Tumor Research Articles

Targeting EBV Episome for Anti-Cancer Therapy: Emerging Strategies and Challenges

As a ubiquitous human pathogen, the Epstein–Barr virus (EBV) has established lifelong persistent infection in about 95% of the adult population. The EBV infection is associated with approximately 200,000 human cancer cases and 140,000 deaths per year. The presence of EBV in tumor cells provides a unique advantage in targeting the viral genome (also known as episome), to develop anti-cancer therapeutics. In this review, we summarize current strategies targeting the viral episome in cancer cells. We also highlight emerging technologies, such as clustered regularly interspersed short palindromic repeat (CRISPR)-based gene editing or activation, which offer promising avenues for selective targeting of the EBV episome for anti-cancer therapy. We discuss the challenges, limitations, and future perspectives associated with these strategies, including potential off-target effects, anti-cancer efficacy and safety.

Combination therapy of low-dose radiotherapy and immunotherapy in advanced metastatic nasopharyngeal carcinoma: a case report and literature review.

Nasopharyngeal cancer (NPC) is a common head and neck malignant tumor, which is difficult to treat at the advanced NPC due to its occult and high metastatic potential to the cervical lymph nodes and distant organs. Low-dose radiotherapy (LDRT) is increasingly being investigated for potential cancer treatment. When combined with immune checkpoint inhibitors, LDRT has been shown to significantly improve the immune microenvironment of tumors, thereby promote the immune attack on tumor cells. However, the therapeutic effect of LDRT combined with immunotherapy in advanced NPC is not well understood. We report a case of a 31-year-old man was diagnosed with advanced metastatic nasopharnygeal non-keratinizing carcinoma (T4N3M1 stage IVb AJCC8th). The patient was treated with a high-dose of radiation therapy combined with LDRT and immunotherapy to inhibit tumor cell proliferation and activate the body's immune system. The initial treatment procedure was as follows: chemotherapy regimen (nedaplatin + docetaxel + fluorouracil) induction, followed by radical radiotherapy for the primary lesion, LDRT for the L5 vertebral body metastasis, and concurrent use of low-dose capecitabine beat chemotherapy and toripalimab immunotherapy. The patient was also administered with human granulocyte-macrophage colony-stimulating factor and aspirin to enhance the immune function. This combination therapy approach alleviated patient symptoms, improved bone changes in the L5 vertebral body and resolved the tumor without any adverse effects signals. The progression-free survival (PFS) has reached 27 months and he is currently stable without tumor recurrence. The combination of chemotherapy and LDRT with aspirin and human granulocyte macrophage colony-stimulating factor improved the disease state of advanced NPC cancer, effectively reducing the level of tumor markers, enhanced the immune function without significant adverse reactions.

An OMV-Based Nanovaccine as Antigen Presentation Signal Enhancer for Cancer Immunotherapy.

Antigen-presenting cells (APCs) process tumor vaccines and present tumor antigens as the first signals to T cells to activate anti-tumor immunity, which process requires the assistance of co-stimulatory second signals on APCs. The immune checkpoint programmed death ligand 1 (PD-L1) not only mediates the immune escape of tumor cells but also acts as a co-inhibitory second signal on APCs. The serious dysfunction of second signals due to the high expression of PD-L1 on APCs in the tumor body results in the inefficiency of tumor vaccines. To overcome this challenge, a previously established Plug-and-Display tumor vaccine platform based on bacterial outer membrane vesicles (OMVs) is developed into an "Antigen Presentation Signal Enhancer" (APSE) by surface-modifying PD-L1 antibodies (αPD-L1). While delivering tumor antigens, APSE can activate the expression of co-stimulatory second signals in APCs due to the high immunogenicity of OMVs. More importantly, the surface-modified αPD-L1 binds to the co-inhibitory signals PD-L1, potentially restoring CD80 function and ensuring efficient co-stimulatory second signals and activation of anti-tumor immunity. The results reveal the importance of PD-L1 blockage in the initiation process of anti-tumor immunity, and the second signal modulation capability of APSE can expand the application potential of cancer vaccines to less immunogenic malignancies.

Exploring the mechanism of rosmarinic acid in the treatment of lung adenocarcinoma based on bioinformatics methods and experimental validation.

Rosmarinic acid (RosA) is a natural polyphenol compound that has been shown to be effective in the treatment of inflammatory disease and a variety of malignant tumors. However, its specific mechanism for the treatment of lung adenocarcinoma (LUAD) has not been fully elucidated. Therefore, this study aims to clarify the mechanism of RosA in the treatment of LUAD by integrating bioinformatics, network pharmacology and in vivo experiments, and to explore the potential of the active ingredients of traditional Chinese medicine in treating LUAD. Firstly, the network pharmacology was used to screen the RosA targets, and LUAD-related differential expressed genes (DEGs) were acquired from the GEO database. The intersection of LUAD regulated by RosA (RDEGs) was obtained through the Venn diagram. Secondly, GO and KEGG enrichment analysis of RDEGs were performed, and protein-protein interaction networks (PPIs) were constructed to identify and visualize hub RDEGs. Then, molecular docking between hub RDEGs and RosA was performed, and further evaluation was carried out by using bioinformatics for the predictive value of the hub RDEGs. Finally, the mechanism of RosA in the treatment of LUAD was verified by establishing a xenograft model of NSCLC in nude mouse. Bioinformatics and other analysis showed that, compared with the control group, the expressions of MMP-1, MMP-9, IGFBP3 and PLAU in LUAD tissues were significantly up-regulated, and the expressions of PPARG and FABP4 were significantly down-regulated, and these hub RDEGs had potential predictive value for LUAD. In vivo experimental results showed that RosA could inhibit the growth of transplanted tumors in nude mice bearing tumors of lung cancer cells, reduce the positive expression of Ki67 in lung tumor tissue, and hinder the proliferation of lung tumor cells. Upregulated expression of PPARG and FABP4 by activating the PPAR signaling pathway increases the level of ROS in lung tumor tissues and promotes apoptosis of lung tumor cells. In addition, RosA can also reduce the expression of MMP-9 and IGFBP3, inhibit the migration and invasion of lung tumor tissue cells. This study demonstrated that RosA could induce apoptosis by regulating the PPAR signaling pathway and the expression of MMP-9, inhibit the proliferation, migration and invasion of lung cancer cells, thereby exerting anti-LUAD effects. This study provides new insight into the potential mechanism of RosA in treating LUAD and provides a new therapeutic avenue for treatment of LUAD.

Dysregulation of genes involved in the long-chain fatty acid transport in pancreatic ductal adenocarcinoma

BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is an aggressive lethal malignancy with limited options for treatment and a 5-year survival rate of 11% in the United States. As for other types of tumors, such as colorectal cancer, aberrant de novo lipid synthesis and reprogrammed lipid metabolism have been suggested to be associated with PDAC development and progression. AIM To identify the possible involvement of lipid metabolism in PDAC by analyzing in tumoral and non-tumoral tissues the expression level of the most relevant genes involved in the long-chain fatty acid (FA) import into cell. METHODS A gene expression analysis of FASN , CD36 , SLC27A1 , SLC27A2 , SLC27A3 , SLC27A4 , SLC27A5 , ACSL1 , and ACSL3 was performed by qRT-PCR in 24 tumoral PDAC tissues and 11 samples from non-tumoral pancreatic tissues obtained via fine needle aspiration or via surgical resection. The genes were considered significantly dysregulated between the groups when the p value was < 0.05 and the fold change (FC) was ≤ 0.5 and ≥ 2. RESULTS We found that three FA transporters and two long-chain acyl-CoA synthetases genes were significantly upregulated in the PDAC tissue compared to the non-tumoral tissue: SLC27A2 (FC = 5.66; P = 0.033), SLC27A3 (FC = 2.68; P = 0.040), SLC27A4 (FC = 3.13; P = 0.033), ACSL1 (FC = 4.10; P < 0.001), and ACSL3 (FC = 2.67; P = 0.012). We further investigated any possible association between the levels of the analyzed mRNAs and the specific characteristics of the tumors, including the anatomic location, the lymph node involvement, and the presence of metastasis. A significant difference in the expression of SLC27A3 (FC = 3.28; P = 0.040) was found comparing patients with and without lymph nodes involvement with an overexpression of this transcript in 17 patients presenting tumoral cells in the lymph nodes. CONCLUSION Despite the low number of patients analyzed, these preliminary results seem to be promising. Addressing lipid metabolism through a broad strategy could be a beneficial way to treat this malignancy. Future in vitro and in vivo studies on these genes may offer important insights into the mechanisms linking PDAC with the long-chain FA import pathway.

Mast cells: key players in digestive system tumors and their interactions with immune cells

Abstract Mast cells (MCs) are critical components of both innate and adaptive immune processes. They play a significant role in protecting human health and in the pathophysiology of various illnesses, including allergies, cardiovascular diseases and autoimmune diseases. Recent studies in tumor-related research have demonstrated that mast cells exert a substantial influence on tumor cell behavior and the tumor microenvironment, exhibiting both pro- and anti-tumor effects. Specifically, mast cells not only secrete mediators related to pro-tumor function such as trypsin-like enzymes, chymotrypsin, vascular endothelial cell growth factor and histamine, but also mediators related to anti-tumor progression such as cystatin C and IL-17F. This dual role of mast cells renders them an under-recognized but very promising target for tumor immunotherapy. Digestive system tumors, characterized by high morbidity and associated mortality rates globally, are increasingly recognized as a significant healthcare burden. This paper examines the influence of mast cell-derived mediators on the development of tumors in the digestive system. It also explores the prognostic significance of mast cells in patients with various gastrointestinal cancers at different stages of the disease. Additionally, the article investigates the interactions between mast cells and immune cells, as well as the potential relationships among intratumoral bacteria, immune cells, and mast cell within digestive system microenvironment. The aim is to propose new strategies for the immunotherapy of digestive system tumors by targeting mast cells.

UNC119 regulates T-cell receptor signalling in primary T cells and T acute lymphocytic leukaemia

T-cell receptor recognition of cognate peptide–MHC leads to the formation of signalling domains and the immunological synapse. Because of the close membrane apposition, there is rapid exclusion of CD45, and therefore LCK activation. Much less is known about whether spatial regulation of the intracellular face dictates LCK activity and TCR signal transduction. Moreover, as LCK is a driver in T acute lymphocytic leukaemia, it is important to understand its regulation. Here, we demonstrate a direct role of the ciliary protein UNC119 in trafficking LCK to the immunological synapse. Inhibiting UNC119 reduces localisation of LCK without impairing LCK phosphorylation and reduces T-cell receptor signal transduction. Although important for initial LCK reorganisation, activated CD8+T cells retained their ability to kill target tumour cells when UNC119 was inhibited. UNC119 was also needed to sustain proliferation in patient-derived T-ALL cells. UNC119 may therefore represent a novel therapeutic target in T acute lymphocytic leukaemia, which alters the subcellular localisation of LCK in T acute lymphocytic leukaemia cells but preserves the function of existing cytotoxic lymphocytes.

Investigation of chitin grafting: thermal, antioxidant and antitumor properties.

In this study, firstly chitin was reacted with chloracetyl chloride to synthesize the macroinitiator chitinchloroacetate (Ch.ClAc). Then, graft copolymers of methacrylamide (MAM), diacetone acrylamide (DAAM), N-(4-nitrophenyl)acrylamide (NPA), and 2-hydroxyethyl methacrylate (HEMA) monomers were synthesized by atom transfer radical polymerization (ATRP). All of the polymers were characterized by FTIR spectra and elemental analysis. According to the elemental analysis results, the mole percent (y) of the macro initiator was found to be 17.39%. The thermal stability of all the polymers (chitin, Ch.ClAc and its graft copolymers) was determined by thermogravimetric analysis (TGA) method and the highest thermal stability was observed in the ungrafted raw chitin. DPPH• scavenging activity and antitumor activity of all polymers were then investigated. Ch.ClAc was found to be the polymer that inhibited the proliferation of tumor cells more than chitin and graft copolymers. It was observed that the antitumor (L1210 cell lines) effect increased with increasing time and concentration in all polymers.

Combining Top-Down and Bottom-Up: An Open Microfluidic Microtumor Model for Investigating Tumor Cell-ECM Interaction and Anti-Metastasis.

Using a combined top-down (i.e., operator-directed) and bottom-up (i.e., cell-directed) strategy, an Under-oil Open Microfluidic System (UOMS)-based microtumor model is presented for investigating tumor cell migration and anti-metastasis drug test. Compared to the mainstream closed microfluidics-based microtumor models, the UOMS microtumor model features: i) micrometer-scale lateral resolution of surface patterning with open microfluidic design for flexible spatiotemporal sample manipulation (i.e., top-down); ii) self-organized extracellular matrix (ECM) structures and tumor cell-ECM spontaneous remodeling (i.e., bottom-up); and iii) free physical access to the samples on a device with minimized system disturbance. The UOMS microtumor model - allowing a controlled but also self-organized, cell-directed tumor-ECM microenvironment in an open microfluidic configuration - is used to test an anti-metastasis drug (incyclinide, aka CMT-3) with a triple-negative breast cancer cell line (MDA-MB-231). The in vitro results show a suppression of tumor cell migration and ECM remodeling echoing the in vivo mice metastasis results.

Can we diagnose noninvasive follicular thyroid neoplasm with papillary-like nuclear features before surgery?

Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) can be differentiated from invasive encapsulated follicular variant of papillary thyroid carcinoma (eFV-PTC) by the presence of a tumor capsule or blood vessel invasion in histological examination. The objective of this study was to investigate whether it is possible to distinguish between NIFTP and invasive eFV-PTC before surgery. Patients diagnosed with NIFTP and invasive eFV-PTC from 2017 to 2023 were analyzed for biochemical, ultrasonographic, and cytological features. No differences were found in thyroid function tests, thyroid autoantibody levels, tumor size, or ultrasonographic characteristics. However, patients with invasive eFV-PTC had higher preoperative neutrophil-to-lymphocyte ratio (NLR) values and a higher Bethesda cytology category compared to those with NIFTP. In the multivariable analysis, NLR was the only significant predictor of invasive eFV-PTC. Nevertheless, there was no reliable NLR cutoff for distinguishing between the two entities. Overall, this study substantiates considerable overlap in demographic and clinical data between NIFTP and invasive eFV-PTC. Although the higher NLR observed in thyroid cancer does not provide strong discrimination, it suggests that the invasive nature of tumor cells might elicit a more profound systemic inflammatory or immune response.

Impact of HIF-1α, LOX and ITGA5 Synergistic Interaction in the Tumor Microenvironment on Colorectal Cancer Prognosis

Background: As colorectal cancers are histopathologically and molecularly highly heterogeneous tumors, it is necessary to consider the tumor’s microenvironment as well as its cellular characteristics in order to determine the biological behavior of the tumor. This study included 100 patients who underwent resection for colorectal cancer. We aimed to investigate the relationships between the expression status of the HIF-1α, LOX and ITGA5 proteins and clinicopathologic parameters. Methods: HIF-1α, LOX and ITGA5 antibodies were applied immunohistochemically to tissue microarrays prepared from tumor samples. Expression status in the tumor microenvironment were evaluated using a combined scoring system based on staining intensity and the percentage of positively stained cells. Nuclear HIF-1α expression in tumor cells was quantified, with >1% considered positive. The staining of HIF-1α, ITGA5 and LOX was analyzed in relation to prognostic and molecular features. Results: The staining of HIF-1α, ITGA5 and LOX in the tumor microenvironment demonstrated a positive correlation with one another and with HIF-1α and LOX expression in tumor cells. In patients with KRAS, NRAS or BRAF mutation and the moderate to strong expression of all three of these proteins in the tumor microenvironment, the number of metastatic lymph nodes was higher than in other patients. Stage IV patients with the moderate to strong expression of HIF-1α, ITGA5 or LOX in the microenvironment had lower progression-free survival than those with weak expression (p < 0.05). In addition, female gender; moderate to strong HIF-1α, LOX and ITGA5 stromal expression; and metastatic first line chemotherapy only were found to be independently associated with an increased risk of progression. Conclusion: These markers may be useful in predicting treatment responses and may also guide the development of alternative or combined treatments that specifically target molecules such as HIF and LOX. Our study should be supported by more comprehensive studies addressing the tumor stroma and its prognostic importance.

Ferroptosis Inducers Erastin and RSL3 Enhance Adriamycin and Topotecan Sensitivity in ABCB1/ABCG2-Expressing Tumor Cells

Acquired resistance to chemotherapeutic drugs is the primary cause of treatment failure in the clinic. While multiple factors contribute to this resistance, increased expression of ABC transporters—such as P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance proteins—play significant roles in the development of resistance to various chemotherapeutics. We found that Erastin, a ferroptosis inducer, was significantly cytotoxic to NCI/ADR-RES, a P-gp-expressing human ovarian cancer cell line. Here, we examined the effects of both Erastin and RSL3 (Ras-Selected Ligand 3) on reversing Adriamycin resistance in these cell lines. Our results show that Erastin significantly enhanced Adriamycin uptake in NCI/ADR-RES cells without affecting sensitive cells. Furthermore, we observed that Erastin enhanced Adriamycin cytotoxicity in a time-dependent manner. The selective iNOS inhibitor, 1400W, reduced both uptake and cytotoxicity of Adriamycin in P-gp-expressing NCI/ADR-RES cells only. These findings were also confirmed in a BCRP-expressing human breast cancer cell line (MCF-7/MXR), which was selected for resistance to Mitoxantrone. Both Erastin and RSL3 were found to be cytotoxic to MCF-7/MXR cells. Erastin significantly enhanced the uptake of Hoechst dye, a well-characterized BCRP substrate, sensitizing MCF-7/MXR cells to Topotecan. The effect of Erastin was inhibited by 1400W, indicating that iNOS is involved in Erastin-mediated enhancement of Topotecan cytotoxicity. RSL3 also significantly increased Topotecan cytotoxicity. Our findings—demonstrating increased cytotoxicity of Adriamycin and Topotecan in P-gp- and BCRP-expressing cells—suggest that ferroptosis inducers may be highly valuable in combination with other chemotherapeutics to manage patients’ cancer burden in the clinical setting.

Spatial Distribution of Tumor Cells in Clear Cell Renal Cell Carcinoma Is Associated with Metastasis and a Matrisome Gene Expression Signature

Background/Objectives: Predicting the behavior of clear cell renal cell carcinoma (ccRCC) is challenging using standard-of-care histopathologic examination. Indeed, pathologic RCC tumor grading, based on nuclear morphology, performs poorly in predicting outcomes of patients with International Society of Urological Pathology/World Health Organization grade 2 and 3 tumors, which account for most ccRCCs. Methods: We applied spatial point process modeling of H&E-stained images of patients with grade 2 and grade 3 ccRCCs (n = 72) to find optimum separation into two groups. Results: One group was associated with greater spatial randomness and clinical metastasis (p < 0.01). Notably, spatial analysis outperformed standard pathologic grading in predicting clinical metastasis. Moreover, cell-to-cell interaction distances in the metastasis-associated group were significantly greater than those in the other patient group and were also greater than expected by the random distribution of cells. Differential gene expression between the two spatially defined groups of patients revealed a matrisome signature, consistent with the extracellular matrix’s crucial role in tumor invasion. The top differentially expressed genes (with a fold change > 3) stratified a larger, multi-institutional cohort of 352 ccRCC patients from The Cancer Genome Atlas into groups with significant differences in survival and TNM disease stage. Conclusions: Our results suggest that the spatial distribution of ccRCC tumor cells can be extracted from H&E-stained images and that it is associated with metastasis and with extracellular matrix genes that are presumably driving these tumors’ aggressive behavior.

Tumor-infiltrating plasma cells are a prognostic factor in penile squamous cell carcinoma.

Penile cancer (PeCa) is a rare disease with poor prognosis in the metastatic stage. Neither effective adjuvant nor palliative therapeutic options are available. Research efforts in this field have so far failed to establish robust predictors of survival. To identify prognostic targets in PeCa, the current project focused on characterizing the tumor microenvironment (TME). A study cohort of 93 men with PeCa was used for the construction of a tissue microarray and immunohistochemical staining for CD3, CD4, CD8, CD20, CD56, CD138, FoxP3, and PD-L1. The quantity and spatial distribution of tumor-infiltrating immune cells were analyzed using digital image analysis. PD-L1 staining of tumor and immune cells was manually scored (combined positivity score (CPS)). T cells, T helper cells, cytotoxic T cells (CTLs), and regulatory T cells were detected in > 90% of PeCa and B cells in 88%, plasma cells in 85%, and NK cells in 23%. Approximately 50% of the PeCa samples were PD-L1 positive. In the univariate survival analysis, high PD-L1 CPS, plasma cells, CTLs, and B cells were significantly associated with favorable overall survival (OS), and the latter two with adverse recurrence-free survival. In multivariate analysis, plasma cells remained a significant factor for favorable OS (p = 0.04). In this study, the immune cells in the TME, especially plasma cells, were favorably associated with patient survival compared to other established prognostic factors in PeCa. Contemporarily, plasma cells have been discussed in the light of contributing to responses to modern immunotherapies. The results of this study support this notion.

Integrated bioinformatics and experimental analysis of CHAF1B as a novel biomarker and immunotherapy target in LUAD

The prognosis and treatment efficacy of lung adenocarcinoma (LUAD), a disease with a high incidence, remains unsatisfactory. Identifying new biomarkers and therapeutic targets for LUAD is essential. Chromosomal assembly factor 1B (CHAF1B), a p60 component of the CAF-1 complex, is closely linked to tumor incidence and cell proliferation. However, CHAF1B's biological role and molecular mechanism in LUAD remain unclear. Here, CHAF1B expression in LUAD was examined using the GEPIA2 and UALCAN databases. Using The Cancer Genome Atlas (TCGA) LUAD database, we analyzed the diagnostic and prognostic significance of CHAF1B and its association with immune infiltration and immunological checkpoints. Gene ontology (GO) enrichment and single-cell function analyses were employed to investigate CHAF1B's possible biological roles. Drug sensitivity analysis predicted CHAF1B's effect on chemotherapeutic drug sensitivity. We also predicted lncRNAs-miRNA-CHAF1B axis to explore the molecular mechanism of CHAF1B in LUAD. Preliminary in vitro studies using qRT-PCR, CCK8, Transwell, glucose, and lactate metabolism confirmed CHAF1B's expression and role in LUAD. Its expression is associated with drug sensitivity, immunological checkpoints, and immune cell infiltration. We predicted that three miRNAs (miR-29c-3p, miR-145-5p, miR-1247-5p) and three lncRNAs (AL139287.1, NEAT1, SHG1) may be target miRNAs and target lncRNAs that regulate CHAF1B. In vitro tests showed that CHAF1B suppression decreased LUAD's migration, invasion, proliferation, and glycolysis. Overall, CHAF1B may be an innovative biomarker and therapeutic target for LUAD.

Dynamic Multilevel Regulation of EGFR, KRAS, and MYC Oncogenes: Driving Cancer Cell Proliferation Through (Epi)Genetic and Post-Transcriptional/Translational Pathways

The epidermal growth factor receptor (EGFR) regulates gene expression through two primary mechanisms: as a growth factor in the nucleus, where it translocates upon binding its ligand, or via its intrinsic tyrosine kinase activity in the cytosol, where it modulates key signaling pathways such as RAS/MYC, PI3K, PLCγ, and STAT3. During tumorigenesis, these pathways become deregulated, leading to uncontrolled proliferation, enhanced migratory and metastatic capabilities, evasion of programmed cell death, and resistance to chemotherapy or radiotherapy. The RAS and MYC oncogenes are pivotal in tumorigenesis, driving processes such as resistance to apoptosis, replicative immortality, cellular invasion and metastasis, and metabolic reprogramming. These oncogenes are subject to regulation by a range of epigenetic and post-transcriptional modifications. This review focuses on the deregulation of EGFR, RAS, and MYC expression caused by (epi)genetic alterations and post-translational modifications. It also explores the therapeutic potential of targeting these regulatory proteins, emphasizing the importance of phenotyping neoplastic tissues to inform the treatment of cancer.

Aberrant E-cadherin Expression in Lobular Carcinoma In Situ: A Comprehensive Immunohistochemical Evaluation of N-terminal, Extracellular, and C-terminal E-cadherin Domains.

E-cadherin (E-cad) immunohistochemistry is commonly used to distinguish lobular carcinoma in situ (LCIS) from ductal carcinoma in situ in histologically uncertain or ambiguous cases. Although most LCIS cases show an absence of E-cad expression on the neoplastic cell membranes, some show aberrant E-cad expression which can lead to diagnostic confusion. Awareness and understanding of the frequency, patterns, and distribution of aberrant E-cad staining in LCIS is crucial to achieving a correct diagnosis. We studied 55 LCIS cases diagnosed on core needle biopsy, classified each case by WHO subtype (classic, pleomorphic, or florid), and evaluated the frequency and patterns of aberrant E-cad expression using 3 different E-cad antibodies targeting the N-terminal (N), extracellular (EC), and C-terminal domains (C). Aberrant E-cad expression in one or more of the E-cad domains was identified in 17 cases (31%) and was significantly more frequent among LCIS variants (10/19, 56%) than among classic cases (7/36, 19.4%) (P=0.02). Among these 17 cases, aberrant E-cad expression was seen for all 3 domains in 10 cases, for EC+C in 4, for EC+N in 2, and for N only in 1. These results indicate that about one-third of cases of LCIS can show aberrant E-cad expression, that this is more common in variants than classic types of LCIS, and that this may be seen in different E-cad domains, most often in combination. These different patterns of aberrant E-cad expression may reflect different mechanisms of E-cad alterations in LCIS, the underlying nature of which merits further studies.

Targeting glycolysis: exploring a new frontier in glioblastoma therapy

Glioblastoma(GBM) is a highly malignant primary central nervous system tumor that poses a significant threat to patient survival due to its treatment resistance and rapid recurrence.Current treatment options, including maximal safe surgical resection, radiotherapy, and temozolomide (TMZ) chemotherapy, have limited efficacy.In recent years, the role of glycolytic metabolic reprogramming in GBM has garnered increasing attention. This review delves into the pivotal role of glycolytic metabolic reprogramming in GBM, with a particular focus on the multifaceted roles of lactate, a key metabolic product, within the tumor microenvironment (TME). Lactate has been implicated in promoting tumor cell proliferation, invasion, and immune evasion. Additionally, this review systematically analyzes potential therapeutic strategies targeting key molecules within the glycolytic pathway, such as Glucose Transporters (GLUTs), Monocarboxylate Transporters(MCTs), Hexokinase 2 (HK2), 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 3 (PFKFB3), Pyruvate Kinase Isozyme Type M2 (PKM2), and the Lactate Dehydrogenase A (LDHA). These studies provide a novel perspective for GBM treatment. Despite progress made in existing research, challenges remain, including drug penetration across the blood-brain barrier, side effects, and resistance. Future research will aim to address these challenges by improving drug delivery, minimizing side effects, and exploring combination therapies with radiotherapy, chemotherapy, and immunotherapy to develop more precise and effective personalized treatment strategies for GBM.

Comparative Single-Cell Transcriptomics of Human Neuroblastoma and Preclinical Models Reveals Conservation of an Adrenergic Cell State.

Transgenic mice and organoid models, such as three-dimensional tumoroid cultures, have emerged as powerful tools for investigating cancer development and targeted therapies. Yet, the extent to which these preclinical models recapitulate the cellular identity of heterogeneous malignancies, like neuroblastoma (NB), remains to be validated. Here, we characterized the transcriptional landscape of TH-MYCN tumors by single-cell RNA sequencing (scRNA-seq) and developed ex vivo tumoroids. Integrated analysis with murine fetal adrenal samples confirmed that both TH-MYCN tumors and tumoroids closely mirror the cellular profiles of normal embryonic sympathoblasts and chromaffin cells. Comprehensive comparison between tumors from NB patients and TH-MYCN mice demonstrated similarities in adrenergic tumor cell composition. Ex vivo tumoroid cultures displayed histological resemblance and shared transcriptional profiles with the originating TH-MYCN tumors and human NB. Importantly, subpopulations within tumoroids exhibited gene expression associated with poor NB patient survival. Notably, recurrent observations of a low-proliferative chromaffin phenotype connected to the highly proliferative sympathetic phenotype suggested that pushing sympathoblasts into a chromaffin-like state may offer an interesting therapeutic strategy for NB. Together, this study not only deepens our understanding of a widely used transgenic mouse NB model but also introduces an ex vivo model that maintains critical adrenergic cell state identity, thereby enhancing its translational potential for NB research.

Reconstruction of Local Three-dimensional Temperature Field of Tumor Cells with Low-toxic Nanoscale Quantum-dot Thermometer and Cepstrum Spatial Localization Algorithm.

The optimal method for three-dimensional thermal imaging within cells involves collecting intracellular temperature responses while simultaneously obtaining corresponding 3D positional information. Current temperature measurement techniques based on the photothermal properties of quantum dots face several limitations, including high cytotoxicity and low fluorescence quantum yields. These issues affect the normal metabolic processes of tumor cells. This study synthesizes a low-toxicity cell membrane-targeted quantum dot temperature sensor by optimizing the synthesis method of CdTe/CdS/ZnS core-shell structured quantum dots. Compared to CdTe-targeted quantum dot temperature sensors, the cytotoxicity of CdTe/CdS/ZnS-targeted quantum dot temperature sensors is reduced by 40.79%. Additionally, a novel cepstrum-based spatial localization algorithm is proposed to achieve rapidly compute the three-dimensional positions of densely distributed quantum dot temperature sensors. Ultimately, both targeted and non-targeted CdTe/CdS/ZnS quantum dot temperature sensors were used simultaneously to label the internal and external regions of human osteosarcoma cells to obtain temperature data at these labeling positions. By combining this with the cepstrum-based spatial localization algorithm, the spatial coordinates of the quantum dot temperature sensors were obtained. Three-dimensional temperature field reconstruction of three local regions was achieved within a 12 μm axial range in living cells. The method described in this paper can be widely applied to the quantitative study of intracellular thermal responses.