical emission spectrometry and transmission electron microscopy. Effects of the combination of FePt NPs and ionizing radiation were investigated by colony formation assay and animal experiment. Intracellular reactive oxygen species (ROS) were assessed by using fluorescent probes and imaged by a fluorescence-activated-cell-sorting caliber flow cytometer. Oxygen consumption rate (OCR) in mitochondria after FePt NP and IR treatment was investigated by a Seahorse XF24 cell energy metabolism analyzer.
These hCtr1-overexpressing cells exhibited elevated resistance to IR and the resistance could be overcome by FePt NPs via enhanced uptake of FePt NPs. Overexpression of hCtr1 was responsible for the increased uptake/transport of FePt NPs as demonstrated by using
-transfected parental SR3A (SR3A-hCtr1-WT) cells. Increased ROS and drastic mitochondrial damages with substantial reduction of oxygen consumption rate were observed in FePt NPs and IR-treated cells, indicating that structural and functional insults of mitochondria are the lethal mechanism of FePt NPs. Furthermore, FePt NPs also increased the efficacy of radiotherapy in mice bearing SR3A-hCtr1-WT-xenograft tumors.
These results suggest that FePt NPs can potentially be a novel strategy to improve radiotherapeutic efficacy in hCtr1-overexpressing cancer cells via enhanced uptake and mitochondria targeting.
The high-affinity copper transporter (Ctr1; SCLC31A1) plays an important role in regulating copper homeostasis because copper is an essential micronutrient and copper deficiency is detrimental to ...many important cellular functions, but excess copper is toxic. Recent research has revealed that human copper homeostasis is tightly controlled by interregulatory circuitry involving copper, Sp1, and human (hCtr1). This circuitry uses Sp1 transcription factor as a copper sensor in modulating hCtr1 expression, which in turn controls cellular copper and Sp1 levels in a 3-way mutual regulatory loop. Posttranslational regulation of hCtr1 expression by copper stresses has also been described in the literature. Because hCtr1 can also transport platinum drugs, this finding underscores the important role of hCtr1 in platinum-drug sensitivity in cancer chemotherapy. Consistent with this notion is the finding that elevated hCtr1 expression was associated with favorable treatment outcomes in cisplatin-based cancer chemotherapy. Moreover, cultured cell studies showed that elevated hCtr1 expression can be induced by depleting cellular copper levels, resulting in enhanced cisplatin uptake and its cell-killing activity. A phase I clinical trial using a combination of trientine (a copper chelator) and carboplatin has been carried out with encouraging results. This review discusses new insights into the role of hCtr1 in regulating copper homeostasis and explains how modulating cellular copper availability could influence treatment efficacy in platinum-based cancer chemotherapy through hCtr1 regulation.
Proline, glutamine, asparagine, and arginine are conditionally non-essential amino acids that can be produced in our body. However, they are essential for the growth of highly proliferative cells ...such as cancers. Many cancers express reduced levels of these amino acids and thus require import from the environment. Meanwhile, the biosynthesis of these amino acids is inter-connected but can be intervened individually through the inhibition of key enzymes of the biosynthesis of these amino acids, resulting in amino acid starvation and cell death. Amino acid starvation strategies have been in various stages of clinical applications. Targeting asparagine using asparaginase has been approved for treating acute lymphoblastic leukemia. Targeting glutamine and arginine starvations are in various stages of clinical trials, and targeting proline starvation is in preclinical development. The most important obstacle of these therapies is drug resistance, which is mostly due to reactivation of the key enzymes involved in biosynthesis of the targeted amino acids and reprogramming of compensatory survival pathways via transcriptional, epigenetic, and post-translational mechanisms. Here, we review the interactive regulatory mechanisms that control cellular levels of these amino acids for amino acid starvation therapy and how drug resistance is evolved underlying treatment failure.
Heterosis or hybrid vigor is widespread in plants and animals. Although the molecular basis for heterosis has been extensively studied, metabolic and proteomic contributions to heterosis remain ...elusive. Here we report an integrative analysis of time-series metabolome and proteome data in maize (
) hybrids and their inbred parents. Many maize metabolites and proteins are diurnally regulated, and many of these show nonadditive abundance in the hybrids, including key enzymes and metabolites involved in carbon assimilation. Compared with robust trait heterosis, metabolic heterosis is relatively mild. Interestingly, most amino acids display negative mid-parent heterosis (MPH), i.e., having lower values than the average of the parents, while sugars, alcohols, and nucleoside metabolites show positive MPH. From the network perspective, metabolites in the photosynthetic pathway show positive MPH, whereas metabolites in the photorespiratory pathway show negative MPH, which corresponds to nonadditive protein abundance and enzyme activities of key enzymes in the respective pathways in the hybrids. Moreover, diurnally expressed proteins that are upregulated in the hybrids are enriched in photosynthesis-related gene-ontology terms. Hybrids may more effectively remove toxic metabolites generated during photorespiration, and thus maintain higher photosynthetic efficiency. These metabolic and proteomic resources provide unique insight into heterosis and its utilization for high yielding maize and other crop plants.
High atomic number material, such as gold, may be used in conjunction with radiation to provide dose enhancement in tumors. In the current study, we investigated the dose‐enhancing effect and ...apoptotic potential of gold nanoparticles in combination with single‐dose clinical electron beams on B16F10 melanoma tumor‐bearing mice. We revealed that the accumulation of gold nanoparticles was detected inside B16F10 culture cells after 18 h of incubation, and moreover, the gold nanoparticles were shown to be colocalized with endoplasmic reticulum and Golgi apparatus in cells. Furthermore, gold nanoparticles radiosensitized melanoma cells in the colony formation assay (P = 0.02). Using a B16F10 tumor‐bearing mouse model, we further demonstrated that gold nanoparticles in conjunction with ionizing radiation significantly retarded tumor growth and prolonged survival compared to the radiation alone controls (P < 0.05). Importantly, an increase of apoptotic signals was detected inside tumors in the combined treatment group (P < 0.05). Knowing that radiation‐induced apoptosis has been considered a determinant of tumor responses to radiation therapy, and the length of tumor regrowth delay correlated with the extent of apoptosis after single‐dose radiotherapy, these results may suggest the clinical potential of gold nanoparticles in improving the outcome of melanoma radiotherapy. (Cancer Sci 2008; 99: 1479–1484)
Radiotherapy (RT) might lead to atherosclerotic plaque buildup and coronary artery stenosis of breast cancer (BC) survivors, and coronary artery calcium (CAC) might be a sign of preclinical ...atherosclerosis. This study explores possible determinants affecting the acceleration of CAC burden in BC patients after adjuvant RT.
Female BC patients receiving adjuvant RT from 2002 to 2010 were included. All patients received noncontrast computed tomography (NCCT) of thorax before and after adjuvant RT. Their CAC burden was compared with healthy controls from the Multi-Ethnic Study of Atherosclerosis (MESA) cohort. The progression of the CAC burden was manifested by the increment of CAC percentiles (%CACinc).
Ninety-four patients, including both left- and right-side BC, were enrolled in this study. From undergoing the first to second NCCT, the %CACinc in BC patients significantly increased rather than non-BC women. In addition, the %CACinc was significantly higher in left-side than right-side BC patients (p < 0.05), and significant differences in most heart outcomes were found between the two groups. Besides, the lower the mean right coronary artery (RCA) dose, the lower the risks of CAC percentiles increase ≥ 50% after adjusting the disease's laterality.
A significantly higher accelerated CAC burden in BC patients than non-BC women represents that BC could affect accelerated CAC. A higher risk of accelerated CAC burden was found in left-side than right-side BC patients after adjuvant RT. A decrease of the mean RCA dose could reduce more than 50% of the risk of accelerated CAC burden in BC patients.
Abstract Argininosuccinate synthetase 1 (ASS1) is the rate-limiting enzyme that catalyzes the biosynthesis of arginine (Arg). Many malignant human tumors are auxotrophic for Arg because ASS1 is ...silenced. ASS1 has been established as a sensor of Arg auxotrophic response and a chemosensitivity marker for Arg starvation therapy. Here, we report that ASS1 is also a sensor for glutamine (Gln)-deprivation response, and that upregulation of ASS1 expression is associated with resistance to Gln-starvation treatments. Knockdown of ASS1 expression resulted in increased sensitivity to both Arg- and Gln-starvation, whereas increased ASS1 expression by ectopic transfection is associated with resistance to both Arg- and Gln-starvation. The addition of permeable fumarate, a metabolite that bridges the tricarboxylic acid and urea cycles, resulted in downregulation of ASS1 expression and increased sensitivity to both Arg- and Gln-deprivation treatments. Mechanistically, the Gln-deprivation response, like the arginine-auxotrophic response, downregulates HIF-1α resulting in de-silencing of ASS1. Our results demonstrate that ASS1 is a common biosensor for Arg and Gln deprivation response and a shared target for Arg- and Gln-starvation therapies which have been in several current clinical trials.
PDF
