Affect Tumor Progression Research Articles

Single-cell RNA sequencing revealed PPARG promoted osteosarcoma progression: based on osteoclast proliferation

BackgroundOsteosarcoma (OS) is one of the most common primary malignant bone tumors, primarily originating from mesenchymal tissue. It is notorious for its high invasiveness, high disability rate, high mortality rate, and poor prognosis. In most primary and metastatic malignant tumors, bone destruction can promote cancer progression, which is closely related to osteoclast activation and the imbalance between osteoblasts and osteoclasts. A large number of studies confirmed that osteoclasts are an important part of OS, which play an active role in destroying bone homeostasis and promoting the progress of OS. Therefore, we conducted a detailed study of osteoclasts at the single cell level, aiming to find new OS therapeutic targets to prevent tumor progression and local spread.MethodsWe analyzed the single-cell sequencing data of OS patients and usedMonocle2, Cytotrace, and Slingshot software to analyze the pseudo-sequential trajectory during OS progression. CellChat was used to reveal the communication between cells. PySCENIC was used to identify active transcription factors in osteoclasts. Finally, we further demonstrated the results by RT-qPCR analysis, CCK-8 assay, wound healing assay, Transwell assay, etc.ResultsThrough the analysis of single-cell sequencing data in OS, we identified a highly specific subgroup, C2MKI67+ Osteoclast. The key signaling pathway APP and the top 1 transcription factor PPARG in this subgroup played essential roles in osteoclast proliferation and differentiation. Given the pivotal role of osteoclasts in OS progression, we speculated that these signaling pathways and transcription factors could emerge as novel therapeutic targets, offering innovative strategies for OS treatment.ConclusionThis study enhanced our understanding of OS and osteoclasts through scRNA-seq. Furthermore, we discovered that PPARG amplifies osteoclast activation and proliferation, resulting in excessive bone resorption and degradation of the bone matrix, thereby creating a favorable environment for tumor cell proliferation and growth. By innovatively targeting PPARG, it affected osteoclast proliferation and thus affected tumor progression; this work offered new insights and directions for the clinical treatment of OS patients.

UBE2J1 is identified as a novel plasma cell-related gene involved in the prognosis of high-grade serous ovarian cancer

BackgroundImmune cells within tumor tissues play important roles in remodeling the tumor microenvironment, thus affecting tumor progression and the therapeutic response. The current study was designed to identify key markers of plasma cells and explore their role in high-grade serous ovarian cancer (HGSOC).MethodsWe utilized single-cell sequencing data from the Gene Expression Omnibus (GEO) database to identify key immune cell types within HGSOC tissues and to extract related markers via the Seurat package. The effects of immune cell markers on prognosis were analyzed via univariate Cox regression, least absolute shrinkage and selection operator (LASSO) and gene set variation analysis (GSVA) of bulk sequencing data from The Cancer Genome Atlas (TCGA)-HGSOC cohort. Finally, the effects of key markers on HGSOC cells were evaluated via Cell Counting Kit-8 (CCK-8), Transwell, colony formation, wound healing, immunofluorescence and in vivo tumor growth assays.ResultsAt the single-cell level, we detected a significant increase in the proportion of plasma cells in HGSOC samples compared to that in normal ovarian samples. Within HGSOC tissues, these plasma cells were found to interact with CD8 + T cells, fibroblasts and endothelial cells. In addition, patients in the high-plasma cell-related score group had better survival rates and higher epithelial‒mesenchymal transition (EMT), apoptosis and immune scores. Moreover, univariate Cox and LASSO regression analyses revealed that ubiquitin-conjugating enzyme E2 J1 (UBE2J1) is a prognostic marker in HGSOC. Further functional studies revealed that overexpression of UBE2J1 promoted cell proliferation, invasion, migration and colony formation, whereas UBE2J1 knockdown attenuated the abovementioned cellular behaviors. Additionally, UBE2J1 overexpression promoted EMT, as evidenced by alterations in the protein expression levels of N-cadherin, snail family transcriptional repressor 2 (Slug), Twist family BHLH transcription factor 1 (Twist 1) and E-cadherin. Moreover, we found that UBE2J1 silencing was able to inhibit the tumor growth in vivo.ConclusionsOverall, this study elucidated the role of plasma cells and revealed UBE2J1 as a novel oncogene in HGSOC, uncovering new mechanisms related to HGSOC tumorigenesis and promising therapeutic targets for HGSOC patients.

Fibroblast activation protein peptide-targeted NIR-I/II fluorescence imaging for stable and functional detection of hepatocellular carcinoma.

Cancer-associated fibroblasts (CAFs) are the primary stromal component of the tumor microenvironment in hepatocellular carcinoma (HCC), affecting tumor progression and post-resection recurrence. Fibroblast activation protein (FAP) is a key biomarker of CAFs. However, there is limited evidence on using FAP as a target in near-infrared (NIR) fluorescence imaging for HCC. Thus, this study aims to develop a novel NIR fluorescent imaging strategy targeting FAP+ CAFs in HCC. The ICG-FAP-TATA probe was synthesized by conjugating a novel cyclization anti-FAP peptide with an indocyanine green derivative (ICG-NH2) as fluorophore, capable for NIR window I (NIR-I, 700-900nm) and II (NIR-II, 1000-1700nm) imaging. Its efficacy in lesion localization and other potential applications was evaluated. In vivo imaging of subcutaneous HCC models revealed that ICG-FAP-TATA specifically targeted FAP+ CAFs in the stroma and detected differences in CAFs loading within lesions. The fluorescence intensity/tumor-to-background ratio (TBR) positively correlated with FAP expression (R2 > 0.8, p < 0.05). Ex vivo incubation of tumor tissues with ICG-FAP-TATA provided stable fluorescence imaging of tumors in subcutaneous and orthotopic HCC models, including different cell line co-culture systems (LM3-luc, MHCC97H-luc, HepG2-luc + LX2), and various liver backgrounds (healthy/fibrotic) (n = 5 per group). TBR of the tumor mice models was higher for NIR-II than NIR-I imaging (3.89 ± 1.27 vs. 2.64 ± 0.64, p < 0.05). Moreover, NIR-I/II imaging of fresh tissues from seven patients with HCC undergoing surgery incubated with ICG-FAP-TATA visually provided the spatial distribution heterogeneity of CAFs. The targeted fluorescence was relatively enriched more in the blood flow direction and at the tumor edge, both of which were associated with tumor metastasis (all p < 0.05). This study presents a rapid and effective method for detecting HCC lesions, locating FAP+ CAFs, and visualizing high-risk areas for tumor metastasis at the macroscopic level. It offers a new promising approach with translational potential for imaging HCC.

Overexpression of CHMP2B suppresses proliferation of renal clear cell carcinoma cells.

To analyze the association of CHMP2B expression level of with clinicopathological characteristics and prognosis of clear cell renal cell carcinoma (CRCC) and the possible role of CHMP2B in tumorigenesis and progression of CRCC. RNAseq data of CRCC were downloaded from the TCGA database for analysis of CHMP2B expression levels in tumor and adjacent tissues and their correlation with clinicopathological characteristics of the patients. Survival outcomes of the patients with high and low CHMP2B expressions were analyzed using the Kaplan-Meier model, and the COX risk regression model was used for identifying the prognostic factors of the patients. The correlation between CHMP2B expression and immune infiltration, its co-expressed genes, and the effect of CHMP2B gene mutations on immunotherapy responses, and its immunohistochemical expression in CRCC and normal tissues were analyzed. Clinical samples of CRCC were collected to examine CHMP2B expressions using RT-PCR, and cell experiment was carried out to test the effect of CHMP2B overexpression on biological behaviors of CRCC cells. CHMP2B was significantly under-expressed in renal cancer tissues, and its overexpression obviously inhibited the proliferation of CRCC cells in vitro. CHMP2B expression level was significantly correlated with age, gender, lymph node metastasis, and tumor stage, and the patients with low CHMP2B expression had poor survival outcomes. Enrichment and co-expression gene analyses suggested that CHMP2B was mainly involved in viral outgrowth, necrotic apoptosis, endocytosis, and immune-regulatory processes in kidney cancer. CHMP2B is lowly expressed in renal cancer tissues to affect tumor progression and tumor immune processes, and may serve as a prognostic biomarker and therapeutic target for CRCC.

Epigenetic regulation of HOXA2 expression affects tumor progression and predicts breast cancer patient survival.

Accumulating evidence suggests that genetic and epigenetic biomarkers hold potential for enhancing the early detection and monitoring of breast cancer (BC). Epigenetic alterations of the Homeobox A2 (HOXA2) gene have recently garnered significant attention in the clinical management of various malignancies. However, the precise role of HOXA2 in breast tumorigenesis has remained elusive. To address this point, we conducted high-throughput RNA sequencing and DNA methylation array studies on laser-microdissected human BC samples, paired with normal tissue samples. Additionally, we performed comprehensive in silico analyses using large public datasets: TCGA and METABRIC. The diagnostic performance of HOXA2 was calculated by means of receiver operator characteristic curves. Its prognostic significance was assessed through immunohistochemical studies and Kaplan-Meier Plotter database interrogation. Moreover, we explored the function of HOXA2 and its role in breast carcinogenesis through in silico, in vitro, and in vivo investigations. Our work revealed significant hypermethylation and downregulation of HOXA2 in human BC tissues. Low HOXA2 expression correlated with increased BC aggressiveness and unfavorable patient survival outcomes. Suppression of HOXA2 expression significantly heightened cell proliferation, migration, and invasion in BC cells, and promoted tumor growth in mice. Conversely, transgenic HOXA2 overexpression suppressed these cellular processes and promoted apoptosis of cancer cells. Interestingly, a strategy of pharmacological demethylation successfully restored HOXA2 expression in malignant cells, reducing their neoplastic characteristics. Bioinformatics analyses, corroborated by in vitro experimentations, unveiled a novel implication of HOXA2 in the lipid metabolism of BC. Specifically, depletion of HOXA2 leaded to a concomitantly decreased expression of PPARγ and its target CIDEC, a master regulator of lipid droplet (LD) accumulation, thereby resulting in reduced LD abundance in BC cells. In summary, our study identifies HOXA2 as a novel prognosis-relevant tumor suppressor in the mammary gland.

Genetic variants of FER and SULF1 in the fibroblast-related genes are associated with non-small-cell lung cancer survival.

Fibroblasts are important components in the tumor microenvironment and can affect tumor progression and metastasis. However, the roles of genetic variants of the fibroblast-related genes (FRGs) in the prognosis of non-small-cell lung cancer (NSCLC) patients have not been reported. Therefore, we investigated the associations between 26,544 single nucleotide polymorphisms (SNPs) in 291 FRGs and survival of NSCLC patients from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. In Cox regression multivariable analysis, we found that 661 SNPs were associated with NSCLC overall survival (OS). Then we validated these SNPs in another independent replication dataset of 984 patients from the Harvard Lung Cancer Susceptibility (HLCS) Study. Finally, we identified two independent SNPs (i.e., FER rs7716388 A>G and SULF1 rs11785839 G>C) that remained significantly associated with NSCLC survival with hazards ratios (HRs) of 0.87 (95% confidence interval [CI] = 0.77-0.98, p = 0.018) and 0.88 (95% CI = 0.79-0.99, p = 0.033), respectively. Combined analysis for these two SNPs showed that the number of protective alleles was associated with better OS and disease-specific survival. Expression quantitative trait loci analysis indicated that the FER rs7716388 G allele was associated with the up-regulation of FER mRNA expression levels in lung tissue. Our results indicated that these two functional SNPs in the FRGs may be prognostic biomarkers for the prognosis of NSCLC patients, and the possible mechanism may be through modulating the expression of their corresponding genes.

Knockdown of Methylation-Related Gene MBD2 Blocks Cell Growth by Upregulating p21 Expression in Head and Neck Squamous Cell Carcinoma.

Methyl-CpG-binding domain 2 (MBD2) attaches to methylated DNA, which mediates methylated gene transcription, leading to gene silencing and affecting tumor progression. The molecular mechanisms of MBD2 in head and neck squamous cell carcinoma (HNSCC) remain insufficiently characterized. This study sought to assess the clinical relevance of MBD2 expression in HNSCC, with a particular focus on elucidating its functional role in tumor progression and its regulatory influence on p21 expression and cellular proliferation. We analyzed the relationships between MBD2 expression, clinicopathological features, and survival outcomes in HNSCC patients using data from the UALCAN, TCGA, and cBioPortal databases. The functional role of MBD2 in HNSCC was further investigated through invitro experiments. p21 expression was assessed using western blotting and qRT-PCR in TU212 and AMC-HN8 cells. These cells were treated with either shRNA targeting MBD2, 5-azacytidine (5-Aza), or a combination of shRNA MBD2 and 5-Aza. Additionally, cell proliferation and viability were measured in each treatment group. MBD2 was found to be frequently overexpressed in HNSCC tissues, and its altered expression was significantly associated with reduced overall survival (OS) and disease-free survival (DFS). Both shRNA-mediated MBD2 knockdown and 5-Aza treatment increased p21 expression in HNSCC cells, exhibiting similar functions with additive effects. Furthermore, both treatments significantly inhibited cell proliferation and viability. These results indicated that shRNA-mediated MBD2 knockdown suppresses HNSCC cell growth by upregulating p21 expression. In addition to its role as an oncogene, MBD2 may serve as a prognostic biomarker and therapeutic target for HNSCC patients.

Morphoregulatory ADD3 underlies glioblastoma growth and formation of tumor-tumor connections.

Glioblastoma is a major unmet clinical need characterized by striking inter- and intra-tumoral heterogeneity and a population of glioblastoma stem cells (GSCs), conferring aggressiveness and therapy resistance. GSCs communicate through a network of tumor-tumor connections (TTCs), including nanotubes and microtubes, promoting tumor progression. However, very little is known about the mechanisms underlying TTC formation and overall GSC morphology. As GSCs closely resemble neural progenitor cells during neurodevelopment, we hypothesized that GSCs' morphological features affect tumor progression. We identified GSC morphology as a new layer of tumoral heterogeneity with important consequences on GSC proliferation. Strikingly, we showed that the neurodevelopmental morphoregulator ADD3 is sufficient and necessary for maintaining proper GSC morphology, TTC abundance, cell cycle progression, and chemoresistance, as well as required for cell survival. Remarkably, both the effects on cell morphology and proliferation depend on the stability of actin cytoskeleton. Hence, cell morphology and its regulators play a key role in tumor progression by mediating cell-cell communication. We thus propose that GSC morphological heterogeneity holds the potential to identify new therapeutic targets and diagnostic markers.

IMMU-15. CD74/MIF SIGNALING AXIS DISRUPTION IN BONE MARROW-DERIVED MYELOID CELLS DELAYS MALIGNANT PROGRESSION IN A PRECLINICAL MODEL OF GLIOMA

Abstract INTRODUCTION CD74, a chaperone associated with the major histocompatibility complex class II (MHC-II), plays a crucial role in assembling and transporting MHC-II molecules on the cellular surface. Beyond its physiological function in antigen presentation, CD74 is a negative regulator of inflammation, and its dysregulation is associated with inflammatory disorders and cancer. Notably, tumor stem cells release macrophage migration inhibitory factor (MIF) to trigger CD74 immunosuppressive signaling in tumor-infiltrating immune cells, thereby abrogating CD8+ T cell activation and promoting angiogenesis. While CD74 expression is known in dendritic cells, macrophages and B cells, our recent findings reveal its upregulation in immunosuppressive macrophages within the low-grade glioma (LGG) tumor microenvironment, and its negative correlation with the survival of adolescent and young adult patients with LGG. HYPOTHESIS. We hypothesize that inhibiting CD74/MIF in immunosuppressive myeloid cells may affect tumor progression and prevent malignant transformation (MT) to high-grade glioma (HGG). METHODS To test our hypothesis, we isolated bone marrow cells from immunocompetent RCAS n/tv-a LGG bearing animals, differentiated them into bone marrow-derived myeloid cells (BMDMs), silenced CD74 expression, and co-cultured them with primary CD8+T cells. Moreover, we inhibited CD74/MIF signaling in vivo. RESULTS. Deconvolution analysis of tumor-infiltrating immune cells revealed upregulation of CD74 and its network in myeloid cells during LGG compared to HGG. Silencing CD74 in LGG BMDMs in vitro resulted in the downregulation of genes associated with migration, proliferation, and immunosuppression. The co-culture of LGG CD74KD-BMDMs with CD8+ T cells increased the expression of T cell activation genes. In vivo treatment of LGG mice with MIF inhibitors significantly decreased myeloid cell infiltration in the tumor microenvironment (TME) and prolonged survival. CONCLUSIONS These preclinical studies highlight a role for the CD74/MIF signaling axis in glioma and present a novel immunotherapeutic target to modulate the activity of immunosuppressive myeloid cells in order to delay MT.

Extracellular vesicle-packaged miR-4253 secreted by cancer-associated fibroblasts facilitates cell proliferation in gastric cancer by inducing macrophage M2 polarization

ABSTRACT Cancer-associated fibroblasts (CAFs) can interact with macrophages in the tumor microenvironment by secreting extracellular vesicles (EVs), thereby affecting tumor progression. However, the mechanisms of CAF-secreted EVs in gastric cancer (GC) remain not well understood. Here, we investigated the effect of CAF-EVs on macrophage polarization in GC and the underlying mechanisms. Macrophage polarization was evaluated using flow cytometry and quantitative real-time polymerase chain reaction. GC cell proliferation was determined using cell counting kit-8, EdU, and colony formation assays. The molecular mechanism was explored using microarray analysis, dual-luciferase reporter assay, and RNA pull-down analysis. The results showed that CAFs secreted EVs that inhibit macrophage M1 polarization and promote M2 polarization. Moreover, miR-4253 expression was increased in CAF-EVs, and inhibition of miR-4253 reversed the macrophage polarization induced by EVs. IL6R was identified as the target of miR-4253. Additionally, macrophages treated with EVs that encapsulated miR-4253 promote GC cell proliferation. In conclusion, CAF-secreted EVs packaging miR-4253 facilitate macrophage polarization from M1 to M2 phenotype by targeting IL6R, thereby accelerating GC cell proliferation. The findings suggest that EV-encapsulated miR-4253 may be a promising therapeutic target of GC.

FBXO2 as a switch guides a special fate of tumor clones evolving into a highly malignant transcriptional subtype in oral squamous cell carcinoma.

Tumors comprise a heterogeneous collection of tumor cells with distinct genetic and phenotypic characteristics that differentially promote malignant progression. Therefore, it is essential to depict the heterogeneous landscape of clones for understanding the cancer biology and overcoming the resistance of cancer therapy. To determine the dynamic clonal feature of OSCC, we constructed the evolutionary trajectory of tumor cells based on single-cell RNA sequencing data. A special transcriptional states of clones with distinct highly malignant features was identified, and FBXO2 was determined as the key switch gene causing the transition of tumor cells into this special state. FBXO2 exhibited a significantly high expression in OSCC than normal samples, especially in those with high clinical stages. The knockdown or overexpression of FBXO2 in OSCC cells correspondingly inhibited or promoted the abilities of proliferation, G1-S phase transition, migration, invasion, EMT, and resisting apoptosis. Moreover, FBXO2 was indicated to be involved in an intricate network to regulate multiple processes, modifying the interactions between tumor cells and other cells and thus defining different functional subtypes of tumor cells to affect tumor progression. These results provide new insights into clonal fate and pave the way for more effective therapy of OSCC.

Biglycan promotes tumour proliferation and invasion in human colon cancers.

To investigate the role of biglycan (BGN) in colon cancer progression. The association between BGN mRNA levels and the survival time of patients with colon cancer was analysed by referencing data from the Gene Expression Omnibus and The Cancer Genome Atlas (TCGA). Gene Set Enrichment Analysis (GSEA) was conducted to explore gene sets and pathways associated with BGN. In vitro analyses were undertaken in HCT116 cells to analyse cell proliferation, migration, invasion, cell cycle control and apoptosis. GSEA, Western blot analysis and small interfering RNAs were used to explore the molecular mechanisms of BGN in colon cancer cells. Analysis of the pairs of tissues from colon cancer patients showed that BGN protein levels were higher in colon cancer tissues compared with adjacent non-tumour tissues. High BGN levels were significantly associated with shorter survival times. BGN knockdown inhibited cell proliferation, migration and invasion; and induced cell cycle arrest in the G0/G1 phase and promoted apoptosis in HCT116 cells. GSEA found that BGN might affect tumour progression via the mitogen-activated protein kinase (MAPK) signalling pathway. BGN might promote colon cancer progression via the MAPK signalling pathway and could be a potential target for future novel therapeutic strategies.

Pancancer analysis of NDUFA4L2 with focused role in tumor progression and metastasis of colon adenocarcinoma.

Colon adenocarcinoma (COAD) is a prevalent gastrointestinal malignant disease with a high mortality rate, and identification of novel prognostic biomarkers and therapeutic targets is urgently needed. Although NDUFA4L2 has high expressions in various tumors and affects tumor progression, its role in COAD remains unclear. The role of NDUFA4L2 in COAD was analyzed utilizing datasets available from public databases including The Cancer Genome Atlas, The Genotype-Tissue Expression (GTEx), Gene Expression Omnibus, Alabama Cancer Database (UALCAN), and The Human Protein Atlas databases. The prognostic value of NDUFA4L2 was determined using Kaplan-Meier analysis and Cox regression analysis. To investigate the possible mechanism underlying the role of NDUFA4L2 in COAD, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) were employed. The correlation between NDUFA4L2 expression and immune cell infiltration levels was examined through single-sample gene set enrichment analysis (ssGSEA). The NDUFA4L2 expression levels in COAD patients and cell lines were validated through immunohistochemistry, immunofluorescence, qRT-PCR, and Western blot. Wound healing assay was also performed to evaluate the effect of NDUFA4L2 on COAD metastasis. Furthermore, the NDUFA4L2 mediated competing endogenous RNA (ceRNA) regulatory network was predicted and constructed through a variety of databases. The comprehensive pan-cancer analysis showed that NDUFA4L2 possesses diagnostic and prognostic value in many cancers, especially in COAD. GO-KEGG and GSEA analyses indicated that NDUFA4L2 was associated with multiple biological functions including epithelial-mesenchymal transition and adaptation to hypoxia. The ssGSEA analysis showed that NDUFA4L2 expression was associated with immune infiltration. In vitro experiments confirmed upregulation of NDUFA4L2 in COAD tissues and cell lines, and NDUFA4L2 overexpression significantly promoted migration of COAD cells. In addition, the C9orf139 /miR-194-3p axis was speculated as the possible upstream regulators of NDUFA4L2 in COAD. This study demonstrated that NDUFA4L2 upregulation was correlated with tumor progression, relapsed prognosis and aggressive migration of COAD, suggesting that NDUFA4L2 can act as an effective prognostic biomarker and a promising therapeutic target for COAD treatment.

Invisible Bridges: Unveiling the Role and Prospects of Tunneling Nanotubes in Cancer Therapy.

Tunneling nanotubes (TNTs) are essential intercellular communication channels that significantly impact cancer pathophysiology, affecting tumor progression and resistance. This review methodically examines the mechanisms of TNTs formation, their structural characteristics, and their functional roles in material and signal transmission between cells. Highlighting their regulatory functions within the tumor microenvironment, TNTs are crucial for modulating cell survival, proliferation, drug resistance, and immune evasion. The review critically evaluates the therapeutic potential of TNTs, focusing on their applications in targeted drug delivery and gene therapy. It also proposes future research directions to thoroughly understand TNTs biogenesis, identify cell-specific molecular targets, and develop advanced technologies for the real-time monitoring of TNTs. By integrating insights from molecular biology, nanotechnology, and immunology, this review highlights the transformative potential of TNTs in advancing cancer treatment strategies.

Hyaluronan-Based Hydrogels for 3D Modeling of Tumor Tissues.

Although routine two-dimensional (2D) cell culture techniques have advanced basic cancer research owing to their simplicity, cost-effectiveness, and reproducibility, they have limitations that necessitate the development of advanced three-dimensional (3D) tumor models that better recapitulate the tumor microenvironment. Various biomaterials have been used to establish these 3D models, enabling the study of cancer cell behavior within different matrices. Hyaluronic acid (HA), a key component of the extracellular matrix (ECM) in tumor tissues, has been widely studied and employed in the development of multiple cancer models. This review first examines the role of HA in tumors, including its function as an ECM component and regulator of signaling pathways that affect tumor progression. It then explores HA-based models for various cancers, focusing on HA as a central component of the 3D matrix and its mobilization within the matrix for targeted studies of cell behavior and drug testing. The tumor models discussed included those for breast cancer, glioblastoma, fibrosarcoma, gastric cancer, hepatocellular carcinoma, and melanoma. The review concludes with a discussion of future prospects for developing more robust and high-throughput HA-based models to more accurately mimic the tumor microenvironment and improve drug testing. Impact Statement This review underscores the transformative potential of hyaluronic acid (HA)-based hydrogels in developing advanced tumor models. By exploring HA's dual role as a critical extracellular matrix component and a regulator of cancer cell dynamics, we highlight its unique contributions to replicating the tumor microenvironment. The recent advancements in HA-based models provide new opportunities for more accurate studies of cancer cell behavior and drug responses. Looking ahead, these innovations pave the way for high-throughput, biomimetic platforms that could revolutionize drug testing and accelerate the discovery of effective cancer therapies.

BRCA1/2 Immunohistochemical Analysis in Unicystic Ameloblastoma, Multicystic Ameloblastoma, and Ameloblastic Carcinoma

Background: Lesions arising from odontogenic tissues cover a wide spectrum, from simple cysts to benign tumors and even carcinomas. Unicystic ameloblastoma (UA), multicystic ameloblastoma (MA), and ameloblastic carcinoma (AC) are relatively common among these odontogenic lesions. Nevertheless, the exact origin of these lesions remains unclear. It is noteworthy that BRCA1/2 mutations have been identified as potential contributing factors to the onset of various cancers. The aim of the current study was to scrutinize the BRCA1/2 expression profiles in UA, MA, and AC samples. Methods: Biopsy specimens were collected from 60 patients, with 20 samples representing each lesion, sourced from the pathology department archive of a teaching hospital from 2000 to 2019. Immunohistochemical staining was conducted on all biopsy samples. Statistical analyses were performed using the Kruskal-Wallis H test. The differences in the data were compared with Mann- Whitney U test, and P&lt;0.05 was considered to be significant. Results: The Kruskal-Wallis test results revealed significant differences between the examined samples in terms of the cytoplasmic expression level of the BRCA1 basal cells (P&lt;0.001). Regarding the cytoplasmic expression of BRCA1 stellate reticulum-like cells, there was a statistically significant difference between the examined groups (P&lt;0.001). Furthermore, the results of the Kruskal-Wallis test demonstrated a significant difference concerning the cytoplasmic expression levels of BRCA2 basal cells between the studied groups (P&lt;0.003). Based on the Kruskal-Wallis results, significant differences were found in terms of the cytoplasmic expression level of BRCA2 stellate reticulum-like cells between the investigated samples (P&lt;0.001). The Mann-Whitney U test compared differences between the two examined groups. Conclusion: The findings mainly revealed the expression of BRCA1/2 at the invasive front, which is composed of the most aggressive cells. Molecular interactions in this area may affect tumor progression. BRCA1/2 mutations can be a promising future treatment option for ameloblastoma and related lesions.

Advancements and Challenges in Personalized Therapy for BRAF-Mutant Melanoma: A Comprehensive Review.

Over the past several decades, advancements in the treatment of BRAF-mutant melanoma have led to the development of BRAF inhibitors, BRAF/MEK inhibitor combinations, anti-PD-1 therapy, and anti-CTLA4 therapy. Although these therapies have shown substantial efficacy in clinical trials, their sustained effectiveness is often challenged by the tumor microenvironment, which is a highly heterogeneous and complex milieu of immunosuppressive cells that affect tumor progression. The era of personalized medicine holds substantial promise for the tailoring of treatments to individual genetic profiles. However, tumor heterogeneity and immune evasion mechanisms contribute to the resistance to immunotherapy. Despite these challenges, tumor-infiltrating lymphocyte (TIL) therapy, as exemplified by lifileucel, has demonstrated notable efficacy against BRAF V600-mutant melanoma. Additionally, early response biomarkers, such as COX-2 and MMP2, along with FDG-PET imaging, offer the potential to improve personalized immunotherapy by predicting patient responses and determining the optimal treatment duration. Future efforts should focus on reducing the T-cell harvesting periods and costs associated with TIL therapy to enhance efficiency and accessibility.

Exosome-transmitted circ_0004664 suppresses the migration and invasion of cadmium-transformed human bronchial epithelial cells by regulating PTEN expression via miR-942-5p

Exosomes play a crucial role in regulating extracellular communication between normal and cancer cells within the tumor microenvironment, thereby affecting tumor progression through their cargo molecules. However, the specific impact of exosomal circular RNAs (circRNAs) on the development of cadmium-induced carcinogenesis remains unclear. To address this, we investigated whether exosomes derived from normal human bronchial epithelial BEAS-2B (N–B2B) cells could transmit circRNA to cadmium-transformed BEAS-2B (Cd–B2B) cells and the potential effects on Cd–B2B cells. Our findings demonstrated a significant downregulation of circ_0004664 in Cd–B2B cells compared to N–B2B cells (P < 0.01). Overexpression of circ_0004664 in Cd–B2B cells led to a significant inhibition of cell migration and invasion (P < 0.01 or P < 0.05). Furthermore, N–B2B cells could transfer circ_0004664 into recipient Cd–B2B cells via exosomes, subsequently inhibiting cell migration and invasion (P < 0.05 or P < 0.01). Mechanistic investigations revealed that exosomal circ_0004664 functioned as a competitive endogenous RNA for miR-942-5p, resulting in an upregulation of PTEN (P < 0.05). Our study highlights the involvement of exosomal circ_0004664 in cell-cell communication during cadmium carcinogenesis, providing a novel insight into the role of exosomal circRNA in this process.

Extracellular glypican-1 affects tumor progression and prognosis in esophageal cancer.

Cells are covered with a glycan surface layer that is referred to as the glycocalyx (GCX). It has been reported that the formation of the GCX is promoted on cancer cells and is associated with tumor growth and metastasis. Heparan sulfate proteoglycan glypican-1 (GPC1) is a core protein of the GCX that is overexpressed in esophageal squamous cell carcinoma (ESCC) and is involved in the development and progression of cancer cells. The purpose of the present study is to analyze the utility of GPC1 as a new biomarker ralated to glycocalyx that reflects therapeutic effect and prognosis of ESCC. We measured the concentration of GPC1 protein in preoperative plasma from advanced esophageal cancer patients and examined its relationships with clinicopathological factors and therapeutic efficacy, and the effects of extracellular GPC1 were investigated. The following clinical factors were significantly correlated with the preoperative high GPC1 concentration: male, tumor size ≥30 mm, venous invasion, pT factor ≥2, pStage ≥3, residual tumor, and distant metastatic recurrence. Both overall and recurrence-free survival were significantly worse in the high GPC1 group. Extracellular GPC1 protein concentration reflected intracellular GPC1 expression. Furthermore, we examined the effects of extracellular recombinant human (rh)GPC1 on ESCC cells, and found that extracellular rhGPC1 affects cell motility, including migration and invasion. These results demonstrated the utility of extracellular GPC1 as a biomarker, which can be assayed from a less invasive blood sample-based liquid biopsy. Extracellular GPC1 protein plays a role in both tumor cell motility and cancer progression. Thus, plasma GPC1 is a useful biomarker for esophageal cancer progression and may be a potential candidate of therapeutic target.

Ginsenoside Re inhibits non-small cell lung cancer progression by suppressing macrophage M2 polarization induced by AMPKα1/STING positive feedback loop.

Tumor-associated macrophages (TAMs) in non-small cell lung cancer (NSCLC) promote tumor cell metastasis by interacting with cancer cells. Ginsenoside Re is capable of modulating the host immune system and exerts anticancer effects through multiple pathways. Both AMPK and STING are involved in the regulation of MΦ polarization, thereby affecting tumor progression. However, whether there is a regulatory relationship between them and its effect on MΦ polarization and tumor progression is unclear. The aim of this study was to provide mechanistic evidence that ginsenoside Re modulates MΦ phenotype through inhibition of the AMPKα1/STING positive feedback loop and thus exerts an antimetastatic effect in NSCLC immunotherapy. Cell culture models and conditioned media (CM) systems were constructed, and the treated MΦ were analyzed by database analysis, RT-PCR, Western blotting, flow cytometry, and immunofluorescence to determine the regulatory relationship between AMPK and STING and the effects of ginsenoside Re on MΦ polarization and tumor cells migration. The effects of ginsenoside Re (10, 20 mg/kg/day) on TAMs phenotype as well as tumor progression in mice were assessed by HE staining, immunohistochemical staining, and Western blotting. In this study, AMPKα1/STING positive feedback loop in NSCLC TAMs induced M2 type polarization, which in turn promoted NSCLC cell migration. In addition, ginsenoside Re was discovered to inhibit M2-like MΦ polarization, thereby inhibiting NSCLC cell migration. Mechanistically, Re was able to inhibit the formation of the AMPKα1/STING positive feedback loop, thereby inhibiting its induction of M2-like MΦ and consequently inhibiting the epithelial-mesenchymal transition (EMT) process of NSCLC cells. Furthermore, in mouse models, Re was found to suppress LLC tumor growth and colonization by inhibiting M2-type polarization of TAMs. Our finding indicates that ginsenoside Re can effectively modulate MΦ polarization and thus play an important role in antimetastatic immunotherapy of NSCLC.