Rapid Tumor Cell Proliferation Research Articles

The role of lactate-induced protein lactylation in gliomas: implications for preclinical research and the development of new treatments.

The most prevalent primary brain tumors in adults are gliomas. In addition to insufficient therapeutic alternatives, gliomas are fatal mostly due to the rapid proliferation and continuous infiltration of tumor cells into the surrounding healthy brain tissue. According to a growing body of research, aerobic glycolysis, or the Warburg effect, promotes glioma development because gliomas are heterogeneous cancers that undergo metabolic reprogramming. Therefore, addressing the Warburg effect might be a useful therapeutic strategy for treating cancer. Lactate plays a critical role in reprogramming energy metabolism, allowing cells to rapidly access large amounts of energy. Lactate, a byproduct of glycolysis, is therefore present in rapidly proliferating cells and tumors. In addition to the protumorigenesis pathways of lactate synthesis, circulation, and consumption, lactate-induced lactylation has been identified in recent investigations. Lactate plays crucial roles in modulating immune processes, maintaining homeostasis, and promoting metabolic reprogramming in tumors, which are processes regulated by the lactate-induced lactylation of the lysine residues of histones. In this paper, we discuss the discovery and effects of lactylation, review the published studies on how protein lactylation influences cancer growth and further explore novel treatment approaches to achieve improved antitumor effects by targeting lactylation. These findings could lead to a new approach and guidance for improving the prognosis of patients with gliomas.

Mitochondrial-Targeting Nanotrapper Captured Copper Ions to Alleviate Tumor Hypoxia for Amplified Photoimmunotherapy in Breast Cancer.

Hypoxia is a pervasive feature of solid tumors, which significantly limits the therapeutic effect of photodynamic therapy (PDT) and further influences the immunotherapy efficiency in breast cancer. However, the transient alleviation of tumor hypoxia fails to address the underlying issue of increased oxygen consumption, resulting from the rapid proliferation of tumor cells. At present, studies have found that the reduction of the oxygen consumption rate (OCR) by cytochrome C oxidase (COX) inhibition that induced oxidative phosphorylation (OXHPOS) suppression was able to solve the proposed problem. Herein, we developed a specific mitochondrial-targeting nanotrapper (I@MSN-Im-PEG), which exhibited good copper chelating ability to inhibit COX for reducing the OCR. The results proved that the nanotrapper significantly alleviated the hypoxic tumor microenvironment by copper chelation in mitochondria and enhanced the PDT effect in vitro and in vivo. Meanwhile, the nanotrapper improved photoimmunotherapy through both enhancing PDT-induced immunogenetic cell death (ICD) effects and reversing Treg-mediated immune suppression on 4T1 tumor-bearing mice. The mitochondrial-targeting nanotrapper provided a novel and efficacious strategy to enhance the PDT effect and amplify photoimmunotherapy in breast cancer.

Targeting Glucose Metabolism in Cancer Immunotherapy: A Promising Avenue for Enhanced Treatment Strategies

Cancer immunotherapy has emerged as an innovative strategy for treating multiple types of cancer. Recent breakthroughs have emphasized the significance of altering glucose metabolism in malignant cells; specifically, the heightened dependency of cancer cells on glucose metabolism (“Warburg effect”), where cancer cells alter their metabolic pathway so that they utilize glucose as an energy source, even when oxygen is present. This adaptation allows for rapid tumor cell proliferation, enabling them to grow and divide at an accelerated pace. Current research concentrates on the development of cancer treatments aimed at inhibiting glucose metabolism in cancer cells. This approach aims to improve the effectiveness of existing immunotherapies by utilizing the metabolic pathways of malignant cells through direct and indirect inhibition of glycolysis. This review discusses the interplay between glucose metabolism and immune response, explores current efforts in manipulating glucose metabolism for therapeutic benefits, and provides insights into future directions for optimizing this strategy.

Modulation of glucose metabolism through macrophage-membrane-coated metal-organic framework nanoparticles for triple-negative breast cancer therapy

The clinical presentation of triple-negative breast cancer signifies a pathophysiological trajectory characterized by an aggressive nature. To satisfy the rapid tumor cell proliferation, glycolysis emerges as the primary modality for energy production, consequently engendering the copious generation of lactic acid. This, in turn, fosters an acidic microenvironment within the tumor milieu, which facilitates angiogenesis, tumor metastasis, extracellular matrix remodeling, and immune evasion. If the glycolytic flux was attenuated, a heightened influx of glucose-6-phosphate (G6P) towards the pentose phosphate pathway (PPP) ensues, promoting the synthesis of nicotinamide adenine dinucleotide phosphate (NADPH) and reduced glutathione (GSH). This orchestrated metabolic cascade gives rise to reductive equivalents and biosynthetic substrates, emblematic of a salient hallmark in the landscape of cancer cell metabolism. To surmount the quandary presented by aberrant tumor metabolism, we developed macrophage-membrane-coated metal–organic framework nanoparticles (AP@ZIF-Mem) to deliver atorvastatin (an inhibitor of MCT4, a lactic acid transporter within glycolysis) and polydatin (an inhibitor of G6PD, the rate-limiting enzyme of PPP) to interfere the glucose metabolism for sensitizing triple-negative breast cancer treatment. After i.v. injection, AP@ZIF-Mem could be accumulated into the tumor site via macrophage-biomimetic behavior. Through orchestrated intervention, these nanoparticles could provoke the accumulation of lactic acid within tumor cells, thereby precipitating a pronounced intratumoral acidosis; In parallel, the abrogation of G6PD function occasioned a surge in intracellular reactive oxygen species (ROS), consequentially culminating in diminished ribulose-5-phosphate and NADPH production. This dual-pronged intervention not only disrupted the tumor's energy provisioning framework but also perturbed the aberrant redox state of the tumor milieu, thereby sensitizing tumor treatment and impeding the metastatic trajectory. This study provided a paradigm of treatment/adjuvant treatment via the manipulation of glucose metabolism for triple-negative breast cancer.

Strategic Design of Conquering Hypoxia in Tumor for Advanced Photodynamic Therapy.

Photodynamic therapy (PDT), with its advantages of high targeting, minimally invasive, and low toxicity side effects, has been widely used in the clinical therapy of various tumors, especially superficial tumors. However, the tumor microenvironment (TME) presents hypoxia due to the low oxygen (O2 ) supply caused by abnormal vascularization in neoplastic tissues and high O2 consumption induced by the rapid proliferation of tumor cells. The PDT process generally relies on the presence of O2 , so the efficacy of PDT can be hampered by a hypoxic TME. To address this problem, researchers have been developing advanced nanoplatforms and strategies to enhance the therapeutic effect of PDT in tumor treatment. This review summarizes recent advanced PDT therapeutic strategies to against the hypoxic TME during the PDT treatment, thus enhancing PDT efficacy, including increasing O2 content in TME through delivering O2 to the tumors and in situ generations of O2 ; decreasing the O2 consumption during PDT by design of type I photosensitizers. To boost the PDT therapeutic effect, recent synergistically combination therapy of PDT and other therapeutic methods such as chemotherapy, photothermal therapy (PTT), immunotherapy, gas therapy is accounted by addressing the challenging problems of mono PDT in hypoxic environments, including tumor resistance, proliferation, and metastasis. Finally, we provide perspectives of the opportunities and challenges of PDT in future clinical research and translations. This article is protected by copyright. All rights reserved.

Research Progress of Serum VEGF and FAS in Prognosis of Gastric Cancer

Vascular endothelial growth factor (VEGF) is an important factor to promote endothelial cell division and angiogenesis. In physiological conditions, the expression level of VEGF in human tissues is very low. Ischemia, hypoxia and many tumors can promote the synthesis and secretion of VEGF, and its expression level is related to the degree of vascularization of tumors, the proliferation, growth and metastasis of tumor cells. Fatty acid synthase (FAS) is a key enzyme for endogenous fatty acid synthesis, which is expressed at a low level in normal tissue cells, while FASN in a variety of tumor cells is continuously highly expressed to meet the energy needs of cell proliferation and the excessive demand for rapid proliferation of tumor cells to form cell membrane lipids. A large amount of research shows that VEGF and FAS play an important role in the development and development of many tumors, and the abnormally high expression in tumor tissue cells is positively correlated with serum VEGF and FAS levels, which is closely related to the prognosis of tumors. Gastric cancer (GC) is one of the most common clinical malignant tumors of the digestive tract, and its incidence and mortality have shown an increasing trend in recent years, and the prognosis is poor, seriously endangering human health. The biological properties of GC are related to the level of VEGF and FAS expression in tissues and serum. This article reviews the research progress of VEGF and FAS, their expression in GC and their prognosis.

Aminopeptidases in Cancer, Biology and Prospects for Pharmacological Intervention.

Aminopeptidases, which catalyze the cleavage of amino acids from the amino terminus of proteins, are widely distributed in the natural world and play a crucial role in cellular processes and functions, including metabolism, signaling, angiogenesis, and immunology. They are also involved in the homeostasis of amino acids and proteins that are required for cellular proliferation. Tumor cells are highly dependent on the exogenous supply of amino acids for their survival, and overexpression of aminopeptidase facilitates rapid tumor cell proliferation. In addition, clinical studies have demonstrated that patients with cancers with high aminopeptidase expression often have poorer outcomes. Emerging evidence supports the rationale of inhibiting aminopeptidase activity as a targeted approach for novel treatment options, as limiting the availability of amino acids can be selectively lethal to tumor cells. While there are agents that directly target aminopeptidases that demonstrate potential as cancer therapies, such as bestatin and tosedostat, more selective and more targeted therapeutic approaches are needed. This article specifically looks at the biological role of aminopeptidases in both normal and cancer processes, and their potential as a biological target for future therapeutic strategies. When examining previous publications, most do not cover aminopeptidases and their role in cancer processes. Aminopeptidases play a vital role in cell processes and functions; however, their overexpression may lead to a rapid proliferation of tumor cells. Emerging evidence supports the rationale of leveraging aminopeptidase activity as a targeted approach for new oncological treatments. This article specifically looks at the biological role of aminopeptidases in both normal and cancer processes, and their potential as a biological target for future therapeutic strategies.

Use of multimodality imaging, histology, and treatment feasibility to characterize a transgenic Rag2-null rat model of glioblastoma.

Many drugs that show potential in animal models of glioblastoma (GBM) fail to translate to the clinic, contributing to a paucity of new therapeutic options. In addition, animal model development often includes histologic assessment, but multiparametric/multimodality imaging is rarely included despite increasing utilization in patient cancer management. This study developed an intracranial recurrent, drug-resistant, human-derived glioblastoma tumor in Sprague-Dawley Rag2-Rag2 tm1Hera knockout rat and was characterized both histologically and using multiparametric/multimodality neuroimaging. Hybrid 18F-fluoroethyltyrosine positron emission tomography and magnetic resonance imaging, including chemical exchange saturation transfer (18F-FET PET/CEST MRI), was performed for full tumor viability determination and characterization. Histological analysis demonstrated human-like GBM features of the intracranially implanted tumor, with rapid tumor cell proliferation (Ki67 positivity: 30.5 ± 7.8%) and neovascular heterogeneity (von Willebrand factor VIII:1.8 to 5.0% positivity). Early serial MRI followed by simultaneous 18F-FET PET/CEST MRI demonstrated consistent, predictable tumor growth, with exponential tumor growth most evident between days 35 and 49 post-implantation. In a second, larger cohort of rats, 18F-FET PET/CEST MRI was performed in mature tumors (day 49 post-implantation) for biomarker determination, followed by evaluation of single and combination therapy as part of the model development and validation. The mean percentage of the injected dose per mL of 18F-FET PET correlated with the mean %CEST (r = 0.67, P < 0.05), but there was also a qualitative difference in hot spot location within the tumor, indicating complementary information regarding the tumor cell demand for amino acids and tumor intracellular mobile phase protein levels. Finally, the use of this glioblastoma animal model for therapy assessment was validated by its increased overall survival after treatment with combination therapy (temozolomide and idasanutlin) (P < 0.001). Our findings hold promise for a more accurate tumor viability determination and novel therapy assessment in vivo in a recently developed, reproducible, intracranial, PDX GBM.

Metabolic intervention liposome for targeting glutamine-addiction of breast cancer.

The growth and rapid proliferation of tumor cells depend on both glycolysis and glutamine metabolism, leading to metabolic compensation. Here, dual inhibition on the metabolic plasticity by Glucose oxidase and Telaglenastat loaded liposome (Lip@GOx&Tel) were studied for intervening metabolic pathway on energy and material against breast cancer. Lip@GOx&Tel targeting inhibited the two nutrient supply mechanisms employed by tumor cells, reducing the supply of ATP production and biosynthesis precursors essential necessary for tumor, thereby eliciting anti-tumor and anti-metastasis effect. Meanwhile, Lip@GOx&Tel ingeniously amplify the therapeutic effect by up-regulating ROS and down-regulating GSH to disrupt redox homeostasis, thus resulting in inspiring 82% tumor suppression rate on 4T1 tumor model. Moreover, our study solved the limitation of combination between protein drugs and small molecule drugs in vivo by using liposome nanoparticles with clinical translation value. In short, this work provides a unique perspective of nanomedicine for treating diseases from metabolic intervention.

ERp44 Regulates the Proliferation, Migration, Invasion, and Apoptosis of Gastric Cancer Cells Via Activation of ER Stress.

Gastric cancer (GC) is one of the most prevalent malignancies worldwide. Endoplasmic reticulum (ER) stress plays a key role in the progression of GC. Rapid proliferation of tumor cells interferes with ER homeostasis, leading to ER stress and triggering unfolded protein response. Therefore, it is very necessary to investigate abnormally expressed ER resident proteins (ERp) in cancer cells. This study aimed to investigate the possible roles of ERp44. The mRNA and protein expression of genes were detected using qRT-PCR and western blot. Cell apoptosis was calculated using flow cytometry. Cell proliferation was determined using CCK-8 and colony formation assay. Cell migration was detected by wound healing, and cell invasion was measured by transwell assay. We found that ERp44 was obviously decreased in GC tissues. Furthermore, ERp44 overexpression distinctly suppressed the proliferation, migration, and invasion of MGC-803 and KATO III cells. In contrast, apoptosis was promoted by ERp44 overexpression. Furthermore, mechanistic studies revealed that overexpression of ERp44 inhibited malignant biological processes by regulating the eIF-2α/CHOP signaling pathway. Taken together, our data demonstrated that ERp44 regulated the proliferation, migration, invasion, and apoptosis via ERp44/eIF-2α/CHOP axis in GC. Targeting the ERp44and ER stress may be a promising strategy for GC.

Prognostic value of SPARC in hepatocellular carcinoma: A systematic review and meta-analysis.

Hepatocellular carcinoma (HCC) is characterized by a high degree of malignancy, rapid proliferation of tumor cells, and early liver metastasis. Resistance to multiple drugs independent of the high expression of secreted protein acidic and rich in cysteine (SPARC) is associated with a high risk of recurrence and mortality. However, the prognostic value of SPARC in patients with HCC remains unclear. Therefore, we performed a meta-analysis to evaluate the relationship between the expression of SPARC and the prognosis of patients with HCC. We searched for relevant articles in the CNKI, PubMed, EMBASE, and Web of Science databases. The 95% confidence intervals (CIs) were calculated for combined overall survival (OS) and disease-free survival (DFS) to assess the prognostic value of expression of SPARC in patients with HCC. In six of the studies, SPARC expression status was significantly associated with OS (combined hazard ratio [HR], 1.38; 95% CI, 1.0-1.82; Z = 2.27, P = 0.02) but not with DFS (combined HR, 0.79; 95% CI, 0.16-4.00, Z = 0.28, P = 0.78). Therefore, it cannot be assumed that upregulated SPARC expression has an effect on DFS in patients with HCC. Elevated SPARC expression is associated with a low survival rate but not with DFS in patients with HCC. Further studies are needed to confirm our conclusions. INPLASY registration number: INPLASY202180115. https://inplasy.com/inplasy-2021-8-0115/.

The imaging of the hypoxic microenvironment in tumorous tissue using PET/CT and PET/MRI

Tissue hypoxia becomes the driver of the micro-environmental transformation of the malignant tumorous tissue in majority of solid tumors. Even more, during the development of solid tumors, a large amount of nutrients is consumed due to rapid proliferation of tumor cells. The way of use of nutrients could be assessed using the probes during positron emission tomography (PET), the most frequent is the use of 18F-fluorodeoxyglucose (18F-FDG) demonstrating the turn-over of glucose exploitation in a manner of Warburg phenomenon. Even tumor cells can undergo metabolic reprogramming by changing the expression of glycolysis-related proteins, development of hypoxic condition increases glucose uptake to promote their growth. The hypoxic conditions are stimulation also the development of drug and/or radiation resistance, thus, the identification of the hypoxic tissue could play an important role in therapy planning. The process that enables use of hypoxia specific PET radiopharmaceutical starts when it enters cell by passive diffusion. Intracellularly, a model substance - 18F-fluoromisonidazol (18F-FMISO) is reduced by nitroreductase enzymes to become trapped in cells within reduced tissue oxygen partial pressure. The identification of the hypoxic tissue aids to plan the target to radiotherapy in squamous cell carcinomas of head and neck or cervical carcinoma, when 18F-FMISO-PET/CT is used as a planning procedure for a target volume, while 18F-FDG-PET/MRI is being the local and whole body staging procedure. Hypoxia imaging helps to identify the high-grade component of an astrocytic tumor before stereotactic biopsy.

Abstract 178: Multidimensional hydrogel model to benchmark progression of temozolomide-resistant glioblastoma

Abstract Introduction: Glioblastoma (GBM) is the most common and lethal form of brain cancer with a median survival of only 12 months. Due to challenges associated with surgical removal, resistance to chemo- and radiotherapy, and highly invasive nature of the tumor, GBM typically recurs rapidly near the primary tumor site, and the only widely-used therapeutic agent against GBM, temozolomide (TMZ), is merely effective. Previously, we have shown that a methacrylamide-functionalized gelatin (GelMA) hydrogel platform can support addition of brain-mimetic molecules and formation of vascular networks to study GBM behavior. In this study, we assess GBM response to TMZ using a unique set of isogenically matched GBM cell lines (8MGBA-WT vs. 8MGBA-TMZres; 42MGBA-WT vs. 42MBGA-TMZres) that exhibit TMZ responsiveness (WT) or resistance (TMZres) along with disparate proliferative and invasive patterns in two-dimensional culture. This study seeks to define changes in invasion and proliferation in response to TMZ within three-dimensional gelatin hydrogels. Methods: 8MGBA-WT, 8MGBA-TMZres, 42MGBA-WT, and 42MBGA-TMZres cell lines were cultured in DMEM with 10% FBS (100 μM TMZ continuously applied to 8MGBA-TMZres). Cells were encapsulated in GelMA hydrogels and cultured for 8 days with daily media change. After 24 hours, TMZ doses between 0 - 500 μM were applied to the gels and maintained for 7 days with daily media change. Growth rate inhibition (GR) statistics were determined after 7 days of culture. Relative cell count was assessed with the alamarBlue assay. GBM cell spheroids incapsulated in GelMA hydrogels were generated to measure relative invasion of wild type (WT) vs. TMZres lines. Spheroid outgrowth area was quantified with image analysis. Results: We observed changes in proliferative and invasive phenotypes between the cell lines consistent with 2D cell culture. Notably, 42MGBA-TMZres cells exhibited proliferative advantage, while 8MGBA-TMZres exhibited invasive advantage. GR analysis revealed apparent differences between WT and TMZres lines with the following GR50 values: 41 μM, 8MGBA-WT; 150 μM, 8MGBA-TMZres; 77 μM, 42MGBA-WT; 339 μM, 42MGBA-TMZres. These results provide insight into potential common pathways between the “go” or “grow” phenotypes that can be used as therapeutic targets for GBM. Conclusions: We have shown that a GelMA hydrogel platform can be used to assess GBM response to TMZ in 3D culture. This model provides insight into rapid tumor cell proliferation and diffusive local invasion. Further, this platform will be advanced to include a previously-developed model of GBM perivascular niche; this next-generation model will be used to benchmark the effect of perivascular niche on GBM therapeutic resistance and invasion. Hence, ongoing experiments aim to develop a vascularized hydrogel model of GBM to benchmark new TMZ variants hypothesized to overcome perivascular-induced resistance. Citation Format: Viktoriia Kriuchkovskaia, Brendan A. Harley, Rebecca B. Riggins. Multidimensional hydrogel model to benchmark progression of temozolomide-resistant glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 178.

Low-dose arsenic trioxide enhances membrane-GLUT1 expression and glucose uptake via AKT activation to support L-02 cell aberrant proliferation

Long term low dose exposure of arsenic has been reported to lead various cells proliferation and malignant transformation. GLUT1, as the key transporter of glucose, has been reported to have association with rapid proliferation of various cells or tumor cells. In our study, we found that low dose exposure to arsenic trioxide (0.1μmol/L As2O3) could induce an increase in glucose uptake and promote cell viability and DNA synthesis. And, 2-DG, a non-metabolized glucose analog, significantly decreased the glucose uptake and cell proliferation of 0.1μmol/L As2O3 treated L-02 cells. However, 4 mmol/L 2-DG was co-utilized with equal dose glucose had no significant effect on the cell proliferation of 0.1μmol/L As2O3 treated L-02 cells. Further studies showed that exposure to 0.1μmol/L As2O3 could promote the expression of GLUT1 on plasma membrane. Inhibition of GLUT1 expression by 5μmol/L BAY-876 significantly decreased the abilities of glucose uptake and cell proliferation in As2O3-treated L-02 cells. Moreover, 0.1μmol/L As2O3 induced the AKT activation indicated by increased the phospho-AKT (Ser473 and Thr308). Knockdown AKT by shRNA or inhibited AKT activation by LY294002 was followed by significantly decreased glucose uptake, GLUT1 plasma membrane expression and cell proliferation in As2O3-treated L-02 cells. All in all, these results demonstrated that arsenic trioxide-induced AKT activation contributed to the cells proliferation through upregulating expression of GLUT1 on plasma membrane that enhanced glucose uptake.

The Metabolic and Non-Metabolic Roles of UCK2 in Tumor Progression.

Enhanced nucleoside metabolism is one of the hallmarks of cancer. Uridine-cytidine kinase 2 (UCK2) is a rate-limiting enzyme of the pyrimidine salvage synthesis pathway to phosphorylate uridine and cytidine to uridine monophosphate (UMP) and cytidine monophosphate (CMP), respectively. Recent studies have shown that UCK2 is overexpressed in many types of solid and hematopoietic cancers, closely associates with poor prognosis, and promotes cell proliferation and migration in lung cancer and HCCs. Although UCK2 is thought to catalyze sufficient nucleotide building blocks to support the rapid proliferation of tumor cells, we and other groups have recently demonstrated that UCK2 may play a tumor-promoting role in a catalytic independent manner by activating oncogenic signaling pathways, such as STAT3 and EGFR-AKT. By harnessing the catalytic activity of UCK2, several cytotoxic ribonucleoside analogs, such as TAS-106 and RX-3117, have been developed for UCK2-mediated cancer chemotherapy. Moreover, we have demonstrated that the concurrent targeting of the catalytic dependent and independent features of UCK2 could synergistically inhibit tumor growth. These findings suggest that UCK2 may serve as a potential therapeutic target for cancer treatment. In this mini-review, we introduced the genomic localization and protein structure of UCK2, described the role of UCK2 in tumor development, discussed the application of UCK2 in anti-tumor treatment, and proposed concurrent targeting of the catalytic and non-catalytic roles of UCK2 as a potential therapeutic strategy for cancer treatment.

Drug Resistance and Endoplasmic Reticulum Stress in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common and deadly cancers worldwide. It is usually diagnosed in an advanced stage and is characterized by a high intrinsic drug resistance, leading to limited chemotherapeutic efficacy and relapse after treatment. There is therefore a vast need for understanding underlying mechanisms that contribute to drug resistance and for developing therapeutic strategies that would overcome this. The rapid proliferation of tumor cells, in combination with a highly inflammatory microenvironment, causes a chronic increase of protein synthesis in different hepatic cell populations. This leads to an intensified demand of protein folding, which inevitably causes an accumulation of misfolded or unfolded proteins in the lumen of the endoplasmic reticulum (ER). This process is called ER stress and triggers the unfolded protein response (UPR) in order to restore protein synthesis or—in the case of severe or prolonged ER stress—to induce cell death. Interestingly, the three different arms of the ER stress signaling pathways have been shown to drive chemoresistance in several tumors and could therefore form a promising therapeutic target. This review provides an overview of how ER stress and activation of the UPR contributes to drug resistance in HCC.

Research Advances in Antitumor Mechanism of Evodiamine

Evodiamine is a natural alkaloid extracted from Fructus Evodia. This bioactive alkaloid has been reported to have a wide range of biological activities, including anti-injury, antiobesity, vasodilator, and anti-inflammatory effects. In recent years, it has been found that evodiamine has tumor-suppressive effects on a variety of tumors. There is growing evidence that evodiamine can inhibit the rapid proliferation of tumor cells, induce cell cycle arrest at a certain phase, increase the incidence of apoptosis, promote autophagy, inhibit microangiogenesis and migration, and regulate immunotherapy. Evodiamine can inhibit Wnt/β-catenin, mTOR, NF-κB, PI3K/AKT, JAK-STAT, and other signaling pathways in various cancer cells, and it can significantly downregulate the expression of many tumor markers, such as VEGF and COX-2. These facts partially explain the antitumor mechanism of evodiamine. In this article, the antitumor mechanism of evodiamine was reviewed to provide the basis for its clinical application and therapeutic development in the future.

Metabolomic Phenotyping of Gliomas: What Can We Get with Simplified Protocol for Intact Tissue Analysis?

Simple SummaryThe diagnostic protocol for gliomas is based on histological examination and the determination of genetic biomarkers. However, examining molecular biomarkers in cancer tissue is usually labor-intensive and time-consuming when a homogenization step is involved. Therefore, this diagnostic approach has not been fully explored to date. The present study seeks to validate the applicability of solid-phase microextraction (SPME), or chemical biopsy, as a new approach for fast and simple sampling and sample-preparation in the surgery room prior to the application of metabolomic analysis to identify biomarkers. To this end, the metabolomic profiles of brain tumors were compared with genetic biomarkers and the results of histological analysis in order to identify changes of molecular metabolites of statistical significance. The findings of this study indicate that the proposed approach provides complementary information to current diagnostic methods and has the potential to be a valuable on-site analytical tool in future applications.Glioblastoma multiforme is one of the most malignant neoplasms among humans in their third and fourth decades of life, which is evidenced by short patient survival times and rapid tumor-cell proliferation after radiation and chemotherapy. At present, the diagnosis of gliomas and decisions related to therapeutic strategies are based on genetic testing and histological analysis of the tumor, with molecular biomarkers still being sought to complement the diagnostic panel. This work aims to enable the metabolomic characterization of cancer tissue and the discovery of potential biomarkers via high-resolution mass spectrometry coupled to liquid chromatography and a solvent-free sampling protocol that uses a microprobe to extract metabolites directly from intact tumors. The metabolomic analyses were performed independently from genetic and histological testing and at a later time. Despite the small cohort analyzed in this study, the results indicated that the proposed method is able to identify metabolites associated with different malignancy grades of glioma, as well as IDH and 1p19q codeletion mutations. A comparison of the constellation of identified metabolites and the results of standard tests indicated the validity of using the characterization of one comprehensive tumor phenotype as a reflection of all diagnostically meaningful information. Due to its simplicity, the proposed analytical approach was verified as being compatible with a surgical environment and applicable for large-scale studies.

Oxygen nanocarrier broke the hypoxia trap of solid tumors and rescued transfection efficiency for gene therapy

BackgroundGene therapy shows great promise for a broad array of diseases. However, we found that hypoxic tumor microenvironment (TME) exerted significant inhibitory effects on transfection efficiency of a variety of gene vectors (such as Lipo 2000 and PEI) in an oxygen-dependent manner. Solid tumors inevitably resulted in acute hypoxic areas due to the rapid proliferation of tumor cells and the aberrant structure of blood vessels. Thus, the hypoxic TME severely limited the efficiency and application of gene therapy.MethodsIn our previous study, we constructed endoplasmic reticulum-targeted cationic liposomes, PAR-Lipo, which could effectively deliver genes and ensure high transfection efficiency under normoxia. Unsatisfactorily, the transfection efficiency of PAR-Lipo was rather poor under hypoxia. We believed that reoxygenation was the most direct and effective means to rescue the low transfection under hypoxia. Hence, we fabricated liposomes modified with perfluorooctyl bromide (PFOB@Lipo) to load oxygen and deliver it to tumor sites, which effectively alleviated the hypoxic nature of tumor. Then PAR-Lipo were applied to mediate high-efficiency delivery of tumor suppressor gene pTP53 to inhibit tumor progression.ResultsThe results showed that such staged strategy augmented the expression of P53 protein in tumors and extremely suppressed tumor growth.ConclusionThis work was the first attempt to utilize an oxygen nanocarrier to assist the therapeutic effect of gene therapy under hypoxia, providing a new reference for gene therapy in malignant tumors.Graphical Abstarct

MYCN recruits the nuclear exosome complex to RNA polymerase II to prevent transcription-replication conflicts

The MYCN oncoprotein drives the development of numerous neuroendocrine and pediatric tumors. Here we show that MYCN interacts with the nuclear RNA exosome, a 3'-5' exoribonuclease complex, and recruits the exosome to its target genes. In the absence of the exosome, MYCN-directed elongation by RNA polymerase II (RNAPII) is slow and non-productive on a large group of cell-cycle-regulated genes. During the S phase of MYCN-driven tumor cells, the exosome is required to prevent the accumulation of stalled replication forks and of double-strand breaks close to the transcription start sites. Upon depletion of the exosome, activation of ATM causes recruitment of BRCA1, which stabilizes nuclear mRNA decapping complexes, leading to MYCN-dependent transcription termination. Disruption of mRNA decapping in turn activates ATR, indicating transcription-replication conflicts. We propose that exosome recruitment by MYCN maintains productive transcription elongation during S phase and prevents transcription-replication conflicts to maintain the rapid proliferation of neuroendocrine tumor cells.