Association of glutaminase expression with immune-suppressive tumor microenvironment, clinicopathologic features, and clinical outcomes in endometrial cancer.

Objective: Increased glutamine metabolism by cancer cells via upregulation of the drug-targetable enzyme glutaminase may contribute to an immune-suppressive tumor microenvironment. Inhibiting glutamine metabolism can not only suppress tumor growth, but also enhance tumor-specific immunity. We investigated the relationship between glutaminase expression, the immune tumor microenvironment, and clinicopathologic features in endometrial cancer.

Fatty acid synthase inhibitor cerulenin hinders liver cancer stem cell properties through FASN/APP axis as novel therapeutic strategies.

Hepatocellular carcinoma (HCC) poses significant treatment challenges due to high postoperative recurrence rates and the limited effectiveness of targeted medications. Researchers have identified the unique metabolic profiles of cancer stem cells (CSCs) as the primary drivers of cancer recurrence, metastasis, and drug resistance. Therefore, to address the therapeutic conundrum, this study focused on rewinding metabolic reprogramming of CSCs as a novel therapeutic strategy.

Active DNA Demethylase, TET1, Increases Oxidative Phosphorylation and Sensitizes Ovarian Cancer Stem Cells to Mitochondrial Complex I Inhibitor.

Ten-eleven translocation 1 (TET1) is a methylcytosine dioxygenase involved in active DNA demethylation. In our previous study, we demonstrated that TET1 reprogrammed the ovarian cancer epigenome, increased stem properties, and activated various regulatory networks, including metabolic networks. However, the role of TET1 in cancer metabolism remains poorly understood.

PBX1 as a novel master regulator in cancer: Its regulation, molecular biology, and therapeutic applications.

PBX1 is a critical transcription factor at the top of various cell fate-determining pathways. In cancer, PBX1 stands at the crossroads of multiple oncogenic signaling pathways and mediates responses by recruiting a broad repertoire of downstream targets. Research thus far has corroborated the involvement of PBX1 in cancer proliferation, resisting apoptosis, tumor-associated neoangiogenesis, epithelial-mesenchymal transition (EMT) and metastasis, immune evasion, genome instability, and dysregulating cellular metabolism.

Novel cancer treatment paradigm targeting hypoxia-induced factor in conjunction with current therapies to overcome resistance.

Chemotherapy, radiotherapy, targeted therapy, and immunotherapy are established cancer treatment modalities that are widely used due to their demonstrated efficacy against tumors and favorable safety profiles or tolerability. Nevertheless, treatment resistance continues to be one of the most pressing unsolved conundrums in cancer treatment. Hypoxia-inducible factors (HIFs) are a family of transcription factors that regulate cellular responses to hypoxia by activating genes involved in various adaptations, including erythropoiesis, glucose metabolism, angiogenesis, cell proliferation, and apoptosis.

Glucose Transporter 1-Mediated Transcytosis of Glucosamine-Labeled Liposomal Ceramide Targets Hypoxia Niches and Cancer Stem Cells to Enhance Therapeutic Efficacy.

Tumour hypoxia plays an important role in modulating tumorigenesis, angiogenesis, invasion, immunosuppression, resistance to treatment, and even maintenance of the stemness of cancer stem cells (CSCs). Moreover, the targeting and treatment of hypoxic cancer cells and CSCs to reduce the influence of tumor hypoxia on cancer therapy remains an imperative clinical problem that needs to be addressed. Since cancer cells upregulate the expression of glucose transporter 1 (GLUT1) through the Warburg effect, we considered the possibility of GLUT1-mediated transcytosis in cancer cells and developed a tumor hypoxia-targeting nanomedicine.

Frontier Review of the Molecular Mechanisms and Current Approaches of Stem Cell-Derived Exosomes.

Exosomes are effective therapeutic vehicles that may transport their substances across cells. They are shown to possess the capacity to affect cell proliferation, migration, anti-apoptosis, anti-scarring, and angiogenesis, via the action of transporting molecular components. Possessing immense potential in regenerative medicine, exosomes, especially stem cell-derived exosomes, have the advantages of low immunogenicity, minimal invasiveness, and broad clinical applicability.

Recent Advances in Metal-Based NanoEnhancers for Particle Therapy.

Radiotherapy is one of the most common therapeutic regimens for cancer treatment. Over the past decade, proton therapy (PT) has emerged as an advanced type of radiotherapy (RT) that uses proton beams instead of conventional photon RT. Both PT and carbon-ion beam therapy (CIBT) exhibit excellent therapeutic results because of the physical characteristics of the resulting Bragg peaks, which has been exploited for cancer treatment in medical centers worldwide.

Therapeutic Targeting of Glutaminolysis as a Novel Strategy to Combat Cancer Stem Cells.

Rare subpopulations of cancer stem cells (CSCs) have the ability to self-renew and are the primary driving force behind cancer metastatic dissemination and the preeminent hurdle to cancer treatment. As opposed to differentiated, non-malignant tumor offspring, CSCs have sophisticated metabolic patterns that, depending on the kind of cancer, rely mostly on the oxidation of major fuel substrates such as glucose, glutamine, and fatty acids for survival. Glutaminolysis is a series of metabolic reactions that convert glutamine to glutamate and, eventually, α-ketoglutarate, an intermediate in the tricarboxylic acid (TCA) cycle that provides biosynthetic building blocks.

A Few-Shot Learning Approach Assists in the Prognosis Prediction of Magnetic Resonance-Guided Focused Ultrasound for the Local Control of Bone Metastatic Lesions.

Magnetic resonance-guided focused ultrasound surgery (MRgFUS) constitutes a noninvasive treatment strategy to ablate deep-seated bone metastases. However, limited evidence suggests that, although cytokines are influenced by thermal necrosis, there is still no cytokine threshold for clinical responses. A prediction model to approximate the postablation immune status on the basis of circulating cytokine activation is thus needed.

Systems medicine dissection of chr1q-amp reveals a novel PBX1-FOXM1 axis for targeted therapy in multiple myeloma.

Understanding the biological and clinical impact of copy number aberrations (CNAs) on the development of precision therapies in cancer remains an unmet challenge. Genetic amplification of chromosome 1q (chr1q-amp) is a major CNA conferring an adverse prognosis in several types of cancer, including in the blood cancer multiple myeloma (MM). Although several genes across chromosome 1 (chr1q) portend high-risk MM disease, the underpinning molecular etiology remains elusive.

Enhanced Platelet-Rich Plasma (ePRP) Stimulates Wound Healing through Effects on Metabolic Reprogramming in Fibroblasts.

As a source of growth factors for expediting wound healing and tissue regeneration, plasma-rich plasma (PRP) has been extensively applied in diverse fields including orthopaedics, ophthalmology, oral and maxillofacial surgery, dentistry, and gynaecology. However, the function of PRP in metabolic regulations remains enigmatic. A standardized method was devised herein to enrich growth factors and to lyophilize it as enhanced PRP (ePRP) powder, which could become ubiquitously available without mechanical centrifugation in clinical practice.

Development of small molecule inhibitors targeting PBX1 transcription signaling as a novel cancer therapeutic strategy.

PBX1 is a transcription factor involved in diverse cellular functions including organ development, stem cell renewal, and tumorigenesis. is localized at chr1q23.3, a frequently amplified chromosomal region, and it is overexpressed in many human malignancies.

Potential Therapies Targeting Metabolic Pathways in Cancer Stem Cells.

Cancer stem cells (CSCs) are heterogeneous cells with stem cell-like properties that are responsible for therapeutic resistance, recurrence, and metastasis, and are the major cause for cancer treatment failure. Since CSCs have distinct metabolic characteristics that plays an important role in cancer development and progression, targeting metabolic pathways of CSCs appears to be a promising therapeutic approach for cancer treatment. Here we classify and discuss the unique metabolisms that CSCs rely on for energy production and survival, including mitochondrial respiration, glycolysis, glutaminolysis, and fatty acid metabolism.

Inhibition of glutaminolysis in combination with other therapies to improve cancer treatment.

Targeting glutamine catabolism has been attracting more research attention on the development of successful cancer therapy. Catalytic enzymes such as glutaminase (GLS) in glutaminolysis, a series of biochemical reactions by which glutamine is converted to glutamate and then alpha-ketoglutarate, an intermediate of the tricarboxylic acid (TCA) cycle, can be targeted by small molecule inhibitors, some of which are undergoing early phase clinical trials and exhibiting promising safety profiles. However, resistance to glutaminolysis targeting treatments has been observed, necessitating the development of treatments to combat this resistance.

Inhibition of the MYC-Regulated Glutaminase Metabolic Axis Is an Effective Synthetic Lethal Approach for Treating Chemoresistant Ovarian Cancers.

Amplification and overexpression of the oncogene in tumor cells, including ovarian cancer cells, correlates with poor responses to chemotherapy. As MYC is not directly targetable, we have analyzed molecular pathways downstream of MYC to identify potential therapeutic targets. Here we report that ovarian cancer cells overexpressing glutaminase (GLS), a target of MYC and a key enzyme in glutaminolysis, are intrinsically resistant to platinum-based chemotherapy and are enriched with intracellular antioxidant glutathione.

Targeting cancer stem cells from a metabolic perspective.

Unlabelled: The process of cancer development and progression is driven by distinct subsets of cancer stem cells (CSCs) that contribute the self-renewal capacity as the major impetus to the metastatic dissemination and main impediments in cancer treatment. Given that CSCs are so scarce in the tumor mass, there are debatable points on the metabolic signatures of CSCs. As opposed to differentiated tumor progenies, CSCs display exquisite patterns of metabolism that, depending on the type of cancer, predominately rely on glycolysis, oxidative metabolism of glutamine, fatty acids, or amino acids for ATP production.

Spleen tyrosine kinase activity regulates epidermal growth factor receptor signaling pathway in ovarian cancer.

Background: Spleen tyrosine kinase (SYK) is frequently upregulated in recurrent ovarian carcinomas, for which effective therapy is urgently needed. SYK phosphorylates several substrates, but their translational implications remain unclear. Here, we show that SYK interacts with EGFR and ERBB2, and directly enhances their phosphorylation.

Uncovering the Role of N-Acetyl-Aspartyl-Glutamate as a Glutamate Reservoir in Cancer.

N-acetyl-aspartyl-glutamate (NAAG) is a peptide-based neurotransmitter that has been extensively studied in many neurological diseases. In this study, we show a specific role of NAAG in cancer. We found that NAAG is more abundant in higher grade cancers and is a source of glutamate in cancers expressing glutamate carboxypeptidase II (GCPII), the enzyme that hydrolyzes NAAG to glutamate and N-acetyl-aspartate (NAA).

pH- and GSH-Sensitive Hyaluronic Acid-MP Conjugate Micelles for Intracellular Delivery of Doxorubicin to Colon Cancer Cells and Cancer Stem Cells.

A dual-sensitive polymeric drug conjugate (HA-SS-MP) was synthesized by conjugating hydrophobic 6-mercaptopurine (MP) to thiolated hyaluronic acid (HA) as the carrier and ligand to deliver doxorubicin (Dox) to parental colon cancer and colon cancer stem cells. Because of the amphiphilic nature of HA-SS-MP, it was self-assembled in the aqueous media, and Dox was physically encapsulated in the core of the micelles. The particle size and the zeta potential of the micelle were analyzed by dynamic light scattering (DLS), and the morphology of the micelle was investigated using transmission electron microscopy (TEM).

A pH sensitive polymeric micelle for co-delivery of doxorubicin and α-TOS for colon cancer therapy.

Combination therapy through simultaneous delivery of two or more therapeutic agents using nanocarriers has emerged as an advanced tactic for cancer treatment. To ensure that two therapeutic agents can be co-delivered and rapidly release their cargo in tumor cells, a biocompatible pH-sensitive copolymer, methoxy poly(ethylene glycol)-b-poly(hydroxypropyl methacrylamide-g-α-tocopheryl succinate-g-histidine) (abbreviated as PTH), was designed and synthesized. The PTH copolymers spontaneously self-assembled into micellar-type nanoparticles in aqueous solutions and are used for co-delivery of therapeutic agents, doxorubicin (Dox) and α-TOS.

CD44 and CD24 coordinate the reprogramming of nasopharyngeal carcinoma cells towards a cancer stem cell phenotype through STAT3 activation.

Cell surface proteins such as CD44 and CD24 are used to distinguish cancer stem cells (CSCs) from the bulk-tumor population. However, the molecular functionalities of CD24 and CD44, and how these two molecules coordinate in CSCs remain poorly understood. We found that nasopharyngeal carcinoma (NPC) cells with high expression of CD44 and CD24 proteins presented with pronounced CSC properties.

Intraperitoneal (188)Re-Liposome delivery switches ovarian cancer metabolism from glycolysis to oxidative phosphorylation and effectively controls ovarian tumour growth in mice.

Background And Purpose: Cancer stem cells exhibit distinctive cellular metabolism compared with the more differentiated counterparts or normal cells. We aimed to investigate the impact of a novel radionuclide anti-cancer agent (188)Re-Liposome on stemness markers' expression and cellular metabolism in an ovarian cancer model.

Material And Methods: A 2×2 factorial experiment was designed in which factor 1 represented the drug treatment comparing (188)Re-BMEDA, a free form of (188)Re, with (188)Re-Liposome, a nanoparticle-encapsulated form of (188)Re.

Intraperitoneal delivery of a novel liposome-encapsulated paclitaxel redirects metabolic reprogramming and effectively inhibits cancer stem cells in Taxol(®)-resistant ovarian cancer.

Taxol(®) remained as the mainstay therapeutic agent in the treatment of ovarian cancer, however recurrence rate is still high. Cancer stem cells (CSCs) represent a subset of cells in the bulk of tumors and play a central role in inducing drug resistance and recurrence. Furthermore, cancer metabolism has been an area under intensive investigation, since accumulating evidence has shown that CSCs and cancer metabolism are closely linked, an effect named as metabolic reprogramming.