Tumor Metastasis Research Articles

Exosomal miR-4745-5p/3911 from N2-polarized tumor-associated neutrophils promotes gastric cancer metastasis by regulating SLIT2

Tumor cells remodel the phenotype and function of tumor microenvironment (TME) cells to favor tumor progression. Previous studies have shown that neutrophils in TME are polarized to N2 tumor-associated neutrophils (TANs) by tumor derived factors, thus promoting tumor growth and metastasis, angiogenesis, therapy resistance, and immunosuppression. Exosomes act as critical intercellular messengers in human health and diseases including cancer. So far, the biological roles of exosomes from N2 TANs in gastric cancer have not been well characterized. Herein, we represented the first report that exosomes from N2 TANs promoted gastric cancer metastasis in vitro and in vivo. We found that exosomes from N2 TANs transferred miR-4745-5p/3911 to gastric cancer cells to downregulate SLIT2 (slit guidance ligand 2) gene expression. Adenovirus-mediated overexpression of SLIT2 reversed the promotion of gastric cancer metastasis by N2 TANs derived exosomes. We further revealed that gastric cancer cells induced glucose metabolic reprogramming in neutrophils through exosomal HMGB1 (high mobility group protein B1)/NF-κB pathway, which mediated neutrophil N2 polarization and miR-4745-5p/3911 upregulation. We further employed ddPCR (droplet digital PCR) to detect the expression of miR-4745-5p/3911 in N2 TANs exosomes from human serum samples and found their increased levels in gastric cancer patients compared to healthy controls and benign gastric disease patients. Conclusively, our results indicate that N2 TANs facilitate cancer metastasis via regulation of SLIT2 in gastric cancer cells by exosomal miR-4745-5p/3911, which provides a new insight into the roles of TME cells derived exosomes in gastric cancer metastasis and offers a potential biomarker for gastric cancer diagnosis.

Focal adhesion kinase-mediated interaction between tumor and immune cells in the tumor microenvironment: implications for cancer-associated therapies and tumor progression.

Focal adhesion kinase (FAK) expression has been linked to tumor growth, immunosuppression, metastasis, angiogenesis, and therapeutic resistance through kinase-dependent and kinase scaffolding functions in the nucleus and cytoplasm. Hence, targeting FAK alone or with other agents has gained attention as a potential therapeutic strategy. Moreover, mounting evidence shows that FAK activity can influence the tumor immune microenvironment crosstalk to support tumor progression. Recently, tumor immune microenvironment interaction orchestrators have shown to be promising therapeutic agents for cancer immunotherapies. Therefore, this review highlights how FAK regulates the tumor immune microenvironment interplay to promote tumor immune evasive mechanisms and their potential for combination therapies with standard cancer treatments.

Oxidative Stress and Age-Related Tumors.

Oxidative stress is the result of the imbalance between reactive oxygen and nitrogen species (RONS), which are produced by several endogenous and exogenous processes, and antioxidant defenses consisting of exogenous and endogenous molecules that protect biological systems from free radical toxicity. Oxidative stress is a major factor in the aging process, contributing to the accumulation of cellular damage over time. Oxidative damage to cellular biomolecules, leads to DNA alterations, lipid peroxidation, protein oxidation, and mitochondrial dysfunction resulting in cellular senescence, immune system and tissue dysfunctions, and increased susceptibility to age-related pathologies, such as inflammatory disorders, cardiovascular and neurodegenerative diseases, diabetes, and cancer. Oxidative stress-driven DNA damage and mutations, or methylation and histone modification, which alter gene expression, are key determinants of tumor initiation, angiogenesis, metastasis, and therapy resistance. Accumulation of genetic and epigenetic damage, to which oxidative stress contributes, eventually leads to unrestrained cell proliferation, the inhibition of cell differentiation, and the evasion of cell death, providing favorable conditions for tumorigenesis. Colorectal, breast, lung, prostate, and skin cancers are the most frequent aging-associated malignancies, and oxidative stress is implicated in their pathogenesis and biological behavior. Our aim is to shed light on the molecular and cellular mechanisms that link oxidative stress, aging, and cancers, highlighting the impact of both RONS and antioxidants, provided by diet and exercise, on cellular senescence, immunity, and development of an antitumor response. The dual role of ROS as physiological regulators of cell signaling responsible for cell damage and diseases, as well as its use for anti-tumor therapeutic purposes, will also be discussed. Managing oxidative stress is crucial for promoting healthy aging and reducing the risk of age-related tumors.

FOXF1 inhibits invasion and metastasis of lung adenocarcinoma cells and enhances anti-tumor immunity via MFAP4/FAK signal axis

Based on the joint analysis of multi-omic data and the biological experiments, we demonstrate that FOXF1 inhibits invasion and metastasis of lung adenocarcinoma cells and enhances anti-tumor immunity via regulating MFAP4/FAK signal axis in this study. The levels of FOXF1 and MFAP4 are significantly down-regulated in LUAD, and the increased levels of two genes can improve the clinical prognosis of LUAD patients. Fluorescein reporter gene determination, chromatin immunoprecipitation and gene co-expression analysis indicate that MFAP4 level is positively regulated by transcription factor FOXF1. The function enrichment analysis shows that the levels of FOXF1 and MFAP4 are closely associated with an enrichment of tumor metastasis signatures. FOXF1 can inhibit the migration and invasion of LAUD cells by transcriptionally activating MFAP4 expression. And the overexpression of FOXF1/MFAP4 can reduce focal adhesion kinase (FAK) phosphorylation, while their knockdown result in the opposite effects. The increased levels of FOXF1/MFAP4 enhance the antitumor immunity by increasing the infiltration of dendritic cells and CD4+ T cells, and the interactions between LUAD cells and immune cells, and activating multiple anti-tumor immunity-related pathways. In conclusion, our study reveals the potential function of FOXF1/MFAP4/FAK signal axis in inhibiting metastasis of LUAD cells and modulating anti-tumor immunity of LUAD patients.

Upregulation of EFCAB7 after radiofrequency ablation promoting hepatocellular carcinoma metastasis and survival by regulating PARK7.

Radiofrequency ablation (RFA) is an established treatment for unresectable and early-stage hepatocellular carcinoma (HCC). However, in some cases, residual tumor cells undergo malignant transformation following RFA. The molecular mechanisms underlying this phenomenon remain poorly understood. EFCAB7, a member of the EF-hand structure family, is of particular interest due to its association with oncogenesis. Nevertheless, the role of EFCAB7 in oncogenesis remains unclear. Gene expression level of EFCAB7 in HCC tissues before and after RFA was measured, while in vitro and in vivo experiments were proposed for exploring the roles of EFCAB7 in tumor cell proliferation and metastasis. Mass spectrometry and CO-IP were adopted to validate the interaction between PARK7 and EFCAB7. Finally, PARK7 in EFCAB7 silencing cells was overexpressed and different functions were measured in vitro to determine regulation between two genes. EFCAB7 showed increased expression after RFA in patient samples and EFCAB7 expression correlated with poor prognosis in HCC patients from the TCGA database. Then, EFCAB7 promoted HCC tumor cell proliferation and metastasis while inhibiting apoptosis. Furthermore, Mass spectrometry and Co-IP experiments revealed a direct interaction between EFCAB7 and PARK7. Finally, when we overexpressed PARK7 in EFCAB7 knockdown tumor cells, it rescued proliferation and metastasis, indicating a functional relationship between these two genes. EFCAB7 might be a core contributor to HCC cells' malignant transformation after RFA and could be a potential novel target to provide a therapeutic strategy for the prevention of recurrence after RFA in HCC.

Inhibition of WNK kinases in NK cells disrupts cellular osmoregulation and control of tumor metastasis.

The serine/threonine With-No-Lysine (WNK) kinase family function in blood pressure control, electrolyte homeostasis, and cellular osmoregulation. These kinases and their downstream effectors are considered promising therapeutic targets in hypertension and stroke. However, the role of WNK kinases in immune cells remains poorly understood. Using the small-molecule WNK kinase inhibitors WNK463 and WNK-IN-11, we investigated how WNK kinase inhibition affects natural killer (NK) cell physiology. WNK kinase inhibition with WNK463 or WNK-IN-11 significantly decreased IL-2-activated NK-cell volume, motility, and cytolytic activity. Treatment of NK cells with these inhibitors induced autophagy by activating AMPK and inhibiting mTOR signaling. Moreover, WNK kinase inhibition increased phosphorylation of Akt and c-Myc by misaligning activity of activating kinases and inhibitory phosphatases. Treatment of tumor-bearing mice with WNK463 impaired tumor metastasis control by adoptively transferred NK cells. The catalytic activity of WNK kinases has a critical role of multiple aspects of NK cell physiology and their pharmacologic inhibition negatively impacts NK cell function.

Neuroendocrine Differentiation in Prostate Cancer Requires ASCL1.

Most patients with prostate adenocarcinoma develop resistance to therapies targeting the androgen receptor (AR). Consequently, a portion of these patients develop AR-independent neuroendocrine prostate cancer (NEPC), a rapidly progressing cancer with limited therapies and poor survival outcomes. Current research to understand the progression to NEPC suggests a model of lineage plasticity whereby AR-dependent luminal-like tumors progress towards an AR-independent NEPC state. Genetic analysis of human NEPC identified frequent loss of RB1 and TP53, and the loss of both genes in experimental models mediates the transition to a neuroendocrine lineage. Transcriptomics studies have shown that lineage transcription factors ASCL1 and NEUROD1 are present in NEPC. In this study, we modeled the progression of prostate adenocarcinoma to NEPC by establishing prostate organoids and subsequently generating subcutaneous allograft tumors from genetically-engineered mouse models harboring Cre-induced loss of Rb1 and Trp53 with Myc overexpression (RPM). These tumors were heterogeneous and displayed adenocarcinoma, squamous, and neuroendocrine features. ASCL1 and NEUROD1 were expressed within neuroendocrine-defined regions, with ASCL1 being predominant. Genetic loss of Ascl1 in this model did not decrease tumor incidence, growth, or metastasis; however, there was a notable decrease in neuroendocrine identity and an increase in basal-like identity. This study provides an in vivo model to study progression to NEPC and establishes the requirement for ASCL1 in driving neuroendocrine differentiation in prostate cancer.

Simultaneous Targeting of NQO1 and SOD1 Eradicates Breast Cancer Stem Cells via Mitochondrial Futile Redox Cycling.

Triple negative breast cancer (TNBC) contains the highest proportion of cancer stem-like cells (CSCs), which display intrinsic resistance to currently available cancer therapies. This therapeutic resistance is partially mediated by an antioxidant defense coordinated by the transcription factor NRF2 and its downstream targets including NQO1. Here, we identified the antioxidant enzymes NQO1 and SOD1 as therapeutic vulnerabilities of ALDH+ epithelial-like CSCs and CD24-/loCD44+/hi mesenchymal-like CSCs in TNBC. Effective targeting of these CSC states was achieved by utilizing IB-DNQ, a potent and specific NQO1-bioactivatable futile redox cycling molecule, which generated large amounts of reactive oxygen species (ROS) including superoxide and hydrogen peroxide. Furthermore, the CSC killing effect was specifically enhanced by genetic or pharmacological inhibition of SOD1, a copper-containing superoxide dismutase highly expressed in TNBC. Mechanistically, a significant portion of NQO1 resided in the mitochondrial intermembrane space, catalyzing futile redox cycling from IB-DNQ to generate high levels of mitochondrial superoxide, and SOD1 inhibition markedly potentiated this effect resulting in mitochondrial oxidative injury, cytochrome c release, and activation of the caspase 3-mediated apoptotic pathway. Treatment with IB-DNQ alone or together with SOD1 inhibition effectively suppressed tumor growth, metastasis, and tumor-initiating potential in xenograft models of TNBC expressing different levels of NQO1. This futile oxidant-generating strategy, which targets CSCs across the epithelial-mesenchymal continuum, could be a promising therapeutic approach for treating TNBC patients.

Single-Cell RNA Sequencing Revealing that MMP12+ Macrophages are Associated with Cancer Liver Metastasis.

We aimed to explore the MMP12+ macrophages function in liver metastasis of Colorectal cancer [CRC]. CRC has a high incidence, and a great many patients develop liver metastases. Some studies have found that macrophages may participate in the liver metastasis of CRC. This study aimed to determine the factors and major signaling pathways of MMP12+ macrophages affecting liver metastasis of CRC. The single-cell RNA sequencing [scRNA-seq] data of CRC and bulk transcriptome data were downloaded. After filtering scRNA-seq data, dimensionality reduction and clustering were performed to identify different cell subgroups. The FindAll- Markers function was used to calculate the differentially expressed genes in each cell subgroup, and the genes in the promising set were uploaded to the DAVID database to analyze the biological processes to which these genes were enriched. Differentially expressed genes among macrophage subgroups were selected by the AverageExpression function. Then, the CIBERSORT algorithm was used to compute the proportion of each macrophage subgroup in each bulk tissue and determine the most significant macrophage subgroup. The dynamic changes of gene expression in macrophage subgroup were computed by Pseudotime. Finally, CellChat was applied to investigate the effect of the macrophage subgroup on epithelial cells and the ligand-receptor effect of B cells and T cells. Clustering scRNA-seq data showed a larger proportion of macrophages in liver metastases. The proportion of MMP12+ macrophage subtypes increased gradually among normal, tumor, and liver metastasis groups, and MMP12+ macrophages were associated with angiogenesis, cell migration, and inhibited T cell proliferation. The Pseudotime showed higher expression levels of genes related to angiogenesis and enhanced TGF-β signaling pathway and the negative regulation of T cell proliferation with the occurrence of liver metastasis in MMP12+ macrophages. MMP12+ macrophages can promote the proliferation of epithelial cells and inhibit the activation of T cells and B cells. MMP12+ macrophages promoted liver metastasis of CRC by influencing angiogenesis, TGF-β signaling pathway expression, and regulation of T cells and B cells.

Preparation and effects of functionalized liposomes targeting breast cancer tumors using chemotherapy, phototherapy, and immunotherapy

Breast cancer therapy has significantly advanced by targeting the programmed cell death-ligand 1/programmed cell death-1 (PD-L1/PD-1) pathway. BMS-202 (a smallmolecule PD-L1 inhibitor) induces PD-L1 dimerization to block PD-1/PD-L1 interactions, allowing the T-cell-mediated immune response to kill tumor cells. However, immunotherapy alone has limited effects. Clinically approved photodynamic therapy (PDT) activates immunity and selectively targets malignant cells. However, PDT aggravates hypoxia, which may compromise its therapeutic efficacy and promote tumor metastasis. We designed a tumor-specific delivery nanoplatform of liposomes that encapsulate the hypoxia-sensitive antitumor drug tirapazamine (TPZ) and the small-molecule immunosuppressant BMS. New indocyanine green (IR820)-loaded polyethylenimine-folic acid (PEI-FA) was complexed with TPZ and BMS-loaded liposomes via electrostatic interactions to form lipid nanocomposites. This nanoplatform can be triggered by near-infrared irradiation to induce PDT, resulting in a hypoxic tumor environment and activation of the prodrug TPZ to achieve efficient chemotherapy. The in vitro and in vivo studies demonstrated excellent combined PDT, chemotherapy, and immunotherapy effects on the regression of distant tumors and lung metastases, providing a reference method for the preparation of targeted agents for treating breast cancer.Graphical abstract

Transcriptional Regulation of De Novo Lipogenesis by SIX1 in Liver Cancer Cells.

De novo lipogenesis (DNL), a hallmark of cancer, facilitates tumor growth and metastasis. Therapeutic drugs targeting DNL are being developed. However, how DNL is directly regulated in cancer remains largely unknown. Here, transcription factor sine oculis homeobox 1 (SIX1) is shown to directly increase the expression of DNL-related genes, including ATP citrate lyase (ACLY), fatty acid synthase (FASN), and stearoyl-CoA desaturase 1 (SCD1), via histone acetyltransferases amplified in breast cancer 1 (AIB1) and lysine acetyltransferase 7 （HBO1/KAT7）, thus promoting lipogenesis. SIX1 expression is regulated by insulin/lncRNA DGUOK-AS1/microRNA-145-5p axis, which also modulates DNL-related gene expression as well as DNL. The DGUOK-AS1/microRNA-145-5p/SIX1 axis regulates liver cancer cell proliferation, invasion, and metastasis in vitro and in vivo. In patients with liver cancer, SIX1 expression is positively correlated with DGUOK-AS1 and SCD1 expression and is negatively correlated with microRNA-145-5p expression. DGUOK-AS1 is a good predictor of prognosis. Thus, the DGUOK-AS1/microRNA-145-5p/SIX1 axis strongly links DNL to tumor growth and metastasis and may become an avenue for liver cancer therapeutic intervention.

Single-cell RNA sequencing reveals the communications between tumor microenvironment components and tumor metastasis in osteosarcoma

Single-cell RNA sequencing reveals the communications between tumor microenvironment components and tumor metastasis in osteosarcoma

Comparison of prognosis between oncocytic thyroid carcinoma and follicular thyroid carcinoma: a population-based propensity score matching analysis.

Oncocytic thyroid carcinoma (OTC) is a rare subtype of thyroid cancer known for its distinctive morphology and high likelihood of recurrence, setting it apart from follicular thyroid carcinoma (FTC). Despite this, there is limited research comparing the clinicopathological characteristics and outcomes of OTC and FTC. We retrospectively searched through the Surveillance, Epidemiology, and End-Results (SEER) database (2004-2015) for histologically diagnosed OTC and FTC patients. Kaplan-Meier analysis, propensity score matching (PSM), univariate Cox proportional risk regression model, and subgroup analysis were employed to investigate the prognostic effect of clinicopathological features and treatment regimens on survival outcomes of OTC and FTC patients. 2329 OTC patients and 5679 FTC patients were included in the study. OTC patients were prone to older age, white race, lymph node metastasis, distal metastasis, extension and multiple primary tumors compared with FTC patients. After using a 1:1 PSM matching ratio, there were no significant differences in demographic and clinicopathological characteristics between the matched groups. Further Cox regression analysis showed that OTC patients had lower overall survival (OS) and cancer-specific survival (CSS) in contrast with FTC patients. Subgroup survival analysis suggested that the OTC patients were related to lower OS in subgroups including those over 55years old, male sex, white ethnicity, extrathyroidal extension, single primary tumor, surgery and without chemotherapy compared with the FTC patients in these subgroups. In addition, the OTC patients were connected with lower CSS in subgroups including male sex, white ethnicity, married status, tumor size is less than 20mm or more than 40mm, N0 stage, localized stage, single primary tumor, surgery, radiotherapy, and without chemotherapy compared with the FTC patients in these subgroups. Meanwhile, the OTC patients had lower CSS compared to FTC patients regardless of age and extrathyroidal extension. The results suggested that OTC patients have unique clinical features and poorer prognoses compared to FTC patients. Surgical resection and radioactive iodine therapy are recommended for OTC patients and FTC patients. It is worth noting that the prognosis of OTC relies largely on the selection of treatment strategies. Therefore, our results highlighted the clinical significance of the early distinguishment and the correct choice of treatment in OTC patients.

Dual-pore protocells with multitasking capacities for simultaneous delivery of therapeutic enzymes and drugs in macrophage depletion therapy.

Macrophages are usually present in solid tumors where they participate in tumor progression, angiogenesis, immunosuppression and metastasis. The design of nanocarriers capable of delivering therapeutic agents to specific cell populations has received considerable attention in the last decades. However, the capacity of many of these nanosystems to deliver multiple therapeutic agents with very different chemical properties is more limited. Herein, a novel multitasking nanoplatform capable of delivering large macromolecules and cytotoxic drugs to macrophages is presented. This novel nanosystem has exhibited excellent skills in performing simultaneous tasks, macrophage depletion and glucose starvation, maintaining the oxygen levels in the tissue. This nanodevice is composed of a dual-pore mesoporous silica core with the capacity to house small cytotoxic drugs, such as doxorubicin or zoledronic acid, and large macromolecules, such as glucose oxidase. The external surface of the silica core was coated with a lipid bilayer to avoid the premature release of the housed drugs. Finally, polymeric nanocapsules loaded with catalase were covalently anchored on the outer lipid bilayer, and carboxy-mannose was attached to the exposed side of the nanocapsules to provide selectivity to the macrophages. These nanoassemblies were able to transport enzymes (Gox and CAT), maintaining their catalytic activity. Therefore, they could induce glucose starvation, keeping the oxygen levels in the tissue, owing to the tandem enzymatic reaction. The capacity of these nanoassemblies to deliver therapeutic agents to macrophages was evaluated both in static and under flow conditions, showing a rapid capture of the nanoparticles by the macrophages. Once there, the nanoassemblies also exhibited excellent capacity to induce potent macrophage depletion. This strategy can be directly adapted for the treatment of different malignancies due to the modular nature of the nanoplatform, which can be loaded with different therapeutic agent combinations and pave the way for the development of personalized nanomedicines for diverse types of tumors.

LncRNA UCA1 promotes vasculogenic mimicry by targeting miR-1-3p in gastric cancer.

Long noncoding RNA urothelial carcinoma-associated 1 (UCA1) has been implicated in several tumors. UCA1 promotes cell proliferation, migration, and invasion of gastric cancer (GC) cells, but the molecular mechanism has not been fully elucidated. This study revealed the oncogenic effects of UCA1 on cell growth and invasion. Furthermore, UCA1 expression was significantly correlated with the overall survival of GC patients, and the clinicopathological indicators, including tumor size, depth of invasion, lymph node metastasis, and TNM stage. Additionally, miR-1-3p was identified as a downstream target of UCA1, which was negatively regulated by UCA1. MiR-1-3p inhibited cell proliferation and vasculogenic mimicry (VM), and induced cell apoptosis by upregulating BAX, BAD, and tumor suppressor TP53 expression levels. Moreover, miR-1-3p almost completely reversed the oncogenic effect caused by UCA1, including cell growth, migration, and VM formation. This study also confirmed that UCA1 promoted tumor growth in vivo. In this study, we also revealed the correlation between UCA1 and VM formation, which is potentially crucial for tumor metastasis. Meanwhile, its downstream target miR-1-3p inhibited VM formation in GC cells. In summary, these findings indicate that the UCA1/miR-1-3p axis is a potential target for GC treatment.

ER membrane remodeling by targeting RTN4 induces pyroptosis to facilitate antitumor immune.

Pyroptosis is an identified programmed cell death that has been highly linked to endoplasmic reticulum (ER) dynamics. However, the crucial proteins for modulating dynamic ER membrane curvature change that trigger pyroptosis are currently not well understood. In this study, a biotin-labeled chemical probe of potent pyroptosis inducer α-mangostin (α-MG) was synthesized. Through protein microarray analysis, reticulon-4 (RTN4/Nogo), a crucial regulator of ER membrane curvature, was identified as a target of α-MG. We observed that chemically induced proteasome degradation of RTN4 by α-MG through recruiting E3 ligase UBR5 significantly enhances the pyroptosis phenotype in cancer cells. Interestingly, the downregulation of RTN4 expression significantly facilitated a dynamic remodeling of ER membrane curvature through a transition from tubules to sheets, consequently leading to rapid fusion of the ER with the cell plasma membrane. In particular, the ER-to-plasma membrane fusion process is supported by the observed translocation of several crucial ER markers to the "bubble" structures of pyroptotic cells. Furthermore, α-MG-induced RTN4 knockdown leads to PKM2-dependent conventional caspase-3/GSDME cleavages for pyroptosis progression. In vivo, we observed that chemical or genetic RTN4 knockdown significantly inhibited cancer cells growth, which further exhibited an antitumor immune response with anti-PD-1. In translational research, RTN4 high expression was closely correlated with the tumor metastasis and death of patients. Taken together, RTN4 plays a fundamental role in inducing pyroptosis through the modulation of ER membrane curvature remodeling, thus representing a prospective druggable target for anticancer immunotherapy.

The group of hypermethylated long noncoding RNA genes is associated with different types of metastasis in ovarian cancer

Background: Ovarian tumors are characterized by asymptomatic progression until their late stages, when at the time of diagnosis the patient already has extensive metastatic disease. In addition to lymphogenous and hematogenous metastasis in ovarian cancer, there are peritoneal dissemination and metastasis to the greater omentum with ascites; moreover, peritoneal carcinomatosis is the predominant route of metastasizing of ovarian cancer. Epigenetic factors, such as gene methylation, regulatory microRNAs and long non-coding RNAs (lncRNAs), contribute to progression of this cancer. Our previous bioinformatic and experimental studies have identified 13 genes of lncRNAs (GAS5, HOTAIR, LINC00472, LINC00886, MAFG-DT, PLUT/PDX1-AS1, SNHG1, SNHG6, SNHG12, SNHG17, TINCR, TP53TG1, TUG1) hypermethylated in the ovarian neoplasms. Aim: To evaluate the clinical significance of methylation levels of 13 lncRNA genes (GAS5, HOTAIR, LINC00472, LINC00886, MAFG-DT, PLUT/PDX1-AS1, SNHG1, SNHG6, SNHG12, SNHG17, TINCR, TP53TG1, TUG1) associated with various types of ovarian cancer metastasis, including lymphogenous, peritoneal, omental, and distant metastases. Methods: The methylation levels of lncRNA genes GAS5, HOTAIR, LINC00472, LINC00886, MAFG-DT, PLUT/PDX1-AS1, SNHG1, SNHG6, SNHG12, SNHG17, TINCR, TP53TG1, TUG1 were analyzed by quantitative real-time methylation-specific polymerase chain reaction. We tested 122 duplicate samples of ovarian neoplasms, including 104 malignancies and 18 borderline tumors, as well as 45 peritoneal macro metastases, collected in the N.N. Blokhin National Medical Research Center of Oncology in 2020 to 2023. The study included 21 samples of primary tumor from patients with lymphogenous metastases, 45 samples from patients with peritoneal dissemination, 61 from those with omental metastases, 49 from patients with ascites, and 9 with distant metastases. Results: The tumor samples from the patients with lymphatic nodes metastases showed a significant increase in the methylation level of two lncRNA genes: SNHG6 (p = 0.044) and SNHG12 (p = 0.006). Peritoneal dissemination was associated with hypermethylation of four lncRNA genes: GAS5, HOTAIR, LINC00472 (p 0.05), and most significantly TINCR (p = 0.001). GAS5, HOTAIR, LINC00886 (p 0.05) and most significantly LINC00472 (p 0.001) hypermethylation was typical for omental metastasis, and that of LINC00472 and LINC00886, with ascites (p 0.05). Peritoneal macroscopic metastases demonstrated increased methylation of MAFG-DT (p 0.001) and TP53TG1 (p 0.001) and desmethylation of LINC00886 (p = 0.003) and SNHG12 (p = 0.002), compared to their primary tumors. Conclusion: We performed the analysis of clinical significance of 13 hypermethylated lncRNA genes in ovarian cancer and were the first to show that 10 genes (GAS5, HOTAIR, LINC00472, LINC00886, MAFG-DT, SNHG6, SNHG12, TINCR, TP53TG1, TUG1) were associated with various types of ovarian tumor metastasis. Also, we were able to determine certain panels of lncRNA, which, if demonstrate abnormal methylation, were specific for lymphogenous and peritoneal metastasis of ovarian tumors.

Stimuli‐Responsive Nanocarriers as Active Enhancers of Antitumoral Immunotherapy

AbstractIn recent years, the understanding of the role of the immune system in tumor progression and metastasis is paving the way for the development of antitumoral strategies based on the delivery of immunotherapeutic agents. The engineering of stimuli‐responsive nanocarriers able to release their payload in a controlled manner being able to boost potent and sustained immune responses against tumors has provided a powerful tool to eradicate tumors with extreme precision. Paramount advantages to trigger the immune system against tumors are the high selectivity and memory effect of immune response, which allows not only to eradicate primary and metastatic malignancies but also to avoid their relapse. In this review, the recent advances carried out in the development of smart nanocarriers for immunotherapy are presented.

A cancer-associated fibroblasts related risk score (CAFscore) helps to guide prognosis and personal treatment for Glioblastoma

BackgroundRecent studies have identified the presence of cancer-associated fibroblasts (CAFs) within glioblastoma (GBM), yet their biological roles and underlying mechanisms remain poorly understood. This study aimed to construct a CAF-related prognostic model to guide patient prognosis and treatment strategies.MethodWe employed various bioinformatics methods, including enrichment analysis, Weighted Gene Co-expression Network Analysis (WGCNA), Lasso regression analysis, and machine learning techniques such as XGBoost and Random Forest, to develop a novel risk index termed CAFscore. Patients were stratified into high and low CAFscore groups for subsequent survival analysis. The area under the curve (AUC) and concordance index (C-index) for CAFscore were calculated and compared against other clinical characteristics and existing prognostic models. Drug sensitivity assessments were conducted using the Oncopredict package. Functional validation of key genes was performed through scratch and invasion assays in GBM cells.ResultsOur analyses revealed four core CAF-related genes, leading to the establishment of CAFscore. Notably, patients in the high CAFscore group exhibited significantly reduced survival and exhibited enrichment in epithelial-mesenchymal transition (EMT) and inflammation response pathways. Furthermore, CAFscore showed a significant negative correlation with the sensitivity to irinotecan and its analogs, while demonstrating a positive correlation with sensitivity to 505,124 (a TGFβRI inhibitor). LRP10 emerged as a central gene within the CAFscore, displaying markedly elevated expression in GBM and a strong association with CAF infiltration. Silencing LRP10 significantly inhibited the invasive capabilities of GBM cells.ConclusionThis study presented the first CAF related prognostic model (CAFscore) in GBM, and demonstrated that the model could effectively guide patient prognosis and potentially inform personalized treatment strategies. The core gene of CAFscore, LRP10, was significantly overexpressed in GBM and might play a pivotal role in regulating CAF infiltration as well as tumor invasion and metastasis, highlighting LRP10 as a promising therapeutic target for GBM management.

Cancer-associated fibroblast cell surface markers as potential biomarkers or therapeutic targets in lung cancer

Cancer-associated fibroblasts (CAFs) are the vital constituent of the tumor microenvironment, and in communication with other cells, they contribute to tumor progression and metastasis. Fibroblasts are the proposed origin of CAFs, which are mediated by pro-inflammatory cytokines and the recruitment of immune cells akin to wound healing. Although various studies have identified different subpopulations of CAFs in lung cancer, the heterogeneity of CAFs, particularly in lung cancer, and their potential as a therapeutic target remain largely unknown. Notwithstanding CAFs were previously thought to have predominantly tumor-promoting features, their pro- or anti-tumorigenic properties may depend on various conditions and cell origins. The absence of distinct markers to identify CAF subpopulations presents obstacles to the successful therapeutic targeting and treatment of CAFs in cancer. Human clinical and animal studies targeting CAFs have shown that targeting CAFs exacerbates the disease progression, suggesting that subpopulations of CAFs may exert opposing functions in cancer progression. Therefore, it is essential to pinpoint specific markers capable of characterizing these subpopulations and revealing their mechanisms of function. The cell-specific surface markers of CAFs will serve as an initial step in investigating precise CAF subpopulations and their role in diagnosing and targeting therapy against cancer-promoting CAF subsets in lung cancer.