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Metabolic response to radiation therapy in cancer
Abstract
Tumor metabolism has emerged as a hallmark of cancer and is involved in carcinogenesis and tumor growth. Reprogramming of tumor metabolism is necessary for cancer cells to sustain high proliferation rates and enhanced demands for nutrients. Recent studies suggest that metabolic plasticity in cancer cells can decrease the efficacy of anticancer therapies by enhancing antioxidant defenses and DNA repair mechanisms. Studying radiation-induced metabolic changes will lead to a better understanding of radiation response mechanisms as well as the identification of new therapeutic targets, but there are few robust studies characterizing the metabolic changes induced by radiation therapy in cancer. In this review, we will highlight studies that provide information on the metabolic changes induced by radiation and oxidative stress in cancer cells and the associated underlying mechanisms.
... Conversely, 9p24.1 gain may act as a driver of immune activation and ICB response in HPV-negative HNSCC [89] . Together, 9p loss promotes T cell depletion and defective IFNγrelated pathways (CXCL9, JAK2 signaling), with enrichment of suppressive cells (Tregs, MDSCs) [87,88,90] . Hence, 9p loss has been proposed as a biomarker that could better predict the clinical benefit of ICB. ...
Despite intensive efforts and refined techniques, overall survival in HPV-negative head and neck cancer remains poor. Robust immune priming is required to elicit a strong and durable antitumor immune response in immunologically cold and excluded tumors like HPV-negative head and neck cancer. This review highlights how the tumor microenvironment could be affected by different immune and stromal cell types, weighs the need to integrate metabolic regulation of the tumor microenvironment into cancer treatment strategies and summarizes the emerging clinical applicability of personalized immunotherapeutic strategies in HPV-negative head and neck cancer.
... In contrast, the administration of silymarin can result to restore the body weight loss of irradiated animals [61]. It is noteworthy that body weight loss during cancer radiotherapy can happen because of various adverse effects following radiotherapy (such as oral mucositis, dysgeusia, xerostomia, and variation in viscosity of saliva, acute esophagitis, nausea, and vomiting), which result in discomfort and difficulties with eating and thereby reduced food intake, malnutrition-related to anorexia, and metabolic changes as a result of inflammation [62][63][64][65]. ...
Background: Although radiotherapy is one of the main cancer treatment modalities, exposing healthy organs/tissues to ionizing radiation during treatment can lead to different adverse effects. In this regard, it has been shown that the use of radioprotective agents may alleviate the ionizing radiation-induced toxicities.
Objective: The present study aims to review the radioprotective potentials of silymarin/silibinin in the prevention/reduction of ionizing radiation-induced adverse effects on healthy cells/tissues.
Methods: Based on PRISMA guideline, a comprehensive and systematic search was performed for identifying relevant literature on the “potential protective role of silymarin/silibinin in the treatment of radiotherapy-induced toxicities” in the different electronic databases of Web of Science, PubMed, and Scopus up to April 2022. Four hundred and fifty-five articles were obtained and screened in accordance with the inclusion and exclusion criteria of the current study. Finally, 19 papers were included in this systematic review.
Results: The findings revealed that the ionizing radiation-treated groups had reduced survival rate and body weight in comparison with the control groups. It was also found that radiation can induce mild to severe adverse effects on skin, digestive, hematologic, lymphatic, respiratory, reproductive, and urinary systems. Nevertheless, the administration of silymarin/silibinin could mitigate the ionizing radiation-induced adverse effects in most cases. This herbal agent exerts its radioprotective effects through anti-oxidant, anti-apoptosis, anti-inflammatory activities, and other mechanisms.
Conclusion: The results of the current systematic review showed that co-treatment of silymarin/silibinin with radiotherapy alleviates the radiotherapy-induced adverse effects in healthy cells/tissues.
Colorectal cancer (CRC) ranks among the most prevalent malignancies worldwide, driving a quest for comprehensive characterization methods. We report a characterization of the ex vivo autofluorescence lifetime fingerprint of colorectal tissues obtained from 73 patients that underwent surgical resection. We specifically target the autofluorescence characteristics of collagens, reduced nicotine adenine (phosphate) dinucleotide (NAD(P)H), and flavins employing a fiber-based dual excitation (375 nm and 445 nm) optical imaging system. Autofluorescence-derived parameters obtained from normal tissues, adenomatous lesions, and adenocarcinomas were analyzed considering the underlying clinicopathological features. Our results indicate that differences between tissues are primarily driven by collagen and flavins autofluorescence parameters. We also report changes in the autofluorescence parameters associated with NAD(P)H that we tentatively attribute to intratumoral heterogeneity, potentially associated to the presence of distinct metabolic subpopulations. Changes in autofluorescence signatures of tumors were also observed with lymphatic and venous invasion, differentiation grade, and microsatellite instability. Finally, we characterized the impact of radiative treatment in the autofluorescence fingerprints of rectal tissues and observed a generalized increase in the mean lifetime of radiated tumors, which is suggestive of altered metabolism and structural remodeling. Overall, our preliminary findings indicate that multiparametric autofluorescence lifetime measurements have the potential to significantly enhance clinical decision-making in CRC, spanning from initial diagnosis to ongoing management. We believe that our results will provide a foundational framework for future investigations to further understand and combat CRC exploiting autofluorescence measurements.
Significance: Glioblastomas (GBMs) are among the most lethal tumors despite the almost exclusive localization to the brain. This is largely due to therapeutic resistance. Radiation and chemotherapy significantly increase the survival for GBM patients, however, GBMs always recur, and the median overall survival is just over a year. Proposed reasons for such intractable resistance to therapy are numerous and include tumor metabolism, in particular, the ability of tumor cells to reconfigure metabolic fluxes on demand (metabolic plasticity). Understanding how the hard-wired, oncogene-driven metabolic tendencies of GBMs intersect with flexible, context-induced metabolic rewiring promises to reveal novel approaches for combating therapy resistance. Recent Advances: Personalized genome-scale metabolic flux models have recently provided evidence that metabolic flexibility promotes radiation resistance in cancer and identified tumor redox metabolism as a major predictor for resistance to radiation therapy (RT). It was demonstrated that radioresistant tumors, including GBM, reroute metabolic fluxes to boost the levels of reducing factors of the cell, thus enhancing clearance of reactive oxygen species that are generated during RT and promoting survival. Critical Issues: The current body of knowledge from published studies strongly supports the notion that robust metabolic plasticity can act as a (flexible) shield against the cytotoxic effects of standard GBM therapies, thus driving therapy resistance. The limited understanding of the critical drivers of such metabolic plasticity hampers the rational design of effective combination therapies. Future Directions: Identifying and targeting regulators of metabolic plasticity, rather than specific metabolic pathways, in combination with standard-of-care treatments have the potential to improve therapeutic outcomes in GBM.
Alpha-ketoglutarate (α-KG) is a key metabolite and signaling molecule in cancer cells, but the low permeability of α-KG limits the study of α-KG mediated effects in vivo. Recently, cell-permeable monoester and diester α-KG derivatives have been synthesized for use in vivo, but many of these derivatives are not compatible for use in hyperpolarized carbon-13 nuclear magnetic resonance spectroscopy (HP-13C-MRS). HP-13C-MRS is a powerful technique that has been used to noninvasively trace labeled metabolites in real time. Here, we show that using diethyl-[1-13C]-α-KG as a probe in HP-13C-MRS allows for noninvasive tracing of α-KG metabolism in vivo.
Background
The usage of immune checkpoint inhibitors (ICIs) is the standard practice for the treatment of metastatic melanoma. However, a significant amount of patients show no response to immunotherapy, while issues on its reliable response interpretation exist. Aim of this study was to investigate the phenomenon of early disease progression in 2-deoxy-2-( ¹⁸ F)fluoro-D-glucose ( ¹⁸ F-FDG) positron emission tomography/computed tomography (PET/CT) in melanoma patients treated with ICIs.
Methods
Thirty-one patients under ICIs serially monitored with ¹⁸ F-FDG PET/CT were enrolled. All patients exhibited progressive metabolic disease (PMD) after two ICIs’ cycles according to the European Organization for Research and Treatment of Cancer (EORTC) criteria, and were characterized as unconfirmed PMD (uPMD). They were further followed with at least one PET/CT for either confirmation of PMD (cPMD) or demonstration of pseudoprogression remission. Patients were also evaluated with the PET Response Evaluation Criteria for Immunotherapy (PERCIMT). Moreover, in an attempt to investigate immune activation, the spleen to liver ratios (SLR mean , SLR max ) of ¹⁸ F-FDG uptake were measured.
Results
Median follow up was 69.7 months [64.6–NA]. According to EORTC, 26/31 patients with uPMD eventually showed cPMD (83.9%) and 5/31 patients showed pseudoprogression (16.1%). Patients with cPMD ( n = 26) had a median OS of 10.9 months [8.5–NA], while those with pseudoprogression ( n = 5) did not reach a median OS [40.9–NA]. Respectively, after application of PERCIMT, 2/5 patients of the pseudoprogression group were correctly classified as non-PMD, reducing the uPMD cohort to 29 patients; eventually, 26/29 patients demonstrated cPMD (89.7%) and 3/29 pseudoprogression (10.3%). One further patient with pseudoprogression exhibited transient, sarcoid-like, mediastinal/hilar lymphadenopathy, a known immune-related adverse event (irAE). Finally, patients eventually showing cPMD exhibited a significantly higher SLR mean than those showing pseudoprogression after two ICIs’ cycles ( p = 0.038).
Conclusion
PET/CT, performed already after administration of two ICIs’ cycles, can identify the majority of non-responders in melanoma immunotherapy. In order to tackle however, the non-negligible phenomenon of pseudoprogression, another follow-up PET/CT, the usage of novel response criteria and vigilance over emergence of radiological irAEs are recommended. Moreover, the investigation of spleen glucose metabolism may offer further prognostic information in melanoma patients under ICIs.
Radiotherapy is an important component of cancer treatment, with approximately 50% of all cancer patients receiving radiation therapy during their course of illness. Nevertheless, solid tumors frequently exhibit hypoxic areas, which can hinder therapies efficacy, especially radiotherapy one. Indeed, hypoxia impacts the six parameters governing the radiotherapy response, called the « six Rs of radiation biology » (for Radiosensitivity, Repair, Repopulation, Redistribution, Reoxygenation, and Reactivation of anti-tumor immune response), by inducing pleiotropic cellular adaptions, such as cell metabolism rewiring, epigenetic landscape remodeling, and cell death weakening, with significant clinical repercussions. In this review, according to the six Rs, we detail how hypoxia, and associated mechanisms and pathways, impact the radiotherapy response of solid tumors and the resulting clinical implications. We finally illustrate it in hypoxic endocrine cancers through a focus on anaplastic thyroid carcinomas.
Purpose
To evaluate the role of the pre-treatment cervical and lymph node (LN) metabolic parameters of ¹⁸F-fluorodeoxyglucose positron emission tomography-computed tomography (¹⁸F-FDG PET/CT) for locally advanced cervical cancer (LACC) patients receiving concurrent chemoradiotherapy or radiotherapy.
Methods
we reviewed 125 consecutive patients with LACC who underwent pre-treatment ¹⁸F-FDG PET/CT examination and concurrent chemoradiotherapy or radiotherapy from February 2010 to December 2015 at our institute. The mean standardized uptake value (SUVmean), maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of cervical lesion and lymph node (LN) were recorded. Receiver operator characteristic curve, C-index, Kaplan-Meier method, and Cox proportional hazards models were performed.
Results
The median follow-up was 62 months (range, 4-114 months). For 125 included patients with cervical cancer, the 5-year overall survival (OS), disease-free survival (DFS), local control (LC) and distant metastasis-free survival (DMFS) rates were 83.6%, 75.1%, 92.3% and 79.9%, respectively. Cervical MTV (c-index 0.59-0.61) and cervical TLG (c-index 0.60-0.62) values calculated with a threshold of 40% SUVmax presented stronger prediction capability than cervical SUVmean (c-index 0.51-0.58) and cervical SUVmax (c-index 0.53-0.57) for OS, DFS, LC, and DMFS. In univariate analysis, cervical TLG ≥ 113.4 had worse DFS and DMFS. Cervical MTV ≥ 18.3 cm³ had worse OS and DMFS. In multivariate analysis, cervical TLG ≥ 113.4 implied worse OS, DFS, and DMFS. In either univariate or multivariate analyses, cervical SUVmean and cervical SUVmax had no statistically significant correlation with OS, DFS, LC and DMFS. For 55 cervical cancer patients with positive LN, LN SUVmax presented strongest prediction capability for OS (c-index = 0.79), DFS (c-index = 0.72), LC (c-index = 0.62), and DMFS (c-index = 0.79). In multivariate analysis, LN SUVmax remained significant biomarker linked to OS, DFS, and DMFS.
Conclusion
Pre-treatment cervical and LN metabolic parameters were associated with survival outcomes in patients with LACC. In our study, we found that pre-treatment cervical TLG and LN SUVmax may be important prognostic biomarkers for OS, DFS, and DMFS. However, further prospective studies with a large number of patients are required to evaluate the value of the metabolic parameters in survival outcomes prediction.
Background
Radiotherapy to the prostate and pelvic lymph nodes (PLNRT) is part of the curative treatment of high-risk prostate cancer (PCa). Yet, the broader influence of radiotherapy on patient physiology is poorly understood. We conducted comprehensive global metabolomic profiling of urine, plasma and stools sampled from patients undergoing PLNRT for high-risk PCa.
Materials and methods
Samples were taken from 32 patients at six timepoints: baseline, 2/3 and 4/5 weeks of PLNRT; and three, six, and twelve months after PLNRT. We characterised the global metabolome of urine and plasma using ¹H nuclear magnetic resonance (NMR) spectroscopy and ultra-performance liquid chromatography-mass spectrometry (UPLC-MS), and of stools with NMR. Linear mixed-effects modelling was employed to investigate metabolic changes between timepoints for each biofluid and assay and determine metabolites of interest.
Results
Metabolites in urine, plasma and stools changed significantly after PLNRT initiation. Metabolic profiles did not return to baseline up to one year post-PLNRT in any biofluid. Molecules associated with cardiovascular risk were increased in plasma. Pre-PLNRT faecal butyrate levels directly associated with increasing GI side-effects, as did a sharper fall in those levels during and up to one year post-radiotherapy, mirroring our previous results with metataxonomics.
Conclusions
We showed for the first time that an overall metabolic impact is observed in patients undergoing PLNRT up to one year post-treatment. These metabolic changes may impact on long-term morbidity following treatment, which warrants further investigation.
Imaging plays an important role in the diagnosis and treatment of women with uterine cervical and endometrial cancers. Quantitative imaging, through MRI, PET/CT, and hybrid PET/MRI, allows for characterization of primary tumors beyond anatomic and qualitative descriptors. MRI diffusion-weighted imaging (DWI) yields an apparent diffusion coefficient (ADC), which can be applied in both the pre-and post-treatment assessment of uterine tumors. PET/CT assesses metabolic activity, and measurement of tumor standardized uptake value (SUV) is a useful metric in the staging of uterine malignancies. Hybrid PET/MRI is an emerging modality that combines the soft tissue contrast of MRI with the molecular imaging capability of PET. This review provides an overview of these quantitative imaging modalities, and their current and potential roles in the assessment of uterine cervical and cancer.
Autophagy plays a double-edged sword for cancer; particularly, mitophagy plays important roles in the selective degradation of damaged mitochondria. However, whether mitophagy is involved in killing effects of tumor cells by ionizing radiation (IR) and its underlying mechanism remain elusive. The purpose is to evaluate the effects of mitochondrial ROS (mROS) on autophagy after IR; furthermore, we hypothesized that KillerRed (KR) targeting mitochondria could induce mROS generation, subsequent mitochondrial depolarization, accumulation of Pink1, and recruitment of PARK2 to promote the mitophagy. Thereby, we would achieve a new strategy to enhance mROS accumulation and clarify the roles and mechanisms of radiosensitization by KR and IR. Our data demonstrated that IR might cause autophagy of both MCF-7 and HeLa cells, which is related to mitochondria and mROS, and the ROS scavenger N-acetylcysteine (NAC) could reduce the effects. Based on the theory, mitochondrial targeting vector sterile α- and HEAT/armadillo motif-containing protein 1- (Sarm1-) mtKR has been successfully constructed, and we found that ROS levels have significantly increased after light exposure. Furthermore, mitochondrial depolarization of HeLa cells was triggered, such as the decrease of Na+K+ ATPase, Ca2+Mg2+ ATPase, and mitochondrial respiratory complex I and III activities, and mitochondrial membrane potential (MMP) has significantly decreased, and voltage-dependent anion channel 1 (VDAC1) protein has significantly increased in the mitochondria. Additionally, HeLa cell proliferation was obviously inhibited, and the cell autophagic rates dramatically increased, which referred to the regulation of the Pink1/PARK2 pathway. These results indicated that mitophagy induced by mROS can initiate the sensitization of cancer cells to IR and might be regulated by the Pink1/PARK2 pathway.
Background
Metabolic reprogramming is a common phenomenon in tumorigenesis and tumor progression. Amino acids are important mediators in cancer metabolism, and their kinetics in tumor tissue are far from being understood completely. Mass spectrometry imaging is capable to spatiotemporally trace important endogenous metabolites in biological tissue specimens. In this research, we studied L-[ring- ¹³ C 6 ]-labeled phenylalanine and tyrosine kinetics in a human non-small cell lung carcinoma (NSCLC) xenografted mouse model using matrix-assisted laser desorption/ionization Fourier-transform ion cyclotron resonance mass spectrometry imaging (MALDI-FTICR-MSI).
Methods
We investigated the L-[ring- ¹³ C 6 ]-Phenylalanine ( ¹³ C 6 -Phe) and L-[ring- ¹³ C 6 ]-Tyrosine ( ¹³ C 6 -Tyr) kinetics at 10 min ( n = 4), 30 min ( n = 3), and 60 min ( n = 4) after tracer injection and sham-treated group ( n = 3) at 10 min in mouse-xenograft lung tumor tissues by MALDI-FTICR-MSI.
Results
The dynamic changes in the spatial distributions of 19 out of 20 standard amino acids are observed in the tumor tissue. The highest abundance of ¹³ C 6 -Phe was detected in tumor tissue at 10 min after tracer injection and decreased progressively over time. The overall enrichment of ¹³ C 6 -Tyr showed a delayed temporal trend compared to ¹³ C 6 -Phe in tumor caused by the Phe-to-Tyr conversion process. Specifically, ¹³ C 6 -Phe and ¹³ C 6 -Tyr showed higher abundances in viable tumor regions compared to non-viable regions.
Conclusions
We demonstrated the spatiotemporal intra-tumoral distribution of the essential aromatic amino acid ¹³ C 6 -Phe and its de-novo synthesized metabolite ¹³ C 6 -Tyr by MALDI-FTICR-MSI. Our results explore for the first time local phenylalanine metabolism in the context of cancer tissue morphology. This opens a new way to understand amino acid metabolism within the tumor and its microenvironment.
Resistance to ionizing radiation, a first-line therapy for many cancers, is a major clinical challenge. Personalized prediction of tumor radiosensitivity is not currently implemented clinically due to insufficient accuracy of existing machine learning classifiers. Despite the acknowledged role of tumor metabolism in radiation response, metabolomics data is rarely collected in large multi-omics initiatives such as The Cancer Genome Atlas (TCGA) and consequently omitted from algorithm development. In this study, we circumvent the paucity of personalized metabolomics information by characterizing 915 TCGA patient tumors with genome-scale metabolic Flux Balance Analysis models generated from transcriptomic and genomic datasets. Metabolic biomarkers differentiating radiation-sensitive and -resistant tumors are predicted and experimentally validated, enabling integration of metabolic features with other multi-omics datasets into ensemble-based machine learning classifiers for radiation response. These multi-omics classifiers show improved classification accuracy, identify clinical patient subgroups, and demonstrate the utility of personalized blood-based metabolic biomarkers for radiation sensitivity. The integration of machine learning with genome-scale metabolic modeling represents a significant methodological advancement for identifying prognostic metabolite biomarkers and predicting radiosensitivity for individual patients.
To meet the anabolic demands of the proliferative potential of tumor cells, malignant cells tend to rewire their metabolic pathways. Although different types of malignant cells share this phenomenon, there is a large intracellular variability how these metabolic patterns are altered. Fortunately, differences in metabolic patterns between normal tissue and malignant cells can be exploited to increase the therapeutic ratio. Modulation of cellular metabolism to improve treatment outcome is an emerging field proposing a variety of promising strategies in primary tumor and metastatic lesion treatment. These strategies, capable of either sensitizing or protecting tissues, target either tumor or normal tissue and are often focused on modulating of tissue oxygenation, hypoxia-inducible factor (HIF) stabilization, glucose metabolism, mitochondrial function and the redox balance. Several compounds or therapies are still in under (pre-)clinical development, while others are already used in clinical practice. Here, we describe different strategies from bench to bedside to optimize the therapeutic ratio through modulation of the cellular metabolism. This review gives an overview of the current state on development and the mechanism of action of modulators affecting cellular metabolism with the aim to improve the radiotherapy response on tumors or to protect the normal tissue and therefore contribute to an improved therapeutic ratio.
Stearoyl-CoA desaturase (SCD) is a central lipogenic enzyme for the synthesis of monounsaturated fatty acids (MUFA). SCD1 overexpression is associated with a genetic predisposition to hepatocarcinogenesis in mice and rats. This work hypothesized possible roles of SCD1 to genomic stability, lipogenesis, cell proliferation, and survival that contribute to the malignant transformation of non-tumorigenic liver cells. Therefore, HepG2 tumor cells were treated with the SCD1 inhibitor (CAY10566) to ensure a decrease in proliferation/survival, as confirmed by a lipidomic analysis that detected an efficient decrease in the concentration of MUFA. According to that, we switched to a model of normal hepatocytes, the HepaRG cell line, where we: (i) overexpressed SCD1 (HepaRG-SCD1 clones), (ii) inhibited the endogenous SCD1 activity with CAY10566, or (iii) treated with two monounsaturated (oleic OA and/or palmitoleic PA) fatty acids. SCD1 overexpression or MUFA stimulation increased cell proliferation, survival, and the levels of AKT, phospho-AKT(Ser473), and proliferating cell nuclear antigen (PCNA) proteins. By contrast, opposite molecular and cellular responses were observed in HepaRG cells treated with CAY10566. To assess genomic stability, HepaRG-SCD1 clones were treated with ionizing radiation (IR) and presented reduced levels of DNA damage and higher survival at doses of 5 Gy and 10 Gy compared to parental cells. In sum, this work suggests that modulation of SCD1 activity not only plays a role in cell proliferation and survival, but also in maintaining genomic stability, and therefore, contributes to a better understanding of this enzyme in molecular mechanisms of hepatocarcinogenesis projecting SCD1 as a potential translational target.
Dynamic nuclear polarization (DNP) of 13C‐labeled substrates enables the use of magnetic resonance imaging (MRI) to monitor specific enzymatic reactions in tumors and offers an opportunity to investigate these differences. In this study, DNP‐MRI chemical shift imaging with hyperpolarized [1‐13C] pyruvate was conducted to evaluate the metabolic change in glycolytic profiles after radiation of two glioma stem‐like cell‐derived gliomas (GBMJ1 and NSC11) and an adherent human glioblastoma cell line (U251) in an orthotopic xenograft mouse model. The DNP‐MRI showed an increase in Lac/Pyr at 6 and 16 h after irradiation (18% ± 4% and 14% ± 3%, respectively; mean ± SEM) compared with unirradiated controls in GBMJ1 tumors, whereas no significant change was observed in U251 and NSC11 tumors. Metabolomic analysis likewise showed a significant increase in lactate in GBMJ1 tumors at 16 h. An immunoblot assay showed upregulation of lactate dehydrogenase‐A expression in GBMJ1 following radiation exposure, consistent with DNP‐MRI and metabolomic analysis. In conclusion, our preclinical study demonstrates that the DNP‐MRI technique has the potential to be a powerful diagnostic method with which to evaluate GBM tumor metabolism before and after radiation in the clinical setting. Orthotopic brain tumor mice were subjected to 13C‐MRI using hyperpolarized [1‐13C] pyruvate to investigate the effect of radiation exposure on glucose metabolism by measuring lactate‐to‐pyruvate ratio in the tumor. Tissue sampling was conducted independently to quantify the lactate concentration and LDHA expression by metabolomic and immunoblot analyses, respectively. These indicated an acceleration of lactate‐to‐pyruvate conversion in one of the stem‐like cell‐derived gliomas after an irradiation during a 24‐h period of time.
Metabolic genes have played a significant role in tumor development and prognosis. In this study, we constructed a metabolic risk model to predict the prognosis of colon cancer based on The Cancer Genome Atlas (TCGA) and validated the model by Gene Expression Omnibus (GEO). We extracted 753 metabolic genes and identified 139 differentially expressed genes (DEGs) from TCGA database. Then we conducted univariate cox regression analysis and Least Absolute Shrinkage and Selection Operator Cox regression analysis to identify prognosis-related genes and construct the metabolic risk model. An eleven-gene prognostic model was constructed after 1000 resamples. The gene signature has been proved to have an excellent ability to predict prognosis by Kaplan–Meier analysis, time-dependent receiver operating characteristic, risk score, univariate and multivariate cox regression analysis based on TCGA. Then we validated the model by Kaplan–Meier analysis and risk score based on GEO database. Finally, we performed a weighted gene co-expression network analysis and protein–protein interaction network on DEGs, and Kyoto Encyclopedia of Genes and Genomes pathways and Gene Ontology enrichment analyses were conducted. The results of functional analyses showed that most significantly enriched pathways focused on metabolism, especially glucose and lipid metabolism pathways.
Radiation-induced bystander effects (RIBE) may have potential implications for radiotherapy, yet the radiobiological impact and underlying mechanisms in hypoxic tumor cells remain to be determined. Using two human tumor cell lines, hepatoma HepG2 cells and glioblastoma T98G cells, the present study found that under both normoxic and hypoxic conditions, increased micronucleus formation and decreased cell survival were observed in non-irradiated bystander cells which had been co-cultured with X-irradiated cells or treated with conditioned-medium harvested from X-irradiated cells. Although the radiosensitivity of hypoxic tumor cells was lower than that of aerobic cells, the yield of micronucleus induced in bystander cells under hypoxia was similar to that measured under normoxia indicating that RIBE is a more significant factor in overall radiation damage of hypoxic cells. When hypoxic cells were treated with dimethyl sulfoxide (DMSO), a scavenger of reactive oxygen species (ROS), or aminoguanidine (AG), an inhibitor of nitric oxide synthase (NOS), before and during irradiation, the bystander response was partly diminished. Furthermore, when only hypoxic bystander cells were pretreated with siRNA hypoxia-inducible factor-1α (HIF-1α), RIBE were decreased slightly but if irradiated cells were treated with siRNA HIF-1α, hypoxic RIBE decreased significantly. In addition, the expression of HIF-1α could be increased in association with other downstream effector molecules such as glucose transporter 1 (GLUT-1), vascular endothelial growth factor (VEGF), and carbonic anhydrase (CA9) in irradiated hypoxic cells. However, the expression of HIF-1α expression in bystander cells was decreased by a conditioned medium from isogenic irradiated cells. The current results showed that under hypoxic conditions, irradiated HepG2 and T98G cells showed reduced radiosensitivity by increasing the expression of HIF-1α and induced a syngeneic bystander effect by decreasing the expression of HIF-1α and regulating its downstream target genes in both the irradiated or bystander cells.
Simple Summary
Hyperactivation of the de novo serine/glycine biosynthesis across different cancer types and its critical contribution in tumor initiation, progression, and therapy resistance indicate the relevance of serine/glycine metabolism-targeted therapies as therapeutic intervention in cancer. In this review, we specifically focus on the contribution of the de novo serine/glycine biosynthesis pathway to radioresistance. We provide a future perspective on how de novo serine/glycine biosynthesis inhibition and serine-free diets may improve the outcome of radiotherapy. Future research in this field is needed to better understand serine/glycine metabolic reprogramming of cancer cells in response to radiation and the influence of this pathway in the tumor microenvironment, which may provide the rationale for the optimal combination therapies.
Abstract
The activation of de novo serine/glycine biosynthesis in a subset of tumors has been described as a major contributor to tumor pathogenesis, poor outcome, and treatment resistance. Amplifications and mutations of de novo serine/glycine biosynthesis enzymes can trigger pathway activation; however, a large group of cancers displays serine/glycine pathway overexpression induced by oncogenic drivers and unknown regulatory mechanisms. A better understanding of the regulatory network of de novo serine/glycine biosynthesis activation in cancer might be essential to unveil opportunities to target tumor heterogeneity and therapy resistance. In the current review, we describe how the activation of de novo serine/glycine biosynthesis in cancer is linked to treatment resistance and its implications in the clinic. To our knowledge, only a few studies have identified this pathway as metabolic reprogramming of cancer cells in response to radiation therapy. We propose an important contribution of de novo serine/glycine biosynthesis pathway activation to radioresistance by being involved in cancer cell viability and proliferation, maintenance of cancer stem cells (CSCs), and redox homeostasis under hypoxia and nutrient-deprived conditions. Current approaches for inhibition of the de novo serine/glycine biosynthesis pathway provide new opportunities for therapeutic intervention, which in combination with radiotherapy might be a promising strategy for tumor control and ultimately eradication. Further research is needed to gain molecular and mechanistic insight into the activation of this pathway in response to radiation therapy and to design sophisticated stratification methods to select patients that might benefit from serine/glycine metabolism-targeted therapies in combination with radiotherapy.
Acquired and intrinsic radioresistance remains a major challenge during the treatment of patients with colorectal cancer (CRC). Aberrant cholesterol metabolism precipitates the development of multiple cancers. Here, we report that exogenous or endogenous cholesterol enhances the radioresistance of CRC cells. Cholesterol addition protects CRC cells against irradiation in vitro and in vivo. SREBP1/FASN signaling rapidly increased in response to radiation stimuli, resulting in cholesterol accumulation, cell proliferation, and inhibition of apoptosis. Blocking the SREBP1/FASN pathway impeded cholesterol synthesis and accelerated radiation‐induced CRC cell death. Our findings provide novel insights into the role of the SREBP1/FASN/cholesterol axis in radiotherapy and suggest that it may be a potential target for CRC treatment. Clinically, our results suggest that CRC patients undergoing radiotherapy may benefit from a lowered cholesterol intake.
Despite technological advances in radiotherapy and cancer treatment, patients still experience adverse effects. Proton therapy has emerged as a valuable radiotherapy modality, which can improve treatment outcomes. As normal tissue injury is an important determinant of the outcome, for this review, we analyzed two databases, (i) clinical trials registered in ClinicalTrials.gov and (ii) the literature on proton therapy in PubMed, which shows a steady increase in the number of publications. Most studies in proton therapy registered in the ClinicalTrials.gov with results available are nonrandomized early phase studies, with a relatively small number of patients enrolled. From the larger database of nonrandomized trials, we listed adverse events in specific organ/sites among cancer patients treated with photons and protons to identify critical issues. Present data demonstrate dosimetric advantages of proton therapy with favorable toxicity profiles and forms the basis for comparative randomized prospective trials. Comparative analysis of recently completed three randomized trials for normal tissue toxicities suggest the following: (i) for early stage non-small-cell lung cancer, no meaningful comparison could be made between stereotactic body radiotherapy and stereotactic body proton therapy due to low accrual (NCT01511081), (ii) for locally advanced non-small-cell lung cancer, comparison of intensity-modulated radiotherapy with passive scattering proton therapy (now largely replaced by “spot-scanned” intensity-modulated proton therapy), proton therapy did not provide any benefit in normal tissue toxicity or locoregional failure over photon therapy, and (iii) for locally advanced esophageal cancer proton beam therapy provided a lower total toxicity burden; although it did not improve progression free survival and quality-of-life (NCT01512589). The purpose of this review is to inform the limitations of current trials looking at protons and photons, considering advances in technology, physics, and biology are a continuum and advocate for future trials geared towards accurate precision radiation therapy that needs to be viewed as an iterative process in a defined path towards delivering optimal radiation treatment. A foundational understanding of the radiobiological differences between protons and photons in tumor and normal tissue responses is fundamental to, and necessary for, determining the suitability of a given type of biologically optimized radiation therapy to a patient or a cohort.
Treatment of locally advanced, unresectable head and neck squamous cell carcinoma (HNSCC) often yields only modest results with radiochemotherapy (RCT) as standard of care. Prognostic features related to outcome upon RCT might be highly valuable to improve treatment. Monocarboxylate transporters-1 and -4 (MCT1/MCT4) were evaluated as potential biomarkers. A cohort of HNSCC patients without signs for distant metastases was assessed eliciting 82 individuals eligible whereof 90% were diagnosed with locally advanced stage IV. Tumor specimens were stained for MCT1 and MCT4 in the cell membrane by immunohistochemistry. Obtained data were evaluated with respect to overall (OS) and progression-free survival (PFS). Protein expression of MCT1 and MCT4 in cell membrane was detected in 16% and 85% of the tumors, respectively. Expression of both transporters was not statistically different according to the human papilloma virus (HPV) status. Positive staining for MCT1 (n = 13, negative in n = 69) strongly worsened PFS with a hazard ratio (HR) of 3.1 (95%-confidence interval 1.6–5.7, p < 0.001). OS was likewise affected with a HR of 3.8 (2.0–7.3, p < 0.001). Multivariable Cox regression confirmed these findings. We propose MCT1 as a promising biomarker in HNSCC treated by primary RCT.
Simple Summary
PET enables quantitative assessment of tumour biology in vivo. Accumulation of F-18 fluorodeoxyglucose (FDG) may reflect tumour metabolic activity. Quantitative assessment of FDG uptake can be applied for treatment monitoring. Numerous studies indicated biochemical change assessed by FDG-PET as a more sensitive marker than morphological change. Those with complete metabolic response after therapy may show better prognosis. Assessment of metabolic change may be performed using absolute FDG uptake or metabolic tumour volume. More recently, radiomics approaches have been applied to FDG PET. Texture analysis quantifies intratumoral heterogeneity in a voxel-by-voxel basis. Combined with various machine learning techniques, these new quantitative parameters hold a promise for assessing tissue characterization and predicting treatment effect, and could also be used for future prognosis of various tumours.
Abstract
Positron emission tomography (PET) has unique characteristics for quantitative assessment of tumour biology in vivo. Accumulation of F-18 fluorodeoxyglucose (FDG) may reflect tumour characteristics based on its metabolic activity. Quantitative assessment of FDG uptake can often be applied for treatment monitoring after chemotherapy or chemoradiotherapy. Numerous studies indicated biochemical change assessed by FDG PET as a more sensitive marker than morphological change estimated by CT or MRI. In addition, those with complete metabolic response after therapy may show better disease-free survival and overall survival than those with other responses. Assessment of metabolic change may be performed using absolute FDG uptake in the tumour (standardized uptake value: SUV). In addition, volumetric parameters such as metabolic tumour volume (MTV) have been introduced for quantitative assessment of FDG uptake in tumour. More recently, radiomics approaches that focus on image-based precision medicine have been applied to FDG PET, as well as other radiological imaging. Among these, texture analysis extracts intratumoral heterogeneity on a voxel-by-voxel basis. Combined with various machine learning techniques, these new quantitative parameters hold a promise for assessing tissue characterization and predicting treatment effect, and could also be used for future prognosis of various tumours, although multicentre clinical trials are needed before application in clinical settings.
Regulatory T (Treg) cells, although vital for immune homeostasis, also represent a major barrier to anti-cancer immunity, as the tumour microenvironment (TME) promotes the recruitment, differentiation and activity of these cells1,2. Tumour cells show deregulated metabolism, leading to a metabolite-depleted, hypoxic and acidic TME³, which places infiltrating effector T cells in competition with the tumour for metabolites and impairs their function4–6. At the same time, Treg cells maintain a strong suppression of effector T cells within the TME7,8. As previous studies suggested that Treg cells possess a distinct metabolic profile from effector T cells9–11, we hypothesized that the altered metabolic landscape of the TME and increased activity of intratumoral Treg cells are linked. Here we show that Treg cells display broad heterogeneity in their metabolism of glucose within normal and transformed tissues, and can engage an alternative metabolic pathway to maintain suppressive function and proliferation. Glucose uptake correlates with poorer suppressive function and long-term instability, and high-glucose conditions impair the function and stability of Treg cells in vitro. Treg cells instead upregulate pathways involved in the metabolism of the glycolytic by-product lactic acid. Treg cells withstand high-lactate conditions, and treatment with lactate prevents the destabilizing effects of high-glucose conditions, generating intermediates necessary for proliferation. Deletion of MCT1—a lactate transporter—in Treg cells reveals that lactate uptake is dispensable for the function of peripheral Treg cells but required intratumorally, resulting in slowed tumour growth and an increased response to immunotherapy. Thus, Treg cells are metabolically flexible: they can use ‘alternative’ metabolites in the TME to maintain their suppressive identity. Further, our results suggest that tumours avoid destruction by not only depriving effector T cells of nutrients, but also metabolically supporting regulatory populations.
Abstract
Background
Glioblastoma is the deadliest brain tumor in adults and the standard-of-care consists of surgery followed by radiation and treatment with temozolomide. Overall survival times for patients suffering from glioblastoma are unacceptably low indicating an unmet need for novel treatment options.
Methods
Using patient-derived HK-157, HK-308, HK-374, and HK-382 glioblastoma lines, the GL261 orthotopic mouse models of glioblastoma and HK-374 patient-derived orthotopic xenografts we tested the effect of radiation and the dopamine receptor antagonist quetiapine on glioblastoma self-renewal in vitro and survival in vivo. A possible resistance mechanism was investigated using RNA-Sequencing. The blood-brain-barrier-penetrating statin atorvastatin was used to overcome this resistance mechanism. All statistical tests were 2-sided.
Results
Treatment of glioma cells with the dopamine receptor antagonist quetiapine reduced glioma cell self-renewal in vitro and combined treatment of mice with quetiapine and radiation prolonged the survival of glioma-bearing mice. The combined treatment induced the expression of genes involved in cholesterol biosynthesis. This rendered GL261 and HK-374 orthotopic tumors vulnerable to simultaneous treatment with atorvastatin and further statistically significantly prolonged the survival of C57BL/6 (n = 10 to 16 mice per group; median survival not reached; Log-Rank test, p < 0.001) and NSG mice (n = 8 to 21 mice per group; hazard ratio = 3.96, 95% confidence interval = 0.29 to 12.40; Log-Rank test, p < 0.001), respectively.
Conclusions
Our results indicate promising therapeutic efficacy with the triple combination of quetiapine, atorvastatin and radiation treatment against glioblastoma without increasing the toxicity of radiation. With both drugs readily available for clinical use our study could be rapidly translated into a clinical trial.
This article provides an update on the global cancer burden using the GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer. Worldwide, an estimated 19.3 million new cancer cases (18.1 million excluding nonmelanoma skin cancer) and almost 10.0 million cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred in 2020. Female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), colorectal (10.0 %), prostate (7.3%), and stomach (5.6%) cancers. Lung cancer remained the leading cause of cancer death, with an estimated 1.8 million deaths (18%), followed by colorectal (9.4%), liver (8.3%), stomach (7.7%), and female breast (6.9%) cancers. Overall incidence was from 2‐fold to 3‐fold higher in transitioned versus transitioning countries for both sexes, whereas mortality varied <2‐fold for men and little for women. Death rates for female breast and cervical cancers, however, were considerably higher in transitioning versus transitioned countries (15.0 vs 12.8 per 100,000 and 12.4 vs 5.2 per 100,000, respectively). The global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020, with a larger increase in transitioning (64% to 95%) versus transitioned (32% to 56%) countries due to demographic changes, although this may be further exacerbated by increasing risk factors associated with globalization and a growing economy. Efforts to build a sustainable infrastructure for the dissemination of cancer prevention measures and provision of cancer care in transitioning countries is critical for global cancer control.
Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths in the United States and compiles the most recent data on population‐based cancer occurrence. Incidence data (through 2017) were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data (through 2018) were collected by the National Center for Health Statistics. In 2021, 1,898,160 new cancer cases and 608,570 cancer deaths are projected to occur in the United States. After increasing for most of the 20th century, the cancer death rate has fallen continuously from its peak in 1991 through 2018, for a total decline of 31%, because of reductions in smoking and improvements in early detection and treatment. This translates to 3.2 million fewer cancer deaths than would have occurred if peak rates had persisted. Long‐term declines in mortality for the 4 leading cancers have halted for prostate cancer and slowed for breast and colorectal cancers, but accelerated for lung cancer, which accounted for almost one‐half of the total mortality decline from 2014 to 2018. The pace of the annual decline in lung cancer mortality doubled from 3.1% during 2009 through 2013 to 5.5% during 2014 through 2018 in men, from 1.8% to 4.4% in women, and from 2.4% to 5% overall. This trend coincides with steady declines in incidence (2.2%‐2.3%) but rapid gains in survival specifically for nonsmall cell lung cancer (NSCLC). For example, NSCLC 2‐year relative survival increased from 34% for persons diagnosed during 2009 through 2010 to 42% during 2015 through 2016, including absolute increases of 5% to 6% for every stage of diagnosis; survival for small cell lung cancer remained at 14% to 15%. Improved treatment accelerated progress against lung cancer and drove a record drop in overall cancer mortality, despite slowing momentum for other common cancers.
Background: Radiomics refers to the extraction of a large amount of image information from medical images, which can provide decision support for clinicians. In this study, we developed and validated a radiomics-based nomogram to predict the prognosis of colorectal cancer (CRC).
Methods: A total of 381 patients with colorectal cancer (primary cohort: n = 242; validation cohort: n = 139) were enrolled and radiomic features were extracted from the vein phase of preoperative computed tomography (CT). The radiomics score was generated by using the least absolute shrinkage and selection operator algorithm (LASSO). A nomogram was constructed by combining the radiomics score with clinicopathological risk factors for predicting the prognosis of CRC patients. The performance of the nomogram was evaluated by the calibration curve, receiver operating characteristic (ROC) curve and C-index statistics. Functional analysis and correlation analysis were used to explore the underlying association between radiomic feature and the gene-expression patterns.
Results: Five radiomic features were selected to calculate the radiomics score by using the LASSO regression model. The Kaplan-Meier analysis showed that radiomics score was significantly associated with disease-free survival (DFS) [primary cohort: hazard ratio (HR): 5.65, 95% CI: 2.26–14.13, P < 0.001; validation cohort: HR: 8.49, 95% CI: 2.05–35.17, P < 0.001]. Multivariable analysis confirmed the independent prognostic value of radiomics score (primary cohort: HR: 5.35, 95% CI: 2.14–13.39, P < 0.001; validation cohort: HR: 5.19, 95% CI: 1.22–22.00, P = 0.026). We incorporated radiomics signature with the TNM stage to build a nomogram, which performed better than TNM stage alone. The C-index of the nomogram achieved 0.74 (0.69–0.80) in the primary cohort and 0.82 (0.77–0.87) in the validation cohort. Functional analysis and correlation analysis found that the radiomic signatures were mainly associated with metabolism related pathways.
Conclusions: The radiomics score derived from the preoperative CT image was an independent prognostic factor and could be a complement to the current staging strategies of colorectal cancer.
To explain a paradoxical radiosensitizing effect of rosmarinic acid (RA) on the melanoma B16F10 cells, we analyzed the glutathione (GSH) intracellular production on this cell (traditionally considered radioresistant) in comparison with human prostate epithelial cells (PNT2) (considered to be radiosensitive). In PNT2 cells, the administration of RA increased the total GSH content during the first 3 h (p < 0.01) as well as increased the GSH/oxidized glutathione (GSSG) ratio in all irradiated cultures during all periods studied (1h and 3h) (p < 0.001), portraying an increase in the radioprotective capacity. However, in B16F10 cells, administration of RA had no effect on the total intracellular GSH levels, decreasing the GSH/GSSG ratio (p < 0.01); in addition, it caused a significant reduction in the GSH/GSSG ratio in irradiated cells (p < 0.001), an expression of radioinduced cell damage. In B16F10 cells, the administration of RA possibly activates the metabolic pathway of eumelanin synthesis that would consume intracellular GSH, thereby reducing its possible use as a protector against oxidative stress. The administration of this type of substance during radiotherapy could potentially protect healthy cells for which RA is a powerful radioprotector, and at the same time, cause significant damage to melanoma cells for which it could act as a radiosensitive agent.
Background
Radiation therapy is a highly cost-effective treatment for cancer, but the existence of radio-resistant cells remains the most critical obstacle in radiotherapy. We have been established clinically relevant radioresistant (CRR) cell lines by exposure to a stepwise increase of fractionated X-rays. We are trying to overcome the radio-resistance by analyzing the properties of these cells. In this study, we tried to evaluate the effects of hydrogen peroxide (H 2 O 2 ) on the CRR cells because this can evaluate the efficacy of Kochi Oxydol-Radiation Therapy for Unresectable Carcinomas (KORTUC) that treats H 2 O 2 before irradiation. We also established H 2 O 2 -resistant cells to compare the radiation and H 2 O 2 resistant phenotype.
Materials and Methods
We used human cancer cell lines derived from hepatoblastoma (HepG2), oral squamous cell carcinoma (SAS), and cervical cancer (HeLa). We established HepG2, SAS, and HeLa CRR cells and HepG2, SAS, and HeLa H 2 O 2 -resistant cells. To evaluate their sensitivity to radiation or H 2 O 2 , high-density survival assay, or WST assay was performed. CellROX TM was used to detect intracellular Reactive Oxygen Species (ROS).
Results
CRR cells were resistant to H 2 O 2 -induced cell death but H 2 O 2 -resistant cells were not resistant to irradiation. This phenotype of CRR cells was irreversible. The intracellular ROS was increased in parental cells after H 2 O 2 treatment for 3 h, but in CRR cells, no significant increase was observed.
Conclusion
Fractionated X-ray exposure induces H 2 O 2 resistance in CRR cells. Therefore, it is necessary to carry out cancer therapy such as KORTUC with the presence of these resistant cells in mind, and as the next stage, it would be necessary to investigate the appearance rate of these cells immediately and take countermeasures.
Addition of hydrogen peroxide (H2O2) is a method commonly used to trigger cellular oxidative stress. However, the doses used (often hundreds of micromolar) are disproportionally high with regard to physiological oxygen concentration (low micromolar). In this study using polarographic measurement of oxygen concentration in cellular suspensions we show that H2O2 addition results in O2 release as expected from catalase reaction. This reaction is fast enough to, within seconds, decrease drastically H2O2 concentration and to annihilate it within a few minutes. Firstly, this is likely to explain why recording of oxidative damage requires the high concentrations found in the literature. Secondly, it illustrates the potency of intracellular antioxidant (H2O2) defense. Thirdly, it complicates the interpretation of experiments as subsequent observations might result from high/transient H2O2 exposure and/or from the diverse possible consequences of the O2 release.
Metabolic reprogramming to fulfill the biosynthetic and bioenergetic demands of cancer cells has aroused great interest in recent years. However, metabolic reprogramming for cancer metastasis has not been well elucidated. Here, we screened a subpopulation of breast cancer cells with highly metastatic capacity to the lung in mice and investigated the metabolic alternations by analyzing the metabolome and the transcriptome, which were confirmed in breast cancer cells, mouse models, and patients’ tissues. The effects and the mechanisms of nucleotide de novo synthesis in cancer metastasis were further evaluated in vitro and in vivo. In our study, we report an increased nucleotide de novo synthesis as a key metabolic hallmark in metastatic breast cancer cells and revealed that enforced nucleotide de novo synthesis was enough to drive the metastasis of breast cancer cells. An increased key metabolite of de novo synthesis, guanosine-5'-triphosphate (GTP), is able to generate more cyclic guanosine monophosphate (cGMP) to activate cGMP-dependent protein kinases PKG and downstream MAPK pathway, resulting in the increased tumor cell stemness and metastasis. Blocking de novo synthesis by silencing phosphoribosylpyrophosphate synthetase 2 (PRPS2) can effectively decrease the stemness of breast cancer cells and reduce the lung metastasis. More interestingly, in breast cancer patients, the level of plasma uric acid (UA), a downstream metabolite of purine, is tightly correlated with patient’s survival. Our study uncovered that increased de novo synthesis is a metabolic hallmark of metastatic breast cancer cells and its metabolites can regulate the signaling pathway to promote the stemness and metastasis of breast cancer.
Malic enzyme 1 (ME1) is a cytosolic protein that catalyzes the conversion of malate to pyruvate while concomitantly generating NADPH from NADP. Early studies identified ME1 as a mediator of intermediary metabolism primarily through its participatory roles in lipid and cholesterol biosynthesis. ME1 was one of the first identified insulin-regulated genes in liver and adipose and is a transcriptional target of thyroxine. Multiple studies have since documented that ME1 is pro-oncogenic in numerous epithelial cancers. In tumor cells, the reduction of ME1 gene expression or the inhibition of its activity resulted in decreases in proliferation, epithelial-to-mesenchymal transition and in vitro migration, and conversely, in promotion of oxidative stress, apoptosis and/or cellular senescence. Here, we integrate recent findings to highlight ME1's role in oncogenesis, provide a rationale for its nexus with metabolic syndrome and diabetes, and raise the prospects of targeting the cytosolic NADPH network to improve therapeutic approaches against multiple cancers.
This study shows the use of hyperpolarized 13C magnetic resonance spectroscopic imaging (MRSI) to assess therapeutic efficacy in a preclinical tumor model. 13C-labeled pyruvate was used to monitor early changes in tumor metabolism based on the Warburg effect. High-grade malignant tumors exhibit increased glycolytic activity and lactate production to promote proliferation. A rodent glioma model was used to explore altered lactate production after therapy as an early imaging biomarker for therapeutic response. Rodents were surgically implanted with C6 glioma cells and separated into 4 groups, namely, no therapy, radiotherapy, chemotherapy and combined therapy. Animals were imaged serially at 6 different time points with magnetic resonance imaging at 3 T using hyperpolarized [1-13C]pyruvate MRSI and conventional 1H imaging. Using hyperpolarized [1-13C]pyruvate MRSI, alterations in tumor metabolism were detected as changes in the conversion of lactate to pyruvate (measured as Lac/Pyr ratio) and compared with the conventional method of detecting therapeutic response using the Response Evaluation Criteria in Solid Tumors. Moreover, each therapy group expressed different characteristic changes in tumor metabolism. The group that received no therapy showed a gradual increase of Lac/Pyr ratio within the tumor. The radiotherapy group showed large variations in tumor Lac/Pyr ratio. The chemo- and combined-therapy groups showed a statistically significant reduction in tumor Lac/Pyr ratio; however, only combined therapy was capable of suppressing tumor growth, which resulted in low endpoint mortality rate. Hyperpolarized 13C MRSI detected a prompt reduction in Lac/Pyr ratio as early as 2 days post combined chemo- and radiotherapies.
In recent years, lipid metabolism has garnered significant attention as it provides the necessary building blocks required to sustain tumor growth and serves as an alternative fuel source for ATP generation. Fatty acid synthase (FASN) functions as a central regulator of lipid metabolism and plays a critical role in the growth and survival of tumors with lipogenic phenotypes. Accumulating evidence has shown that it is capable of rewiring tumor cells for greater energy flexibility to attain their high energy requirements. This multi-enzyme protein is capable of modulating the function of subcellular organelles for optimal function under different conditions. Apart from lipid metabolism, FASN has functional roles in other cellular processes such as glycolysis and amino acid metabolism. These pivotal roles of FASN in lipid metabolism make it an attractive target in the clinic with several new inhibitors currently being tested in early clinical trials. This article aims to present the current evidence on the emergence of FASN as a target in human malignancies.
FDG-PET scanning has a central role in lymphoma staging and response assessment. There is a growing body of evidence that PET response assessment during and after initial systemic therapy can provide useful prognostic information, and PET response has an evolving role in guiding patient care. This review provides a perspective on the role of PET response assessment for individualised management of patients with the most common aggressive lymphomas, Hodgkin lymphoma and diffuse large B-cell lymphoma.
Importance:
Non-small cell lung cancer (NSCLC) has relatively poor outcomes. Metformin has significant data supporting its use as an antineoplastic agent.
Objective:
To compare chemoradiation alone vs chemoradiation and metformin in stage III NSCLC.
Design, setting, and participants:
The NRG-LU001 randomized clinical trial was an open-label, phase 2 study conducted from August 24, 2014, to December 15, 2016. Patients without diabetes who were diagnosed with unresectable stage III NSCLC were stratified by performance status, histology, and stage. The setting was international and multi-institutional. This study examined prespecified endpoints, and data were analyzed on an intent-to-treat basis. Data were analyzed from February 25, 2019, to March 6, 2020.
Interventions:
Chemoradiation and consolidation chemotherapy with or without metformin.
Main outcomes and measures:
The primary outcome was 1-year progression-free survival (PFS), designed to detect 15% improvement in 1-year PFS from 50% to 65% (hazard ratio [HR], 0.622). Secondary end points included overall survival, time to local-regional recurrence, time to distant metastasis, and toxicity per Common Terminology Criteria for Adverse Events, version 4.03.
Results:
A total of 170 patients were enrolled, with 167 eligible patients analyzed after exclusions (median age, 64 years [interquartile range, 58-72 years]; 97 men [58.1%]; 137 White patients [82.0%]), with 81 in the control group and 86 in the metformin group. Median follow-up was 27.7 months (range, 0.03-47.21 months) among living patients. One-year PFS rates were 60.4% (95% CI, 48.5%-70.4%) in the control group and 51.3% (95% CI, 39.8%-61.7%) in the metformin group (HR, 1.15; 95% CI, 0.77-1.73; P = .24). Clinical stage was the only factor significantly associated with PFS on multivariable analysis (HR, 1.79; 95% CI, 1.19-2.69; P = .005). One-year overall survival was 80.2% (95% CI, 69.3%-87.6%) in the control group and 80.8% (95% CI, 70.2%-87.9%) in the metformin group. There were no significant differences in local-regional recurrence or distant metastasis at 1 or 2 years. No significant difference in adverse events was observed between treatment groups.
Conclusions and relevance:
In this randomized clinical trial, the addition of metformin to concurrent chemoradiation was well tolerated but did not improve survival among patients with unresectable stage III NSCLC.
Trial registration:
ClinicalTrials.gov Identifier: NCT02186847.
Metformin, an antidiabetic drug, has demonstrated a broad spectrum of antitumor activity in preclinical studies: mechanistic effects include inhibition of complex I of the mitochondria oxidative phosphorylation chain, activation of AMPK, suppression of the IGF-1R and PI3K/AKT/mTORC1 pathways, and stimulation of the adaptive immune system.
Isocitrate dehydrogenase 1 (IDH1) mutations that generate the oncometabolite 2‐hydroxyglutarate (2‐HG) from α‐ketoglutarate (α‐KG) have been identified in many types of tumors and are an important prognostic factor in gliomas. 2‐HG production can be determined by hyperpolarized carbon‐13 magnetic resonance spectroscopy (HP‐13C‐MRS) using [1‐13C]‐α‐KG as a probe, but peak contamination from naturally occurring [5‐13C]‐α‐KG overlaps with the [1‐13C]‐2‐HG peak. Via a newly developed oxidative‐Stetter reaction, [1‐13C‐5‐12C]‐α‐KG was synthesized. α‐KG metabolism was measured via HP‐13C‐MRS using [1‐13C‐5‐12C]‐α‐KG as a probe. [1‐13C‐5‐12C]‐α‐KG was synthesized in high yields, and successfully eliminated the signal from C5 of α‐KG in the HP‐13C‐MRS spectra. In HCT116 IDH1 R132H cells, [1‐13C‐5‐12C]‐α‐KG allowed for unimpeded detection of [1‐13C]‐2‐HG. 12C‐enrichment represents a novel method to circumvent spectral overlap, and [1‐13C‐5‐12C]‐α‐KG shows promise as a probe to study IDH1 mutant tumors and α‐KG metabolism. 2‐hydroxyglutarate production can be determined by HP‐13C‐MRS using [1‐13C]‐α‐KG, but contamination from naturally occurring [5‐13C]‐α‐KG overlaps with the [1‐13C]‐2‐HG peak. We synthesized [1‐13C‐5‐12C]‐α‐KG via a newly developed oxidative‐Stetter reaction and eliminated the signal from C5 of α‐KG in the HP‐13C‐MRS spectra, thereby representing a novel method to circumvent spectral overlap.
Radiotherapy is a standard and conventional treatment strategy for nasopharyngeal carcinoma (NPC); however, radioresistance remains refractory to clinical outcomes. Understanding the molecular mechanism of radioresistance is crucial for advancing the efficacy of radiotherapy and improving the prognosis of NPC. In this study, β-lactamase-like-protein 2 (LACTB2) was identified as a potential biomarker for radioresistance using tandem mass tag proteomic analysis of NPC cells, gene chip analysis of NPC tissues, and differential gene analysis between NPC and normal nasopharyngeal tissues from the Gene Expression Omnibus database GSE68799. Meanwhile, LACTB2 levels were elevated in the serum of patients with NPC after radiotherapy. Inhibiting LACTB2 levels and mitophagy can sensitize NPC cells to ionizing radiation. In NPC cells, LACTB2 was augmented at the transcription and protein levels after radiation rather than nucleus-cytoplasm-mitochondria transposition to activate PTEN-induced kinase 1 (PINK1) and mitophagy. In addition, LACTB2 was first authenticated to co-locate with PINK1 by interacting with its N-terminal domain. Together, our findings indicate that overexpressed LACTB2 provoked PINK1-dependent mitophagy to promote radioresistance and thus might serve as a prognostic biomarker for NPC radiotherapy.
Background
Surgery with adjuvant radiotherapy is the accepted standard for treatment of advanced oral cavity squamous cell carcinoma (OCSCC); however, alternative evidence suggests that definitive (chemo)radiotherapy may have similar outcomes.
Methods
Systematic review was performed to assess the therapeutic value of radiotherapy or chemoradiotherapy as a primary modality for treating OCSCC. Meta-analysis of outcomes was performed between articles comparing radiotherapy and primary surgical treatment.
Results
Meta-analysis showed less favorable results of radiotherapy compared to surgery: overall survival at 3-years (odds ratio [OR] = 0.51; 95% confidence interval [CI] = 0.34–0.77) and 5-years (OR = 0.42; 95% CI = 0.29–0.60); disease-specific survival at 3-years (OR = 0.55; 95% CI = 0.32–0.96) and 5-years (OR = 0.55; 95% CI = 0.32–0.96). Odds of feeding tube dependency were higher in primary radiotherapy group (OR = 2.67; 95% CI = 1.27–5.64).
Conclusions
Results of this study support the current perspective favoring primary surgical treatment for OCSCC in the absence of surgical contraindications.
Hypoxia is a common phenomenon in most malignant tumors, especially in pancreatic cancer (PC). Hypoxia is the result of unlimited tumor growth and plays an active role in promoting tumor survival, progression, and invasion. As the part of the hypoxia microenvironment in PC is gradually clarified, hypoxia is becoming a key determinant and an important therapeutic target of pancreatic cancer. To adapt to the severe hypoxia environment, cells have changed their metabolic phenotypes to maintain their survival and proliferation. Enhanced glycolysis is the most prominent feature of cancer cells' metabolic reprogramming in response to hypoxia. It provides the energy source for hypoxic cancer cells (although it provides less than oxidative phosphorylation) and produces metabolites that can be absorbed and utilized by normoxic cancer cells. In addition, the uptake of glutamine and fatty acids by hypoxic cancer cells is also increased, which is also conducive to tumor progression. Their metabolites are pooled in the hexosamine biosynthesis pathway (HBP). As a nutrition sensor, HBP, in turn, can coordinate glucose and glutamine metabolism. Its end product, UDP-GlcNAc, is the substrate of protein post-translational modification (PTM) involved in various signaling pathways supporting tumor progression. Adaptive metabolic changes of cancer cells promote their survival and affect tumor immune cells in the tumor microenvironment (TME), which contributes to tumor immunosuppressive microenvironment and induces tumor immunotherapy resistance. Here, we summarize the hypoxic microenvironment, its effect on metabolic reprogramming, and its contribution to immunotherapy resistance in pancreatic cancer.
Identifying the factors and mechanisms that regulate metabolism under normal and diseased states requires methods to quantify metabolic fluxes of live tissues within their physiological milieu. A number of recent developments have expanded the reach and depth of isotope-based in vivo flux analysis, which have in turn challenged existing dogmas in metabolism research. First, minimally invasive techniques of intravenous isotope infusion and sampling have advanced in vivo metabolic tracer studies in animal models and human subjects. Second, recent breakthroughs in analytical instrumentation have expanded the scope of isotope labeling measurements and reduced sample volume requirements. Third, innovative modeling approaches and publicly available software tools have facilitated rigorous analysis of sophisticated experimental designs involving multiple tracers and expansive metabolomics datasets. These developments have enabled comprehensive in vivo quantification of metabolic fluxes in specific tissues and have set the stage for integrated multi-tissue flux assays.
Fatty acid synthase (FASN), the key enzyme in de novo lipogenesis, is an attractive therapeutic target for diseases characterized by excessive lipid accumulation. Many FASN inhibitors have failed in the clinical trial phase, largely because of poor solubility and safety. In this study, we generated a novel small-molecule FASN inhibitor by structure-based virtual screening. PFI09, the lead compound, is easy to synthesize, and inhibits the lipid synthesis in OP9 mammalian cell line and Caenorhabditis elegans as well as the proliferation of several cancer cell lines via the blockade of FASN. Mechanistic investigations show that PFI09 induces S-phase arrest, cell division reduction and apoptosis. We also develop a chemically stable analog of PFI09, MFI03, which reduces the proliferation of PC3 tumor cells both in vitro and in vivo, without toxicity to mice. In summary, our data suggest that MFI03 is an effective FASN inhibitor and a promising antineoplastic drug candidate.
Mass casualty exposure scenarios from an improvised nuclear device are expected to be far more complex than simple photons. Based on the proximity to the explosion and potential shielding, a mixed field of neutrons and photons comprised of up to approximately 30% neutrons of the total dose is anticipated. This presents significant challenges for biodosimetry and for short-term and long-term medical treatment of exposed populations. In this study we employed untargeted metabolomic methods to develop a biosignature in urine and serum from C57BL/6 mice to address radiation quality issues. The signature was developed in males and applied to samples from female mice to identify potential sex differences. Thirteen urinary (primarily amino acids, vitamin products, nucleotides) and 18 serum biomarkers (primarily mitochondrial and fatty acid β oxidation intermediates) were selected and evaluated in samples from day 1 and day 7 postirradiation. Sham-irradiated groups (controls) were compared to an equitoxic dose (3 Gy X-ray equivalent) from X rays (1.2 Gy/min), neutrons (∼1 Gy/h), or neutrons-photons. Results showed a time-dependent increase in the efficiency of the signatures, with serum providing the highest levels of accuracy in distinguishing not only between exposed from non-exposed populations, but also between radiation quality (photon exposures vs. exposures with a neutron component) and in between neutron-photon exposures (5, 15 or 25% of neutrons in the total dose) for evaluating the neutron contribution. A group of metabolites known as acylcarnitines was only responsive in males, indicating the potential for different mechanisms of action in baseline levels and of neutron-photon responses between the two sexes. Our findings highlight the potential of metabolomics in developing biodosimetric methods to evaluate mixed exposures with high sensitivity and specificity.
The discovery of regulated cell death processes has enabled advances in cancer treatment. In the past decade, ferroptosis, an iron-dependent form of regulated cell death driven by excessive lipid peroxidation, has been implicated in the development and therapeutic responses of various types of tumours. Experimental reagents (such as erastin and RSL3), approved drugs (for example, sorafenib, sulfasalazine, statins and artemisinin), ionizing radiation and cytokines (such as IFNγ and TGFβ1) can induce ferroptosis and suppress tumour growth. However, ferroptotic damage can trigger inflammation-associated immunosuppression in the tumour microenvironment, thus favouring tumour growth. The extent to which ferroptosis affects tumour biology is unclear, although several studies have found important correlations between mutations in cancer-relevant genes (for example, RAS and TP53), in genes encoding proteins involved in stress response pathways (such as NFE2L2 signalling, autophagy and hypoxia) and the epithelial-to-mesenchymal transition, and responses to treatments that activate ferroptosis. Herein, we present the key molecular mechanisms of ferroptosis, describe the crosstalk between ferroptosis and tumour-associated signalling pathways, and discuss the potential applications of ferroptosis in the context of systemic therapy, radiotherapy and immunotherapy.
Redox cofactor production is integral toward antioxidant generation, clearance of reactive oxygen species, and overall tumor response to ionizing radiation treatment. To identify systems-level alterations in redox metabolism that confer resistance to radiation therapy, we developed a bioinformatics pipeline for integrating multi-omics data into personalized genome-scale flux balance analysis models of 716 radiation-sensitive and 199 radiation-resistant tumors. These models collectively predicted that radiation-resistant tumors reroute metabolic flux to increase mitochondrial NADPH stores and reactive oxygen species (ROS) scavenging. Simulated genome-wide knockout screens agreed with experimental siRNA gene knockdowns in matched radiation-sensitive and radiation-resistant cancer cell lines, revealing gene targets involved in mitochondrial NADPH production, central carbon metabolism, and folate metabolism that allow for selective inhibition of glutathione production and H2O2 clearance in radiation-resistant cancers. This systems approach represents a significant advancement in developing quantitative genome-scale models of redox metabolism and identifying personalized metabolic targets for improving radiation sensitivity in individual cancer patients.
The efficacy of ionizing radiation (IR) for head and neck cancer squamous cell carcinoma (HNSCC) is limited by poorly understood mechanisms of adaptive radioresistance. Elevated glutaminase gene expression is linked to significantly reduced survival (p < 0.03). The glutaminase inhibitor, telaglenastat (CB-839), has been tested in Phase I/II cancer trials and is well tolerated by patients. This study investigated if telaglenastat enhances the cellular response to IR in HNSCC models. Using three human HNSCC cell lines and two xenograft mouse models, we examined telaglenastat's effects on radiation sensitivity. IR and telaglenastat combinatorial treatment reduced cell survival (p ≤ 0.05), spheroid size (p ≤ 0.0001) and tumor growth in CAL-27 xenograft bearing mice relative to vehicle (p ≤ 0.01), telaglenastat (p ≤ 0.05) or IR (p ≤ 0.01) monotherapy. Telaglenastat significantly reduced the Oxygen Consumption Rate/Extracellular Acidification Rate ratio in CAL-27 and HN5 cells in the presence of glucose and glutamine (p ≤ 0.0001). Telaglenastat increased oxidative stress and DNA damage in irradiated CAL-27 cells. These data suggest that combination treatment with IR and telaglenastat leads to an enhanced anti-tumor response. This pre-clinical data, combined with the established safety of telaglenastat justifies further investigation for the combination in HNSCC patients.
Significance
This work demonstrates that oncogenic activation of the PI3K-AKT-mTOR signaling pathway suppresses ferroptosis via the sterol regulatory element-binding protein-mediated lipogenesis, and that inhibition of this pathway potentiates the cancer therapeutic effect of ferroptosis induction. This finding unveils mechanisms for the regulation of ferroptosis and provides a potential cancer therapeutic approach for treating cancer patients bearing tumorigenic mutations in the PI3K-AKT-mTOR pathway.
In the past mitochondria were considered as the “powerhouse” of cell, since they generate more than 90% of ATP in aerobic conditions through the oxidative phosphorylation. However, based on the current knowledge, mitochondria play several other cellular functions, including participation in calcium homeostasis, generation of free radicals and oxidative species, triggering/regulation of apoptosis, among others. Additionally, previous discoveries recognized mitochondria as highly dynamic structures, which undergo morphological alterations resulting in long or short fragments inside the living cells. This highly regulated process was referred as mitochondrial dynamics and involves mitochondrial fusion and fission. Thus, the number of mitochondria and the morphology of mitochondrial networks depend on the mitochondrial dynamics, biogenesis, and mitophagy. In each cell, there is a delicate balance between fusion and fission to allow the maintenance of appropriate mitochondrial functions. It has been proposed that the fusion and fission dynamics process controls cell cycle, metabolism, and survival, being implicated in a wide range of physiological and pathological conditions. Mitochondrial fusion is mediated by dynamin-like proteins, including mitofusin 1 (MFN1), mitofusin 2 (MFN2), and optic atrophy 1 protein (OPA1). Conversely, mitochondrial fission results in a large number of small fragments, which is mediated mainly by dynamin-related protein 1 (DRP1). Interestingly, there is growing evidence proposing that tumor cells modify the mitochondrial dynamics rheostat in order to gain proliferative and survival advantages. Increased mitochondrial fission has been reported in several types of human cancer cells (melanoma, ovarian, breast, lung, thyroid, glioblastoma, and others) and some studies have reported a possible direct correlation between increased mitochondrial fusion and chemoresistance of tumor cells. Here, the current knowledge about alterations of mitochondrial dynamics in cancer will be reviewed and its potential as a target for adjuvant cancer chemotherapy will be discussed.
The mechanisms responsible for radioresistance in pancreatic cancer have yet to be elucidated and the suppressive tumor immune microenvironment must be considered. We investigated if the radiotherapy-augmented Warburg effect helped myeloid cells acquire an immunosuppressive phenotype, resulting in limited treatment efficacy of pancreatic ductal adenocarcinoma (PDAC). Radiotherapy enhanced the tumor-promoting activity of myeloid-derived suppressor cells (MDSCs) in pancreatic cancer. Sustained increase in lactate secretion, resulting from the radiation-augmented Warburg effect, was responsible for the enhanced immunosuppressive phenotype of MDSCs after radiotherapy. Hypoxia-inducible factor-1α (HIF-1α) was essential for tumor cell metabolism and lactate-regulated activation of MDSCs via the G protein-coupled receptor 81 (GPR81)/ mammalian target of rapamycin (mTOR)/HIF-1α/STAT3 pathway. Blocking lactate production in tumor cells or deleting Hif-1α in MDSCs reverted antitumor T cell responses and effectively inhibited tumor progression after radiotherapy in pancreatic cancer. Our investigation highlighted the importance of radiation-induced lactate in regulating the inhibitory immune microenvironment of PDAC. Targeting lactate derived from tumor cells and the HIF-1α signaling in MDSCs may hold distinct promise for clinical therapies to alleviate radioresistance in PDAC.
Significance
Hyperpolarized [1- ¹³ C]pyruvate magnetic resonance spectroscopic imaging (MRSI), which measures [1- ¹³ C]pyruvate-to-[1- ¹³ C]lactate conversion, has been widely explored as a metabolic-imaging modality interpreted to reflect LDHA activity and glycolytic flux. However, we show definitively that hyperpolarized [1- ¹³ C]pyruvate-to-[1- ¹³ C]lactate conversion rates are primarily a functional readout of [1- ¹³ C]pyruvate transmembrane influx mediated by MCT1, providing a mechanistic reinterpretation and redirection of clinical translation.