Tumor Progression Research Articles

IL17A/CEBPβ/OPN/LYVE-1 axis inhibits antitumor immunity by promoting tumor-associated tissue resident macrophages

Tumor-associated macrophages (TAMs) are a critical component of the immunosuppressive tumor microenvironment, comprising monocyte-derived macrophages (MDM-TAMs) and tissue-resident macrophages (TRM-TAMs). Here, we discovered that TRM-TAMs mediate the pro-tumor effects of interleukin (IL)-17A and that IL-17A-driven tumor progression requires tumor cell production of osteopontin (OPN). Mechanistically, we identified CEBPβ as a transcription factor downstream of IL-17A in tumor cells and LYVE-1 as an OPN receptor on TRM-TAMs. IL-17A stimulates tumor cell production of OPN, and OPN/LYVE-1 signaling activatesthe JNK/c-Jun pathway, leading to the proliferation of immunosuppressive LYVE-1+ TRM-TAMs. Unlike its effect on LYVE-1+ TRM-TAMs, OPN interacts with α4β1 to promote the chemotaxis of LYVE-1- MDM-TAMs toward tumors. IL-17A neutralization, OPN inactivation in tumor cells, or LYVE-1 deletion in macrophages inhibited TAMs and enhanced anti-tumor immune responses and anti-PDL1 therapy. Thus, the IL-17A/CEBPβ/OPN/LYVE-1 axis offers a mechanism suppressing anti-tumor immune responses and, hence, an effective therapeutic target for cancer.

Shikonin Inhibits Oral Cancer Progression Through Suppression of Metastasis and Angiogenesis and Induction of Autophagy and Apoptosis

Background: Shikonin, a compound extracted from Lithospermum erythrorhizon, has demonstrated therapeutic effects on cancer; however, its effects on oral cancer remain unclear. Objectives: This study aimed to explore the therapeutic value of shikonin for the treatment of oral cancer. Methods: MTT, colony formation, and Transwell assays were employed to evaluate the inhibitory effects of shikonin on the proliferation and migration abilities of human oral cancer cell lines (SCC-4 and SAS). Apoptosis and cell viability were assessed using the TdT-mediated deoxyuridine triphosphate-biotin nick end-labeling (TUNEL) assay. To investigate the potential anticancer mechanisms of shikonin, RNA sequencing, quantitative PCR, and western blotting were performed to analyze changes in the expression levels of oral cancer cell-related genes and proteins (matrix metalloproteinases-2 (MMP-2), matrix metalloproteinases-9 (MMP-9), VEGF-A, VEGF-C, Beclin-1, autophagy-related genes (ATG5), and light chain-3 (LC-3)). Additionally, animal xenograft experiments were conducted to examine the in vivo antitumor effects of shikonin. Results: The findings revealed that the external application of shikonin specifically targeted oral cancer cells without affecting normal cells and led to a dose-dependent inhibition of their growth. Even at non-lethal doses, shikonin effectively suppressed the production of metalloproteinases, thereby inhibiting cancer cell migration and wound healing. Furthermore, shikonin treatment reduced levels of tumor progression factors, such as vascular endothelial growth factor (VEGF)-A and VEGF-C, which are released during the early stages of cancer cell angiogenesis and lymphangiogenesis. Meanwhile, higher doses of shikonin induced cell autophagy and activated proteins such as ATG-5, LC-3B, and Beclin-1. At lethal doses, shikonin further decreased mitochondrial membrane potential, released calcium ions, and triggered apoptotic pathways. However, the administration of a calcium ion chelator (BAPTA-AM) inhibited shikonin-induced apoptosis. Conclusions: These results demonstrate that shikonin induces autophagy and activates apoptotic pathways in oral cancer cells. Shikonin treatment significantly inhibited oral cancer growth and induced apoptosis in a rat model. In conclusion, shikonin effectively inhibited oral cancer cell growth, metastasis, and the expression of tumor progression-related proteins. Given the ease of drug delivery to the affected area in oral cancer, shikonin holds substantial potential for future applications that may improve patient recovery and enhance cure rates.

METTL3-VISTA axis-based combination immunotherapy for APC truncation colorectal cancer

ObjectiveAlthough immune checkpoint blockade (ICB) therapy represents a bright spot in antitumor immunotherapy, its clinical benefits in colorectal cancer (CRC) are limited. Therefore, a new target for mediating CRC immunosuppression...

Interferon gamma-mediated prevention of tumor progression in a mouse model of multiple myeloma.

Malignant plasma cells in multiple myeloma patients reside in the bone marrow and continuously interact with local immune cells. Progression and therapy response are influenced by this immune environment, highlighting the need for a detailed understanding of endogenous immune responses to malignant plasma cells. Here we used the 5TGM1 murine transfer model of multiple myeloma to dissect early immune responses to myeloma cells. We modeled stable and progressive disease by transferring 5TGM1 murine myeloma cells into C57Bl/6 mice and KaLwRij mice, respectively. We used flow cytometry and single-cell and bulk transcriptomic analyses to characterize differential immune responses in stable and progressive disease. Transfer of 5TGM1 cells in C57Bl/6 mice led to stable disease with low tumor burden in a subset of animals. Stable disease was associated with sustained activation and expansion of NK cells, ILC1, and CD8+ T cells, a response that was lost upon disease progression. Single-cell RNA-sequencing of immune cells and bulk RNA sequencing of immune and mesenchymal stromal cells implicated the activation of interferon responses as a central immune pathway during stable disease. Experimentally, neutralization of IFNγ significantly increased myeloma development and progression in C57Bl/6 mice, testifying to the importance of this pathway in early disease control. In conclusion, we provide a framework for studying immune responses to multiple myeloma progression in immunocompetent and genetically modifiable mice and highlight the importance of bone marrow immunity in tumor control.

Regulation of Tumor Growth and Invasion in Oral Squamous Cell Carcinoma by the Tumor Microenvironment Through the Enhancement of IGFBP-3 Expression.

Accumulated evidence indicates that interactions among various stromal cells within the tumor microenvironment (TME) significantly influence cancer progression. Oral cancers not diagnosed at early stages are associated with low five-year survival rates, highlighting the need for substantial improvements in patient outcomes. Understanding the interactions between cancer cells and the tumor microenvironment is crucial for identifying methods and developing treatment strategies that more effectively inhibit tumor progression and metastasis. This study investigated the roles of cancer-associated fibroblasts (CAFs) and THP-1 monocytes in tumor growth and invasion, observing changes in cancer biological characteristics through interactions with stromal cells. HSC2 oral squamous cell carcinoma (OSCC) cells were co-cultured with normal fibroblasts (NF), cancer-associated fibroblasts (CAF), or THP-1 cells. Changes in cancer cell invasion were investigated using Matrigel-coated transwell assays, collagen-based dermal equivalent assays, and in vivo mouse studies. HSC2 cells co-cultured with CAFs or THP-1 exhibited increased invasion compared to those co-cultured with normal fibroblasts (NF) in the dermal equivalent. In a mouse gingival xenograft model, cancer cells co-implanted with CAFs or THP-1 showed significantly increased tumor growth compared to those co-implanted with NF. Micro-CT (μCT) analysis revealed significant alveolar bone resorption around the mandible in tumors grown with CAFs or THP-1 cells. Conditioned media (CM) from CAFs or THP-1 significantly increased HSC2 invasion and migration, an effect that was inhibited by the protein secretion inhibitor Brefeldin (BFA). Furthermore, QuantSeq 3' mRNA sequencing indicated increased expression of IGFBP3, closely associated with cancer invasion, in HSC2 cells co-cultured with CAFs or THP-1. These findings suggest that cancer cells enhance their invasive characteristics through close interactions with the surrounding stromal cells.

Investigation of Effectiveness of Nowarta110 Against Murine Malignant Melanoma in an Implanted Animal Model.

Melanoma is a prevalent and severe disease, making the development of new treatments essential. Nowata110 has demonstrated significant therapeutic efficacy in phase II clinical study against plantar warts. It has shown promising anti-cancer effects in both in vitro and in vivo studies using HPV-16 and HPV-18-induced cervical cancer models. This study evaluated the effectiveness of Nowarta110 in murine melanoma-implanted animals. Nowata110 is a novel compound composed of colloidal silver and fig extract. Male and female immunodeficient C(Cg)-Cd 79 atm 1 (cre) and immunocompetent BALB/c mice were used. Murine melanoma cancer cells (B16-F10) were implanted subcutaneously in experimental animals. Once the top cross-sectional area of tumors reached a minimum of 5 mm2 and approximately 4 mm depth, mice were anesthetized and treated with Nowarta110 intravenously or intratumorally. Control mice received no treatment. In non-treated immunodeficient mice, tumor growth progressed over five weeks, whereas Nowarta110-treated mice drastically reduced tumor volume until five weeks after treatment was initiated. Similarly, in untreated BALB/c mice, tumor growth persisted over five weeks. However, Nowarta110-treated mice exhibited a notable reduction in tumor size. Although intravenous administration of Nowarta110 did not result in complete tumor regression in immunodeficient mice, it did lead to reduced tumor growth. In BALB/c immunocompetent mice, intravenous treatment generally stalled tumor progression. Intratumoral and intravenous administration of Nowarta110 effectively treated murine melanoma in immunodeficient and immunocompetent mice. The Nowarta110 antitumoral efficacy was more pronounced in immunocompetent mice treated intravenously than immunodeficient mice. Clinical studies to examine the efficacy of Nowarta110 in human melanoma and skin cancers are warranted.

Dual-targeting of tumor cells and tumor-associated macrophages by hyaluronic acid-modified MnO2 for enhanced sonodynamic therapy

In addition to tumor cells, M2-like tumor-associated macrophages (TAMs) also promote tumor progression. Accordingly, the strategy of targeted depletion or repolarization of M2-like TAMs becomes attractive. Here, we report a dual-targeting nanoagent SAMMH to tumor cells and M2-like TAMs for combinatorial tumor treatment. After co-loading the sonosensitizer spafloxacin (SPX) and oxidative phosphorylation inhibitor atavaquone (ATO) into hollow MnO2, the addition of Fe3+ and tannic acid-immobilized hyaluronic acid (HA) caused the formation of SAMMH through generating metal-polyphenol networks (MPNs) coatings outside. In vitro endocytosis assays demonstrated the efficient internalization of SAMMH by both tumor cells and M2-like TAMs through the specific CD44-HA interactions. The GSH-sensitive degradation of SAMMH results in the continuous release of SPX and ATO. Meanwhile, SAMMH could catalyze the endogenous H2O2 to extra O2, thus improving the therapeutic effect via the combination of Mn2+-induced CDT and O2-generation/O2-economy dual-enhanced sonodynamic therapy (SDT). Interestingly, SAMMH had a good targeted M2-like TAMs depleting capacity and could promote M2-to-M1 TAMs transformation by CDT-enhanced SDT, leading to a combinational anti-tumor effect. This dual-targeting nanoagent is a promising candidate to achieve CDT-enhanced SDT against both tumor cells and M2-like TAMs, thus providing new insights for the development of highly effective antitumor therapeutics.

The role of super-enhancers in head and neck cancer and its potential therapeutic targets

Head and neck squamous cell carcinoma (HNSCC) poses a significant global health challenge, with over 660,000 new cases diagnosed and more than 325,000 deaths each year. Despite advances in treatment, long-term survival rates for HNSCC patients remain disappointingly low, underscoring the critical need for innovative therapeutic strategies. This review delves into the role of super-enhancers in HNSCC, highlighting their pivotal function in regulating key oncogenes such as KLF4, FOSL1, and ΔNp63, which are crucial for tumor progression and metastasis. Moreover, it explores how super-enhancers contribute to the maintenance of cancer stem cell characteristics by controlling genes like SOX2, BRD4. thereby promoting self-renewal and pluripotency.The study also underscores the potential of BET bromodomain inhibitors, exemplified by JQ1, and CDK7 inhibitors like THZ1, which demonstrate substantial therapeutic promise by effectively disrupting the function of super-enhancers in HNSCC. Overall, this research provides a comprehensive overview of the importance of super-enhancers in HNSCC .

Crocin Potentiates Anti-tumor Properties of 5-FU by Regulating Cell Proliferation and Tumor Necrosis in Breast Cancer

Introduction: Breast cancer is one of the most prevalent malignancies among women around the world. Crocus sativus, a natural food coloring and flavoring, has potent anti-tumor properties. The aim of the current study was to investigate the therapeutic potential of crocin, the main pharmacological active component of saffron, either alone or in combination with the standard chemotherapeutic treatment, 5-FU, in Breast cancer (BC) progression in both cellular and animal models. Material and Methods: MTT, Real-Time PCR, Western Blotting, Hematoxylin and eosin (H&E) tissue staining were applied to determine the anti-tumor properties of crocin in in vitro and in vivo samples. Results: Our findings showed that crocin decreased breast cancer cell proliferation by suppressing cyclin D1 expression and Wnt/β-catenin signaling activation. Moreover, this molecule improved 5- FU anti-cancer activities by decreasing the tumor volume and weight, increasing tumor necrosis, and suppressing tumor inflammation in an animal model. Inflammation-associated anti-cancer activity of crocin is mediated by the down-regulation of pro-inflammatory genes, including IFN-γ and IL-1β, as well as inhibition of oxidative stress responses within the tumor environment. Conclusion: This is the first study demonstrating the potent anti-tumor properties of crocin against BC progression. Our results suggest that this effective and low-toxic molecule could be a promising agent for reducing BC tumor progression when administered either alone or in combination with standard treatment in breast cancer patients.

Type I Diabetes Mellitus impairs cytotoxic immunity through CEACAM5 upregulation in colorectal cancer : Exploring the intersection of autoimmune dysfunction and cancer progression: the role of NF-κB p65 in colorectal cancer.

Type 1 diabetes (T1D) is characterized by an autoimmune-mediated destruction of pancreatic beta cells and a chronic inflammatory state, which may influence the progression of colorectal cancer (CRC) through immune system dysregulation and enhanced tumor immune evasion. This study aims to elucidate the role of p65 in modulating the tumor microenvironment in CRC within the context of T1D and to determine how this modulation affects tumor growth, immune cell infiltration, and the expression of immune evasion molecules such as CEACAM5. NOD mice, which model T1D, were inoculated with MC38 colon carcinoma cells engineered to knock down p65. Tumor growth was monitored, and the tumor microenvironment was analyzed using flow cytometry to assess the infiltration of immune cells. The expression of Ki-67 and CEACAM5 in tumor cells was also evaluated. Additionally, in vitro assays were conducted to study the proliferation and activation of T cells co-cultured with tumor cells. Knockdown of p65 in tumor cells significantly inhibited tumor growth in NOD mice. This was accompanied by an increased infiltration of cytotoxic CD8+ T cells and no significant change in CD4+ or Foxp3 + T regulatory cells within the tumor microenvironment. There was a notable reduction in the expression of Ki-67 and CEACAM5, indicating decreased proliferation and potential immune evasion capabilities of the tumor cells. Our findings demonstrate that the NF-κB p65 subunit plays a crucial role in promoting tumor growth and modulating the immune microenvironment in CRC, particularly in the context of T1D. Knocking down p65 not only reduces tumor progression but also enhances the anti-tumor immune response by decreasing immune evasion mechanisms. These results suggest that targeting the NF-κB pathway may be a viable strategy to improve the efficacy of cancer immunotherapy, especially in patients with autoimmune diseases like T1D. Physical activity enhances the effect of immune checkpoint blockade by inhibiting the intratumoral HIF1-α/CEACAM5 axis.

FAM83H regulated by glis3 promotes triple-negative breast cancer tumorigenesis and activates the NF-κB signaling pathway.

Triple-negative breast cancer (TNBC) is a highly aggressive and invasive form of breast cancer (BC) with a high mortality rate and a lack of effective targeted drugs. Family with sequence similarity 83 member H (FAM83H) is critically implicated in tumorigenesis. However, the potential role of FAM83H in TNBC remains elusive. Here, we discovered that FAM83H exhibited high expression in tumor tissues of patients with TNBC and was associated with TNM stage. Gain- or loss-of-function experiments were conducted to explore the biological role of FAM83H in TNBC. Subsequently, functional enrichment analysis confirmed that FAM83H overexpression promoted TNBC cell proliferation, invasion, migration and epithelial-mesenchymal transition (EMT), accompanied by upregulation of cyclin E, cyclin D, Vimentin, N-cadherin and Slug. As observed, FAM83H knockdown showed anti-cancer effects, such as fostering apoptosis and inhibiting tumorigenicity and metastasis of TNBC cells. Mechanistically, FAM83H activated the NF-κB signaling pathway. Moreover, a dual-luciferase reporter assay demonstrated that GLIS family zinc finger 3 (GLIS3) bound to the promoter of FAM83H and enhanced its transcription. Notably, overexpression of GLIS3 significantly stimulated TNBC cell proliferation and invasion, and all of this was reversed by rescue experiments involving the knockdown of FAM83H. Overall, FAM83H exacerbates tumor progression, and in-depth understanding of FAM83H as a therapeutic target for TNBC will provide clinical translational potential for intervention therapy.

The roles of periostin derived from cancer-associated fibroblasts in tumor progression and treatment response.

Periostin (POSTN), a matricellular protein predominantly secreted by cancer-associated fibroblasts (CAFs), has emerged as a key regulator of cancer progression and therapy response. This review provides an overview of recent findings regarding the diverse roles of periostin in cancer therapy and its potential as a therapeutic target. Studies have elucidated periostin's involvement in tumorigenesis, including tumor growth, metastasis, chemotherapy resistance, and modulation of the tumor microenvironment (TME). CAFs periostin + play a central role in shaping the TME by remodeling the extracellular matrix (ECM) and promoting immune evasion, thus promoting tumor cell survival and dissemination. Elevated periostin expression has been correlated with poor prognosis across multiple cancer types, suggesting its utility as a prognostic biomarker. Periostin has been implicated in mediating resistance to chemotherapy, with CAFs periostin + establishing a pro-tumorigenic niche that confers protection to cancer cells against cytotoxic therapies. Targeting periostin or its downstream effectors presents a promising strategy to overcome therapy resistance and enhance treatment efficacy. While significant progress has been made in understanding the biological functions of periostin in cancer, gaps persist in elucidating its precise mechanisms of action and clinical relevance. Future research should focus on deciphering the signaling pathways and molecular interactions underlying periostin-mediated effects in the TME. Prospective clinical studies are warranted to evaluate periostin as a predictive biomarker and therapeutic target in cancer patients.

Exploring the Role of the KCNK1 Potassium Channel and Its Inhibition Using Quinidine in Treating Head and Neck Squamous Cell Carcinoma.

Our study aimed to explore the role of the potassium channel KCNK1 in head and neck squamous cell carcinoma, focusing on its impact on tumor growth, invasion, and metastasis. We also investigated the therapeutic potential of quinidine, a known KCNK1 inhibitor, in both in vitro cell lines and a zebrafish patient-derived xenograft (PDX) model. We established primary cell cultures from head and neck cancer tissues and employed the FaDu cell line for in vitro studies, modulating KCNK1 expression through overexpression and knockdown techniques. We evaluated cell migration, invasion, and proliferation. Additionally, we developed a zebrafish PDX model to assess the impact of quinidine on tumor growth and metastasis in vivo. RNA sequencing and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted to elucidate the molecular mechanisms underlying the role of KCNK1 in cancer progression. Overexpression of KCNK1 in FaDu cells resulted in enhanced cell migration and invasion, whereas its knockdown diminished these processes. In the zebrafish PDX model, quinidine markedly inhibited tumor growth and metastasis, demonstrating a significant reduction in tumor volume and micrometastasis rates compared to the control groups. The molecular analyses indicated that KCNK1 plays a role in critical signaling pathways associated with tumor growth, such as the Ras and MAPK pathways. Our findings highlight the critical role of KCNK1 in promoting tumor growth and metastasis in head and neck cancer. The inhibitory effect of quinidine on tumor progression in the zebrafish PDX model highlights the therapeutic potential of targeting KCNK1. These results suggest that KCNK1 could serve as a valuable therapeutic target for head and neck cancer, warranting further investigation into treatments that target KCNK1.

A clustering approach to integrative analyses of multiomic cancer data

Rapid technological advances have allowed for molecular profiling across multiple omics domains for clinical decision-making in many diseases, especially cancer. However, as tumor development and progression are biological processes involving composite genomic aberrations, key challenges are to effectively assimilate information from these domains to identify genomic signatures and druggable biological entities, develop accurate risk prediction profiles for future patients, and identify novel patient subgroups for tailored therapy and monitoring. We propose integrative frameworks for high-dimensional multiple-domain cancer data. These Bayesian mixture model-based approaches coherently incorporate dependence within and between domains to accurately detect tumor subtypes, thus providing a catalog of genomic aberrations associated with cancer taxonomy. The flexible and scalable Bayesian nonparametric strategy performs simultaneous bidirectional clustering of the tumor samples and genomic probes to achieve dimension reduction. We describe an efficient variable selection procedure that can identify relevant genomic aberrations and potentially reveal underlying drivers of disease. Although the work is motivated by lung cancer datasets, the proposed methods are broadly applicable in a variety of contexts involving high-dimensional data. The success of the methodology is demonstrated using artificial data and lung cancer omics profiles publicly available from The Cancer Genome Atlas.

Long-term tumor control following gamma-knife radiosurgery of recurrent or residual pituitary adenomas: a population-based cohort study

BackgroundPituitary adenomas (PAs) often require adjuvant Gamma Knife radiosurgery (GKRS) due to partial resection or postoperative recurrence. The purpose of this study was to evaluate the long-term efficacy of GKRS for such cases.MethodsPopulation-based, observational cohort study of patients who underwent GKRS for postoperative residual or recurrent PAs between 1999 and 2020. We assessed long-term progression-free survival (PFS), identified predictors of tumor growth, and documented adverse radiation events (AREs).Results147 patients were included, with a median follow-up time of 8.1 years. Following GKRS, the 5-year and 10-year PFS was 86% and 68%, respectively, with a median PFS of 18.7 years. Somatotrophic adenomas showed a significantly lower risk of tumor progression in the regression analysis (OR 0.11, p = 0.003). Hypopituitarism was the most common ARE, affecting 32% of patients.ConclusionGKRS is an effective treatment option for recurrent or residual PAs, offering substantial long-term control. However, the risk for AREs, particularly hypopituitarism, is not negligeable.

Deciphering potential molecular mechanisms in clear cell renal cell carcinoma based on the ubiquitin-conjugating enzyme E2 related genes: Identifying UBE2C correlates to infiltration of regulatory T cells.

Renal clear cell carcinoma (ccRCC) is a highly aggressive and common form of kidney cancer, with limited treatment options for advanced stages. Recent studies have highlighted the importance of the ubiquitin-proteasome system in tumor progression, particularly the role of ubiquitin-conjugating enzyme E2 (UBE2) family members. However, the prognostic significance of UBE2-related genes (UBE2RGs) in ccRCC remains unclear. In this study, bulk RNA-sequencing and single-cell RNA-sequencing data from ccRCC patients were retrieved from the Cancer Genome Atlas and Gene Expression Omnibus databases. Differential expression analysis was performed to identify UBE2RGs associated with ccRCC. A combination of 10 machine learning methods was applied to develop an optimal prognostic model, and its predictive performance was evaluated using area under the curve (AUC) values for 1-, 3-, and 5-year overall survival (OS) in both training and validation cohorts. Functional enrichment analyses of gene ontology and Kyoto Encyclopedia of Genes and Genomes were conducted to explore the biological pathways involved. Correlation analysis was conducted to investigate the association between the risk score and tumor mutational burden (TMB) and immune cell infiltration. Immunotherapy and chemotherapy sensitivity were assessed by immunophenoscore and tumor immune, dysfunction, and exclusion scores to identify potential predictive significance. In vitro, knockdown of the key gene UBE2C in 786-O cells by specific small interfering RNA to validate its impact on apoptosis, migration, cell cycle, migration, invasion of tumor cells, and induction of regulatory T cells (Tregs). Analysis of sc-RNA revealed that UBE2 activity was significantly upregulated in malignant cells, suggesting its role in tumor progression. A three-gene prognostic model comprising UBE2C, UBE2D3, and UBE2T was constructed by Lasoo Cox regression and demonstrated robust predictive accuracy, with AUC values of 0.745, 0.766, and 0.771 for 1-, 3-, and 5-year survival, respectively. The model was validated as an independent prognostic factor in ccRCC. Patients in the high-risk group had a worse prognosis, higher TMB scores, and low responsiveness to immunotherapy. Additionally, immune infiltration and chemotherapy sensitivity analyses revealed that UBE2RGs are associated with various immune cells and drugs, suggesting that UBE2RGs could be a potential therapeutic target for ccRCC. In vitro experiments confirmed that the reduction of UBE2C led to an increase in apoptosis rate, as well as a decrease in tumor cell invasion and metastasis abilities. Additionally, si-UBE2C cells reduced the release of the cytokine Transforming Growth Factor-beta 1 (TGF-β1), leading to a decreased ratio of Tregs in the co-culture system. This study presents a novel three-gene prognostic model based on UBE2RGs that demonstrates significant predictive value for OS, immunotherapy, and chemotherapy in ccRCC patients. The findings underscore the potential of UBE2 family members as biomarkers and therapeutic targets in ccRCC, warranting further investigation in prospective clinical trials.

FAP+ gastric cancer mesenchymal stromal cells via paracrining INHBA and remodeling ECM promote tumor progression

Gastric cancer (GC) mesenchymal stromal cells (GCMSCs) are the predominant components of the tumor microenvironment (TME) and play a role in the occurrence, development, and metastasis of tumors. However, GCMSCs exhibit phenotypic and functional heterogeneity. The key population of GCMSCs which are vital to tumor progression remains elusive. The expression of fibroblast activation protein (FAP) in gastric cancer was analyzed and verified using clinical pathology data and single-cell RNA sequencing database of gastric cancer patients. FAP positive GCMSCs (FAP+ GCMSCs) were isolated via flow cytometry and characterized through transcriptomic sequencing. The impact of conditioned medium from FAP+ GCMSCs on gastric cancer cell lines was assessed using Enzyme-linked immunosorbent assay (ELISA) and Western blot analyses. Additionally, immunohistochemistry (IHC) and Masson’s trichrome staining were employed to explore the association between FAP+ GCMSCs and extracellular matrix (ECM) deposition in gastric cancer tissues. Our study demonstrates that FAP is predominantly expressed in the mesenchymal stromal cells within the gastric cancer milieu. FAP+ GCMSCs exhibited enhanced proliferation, migration, contraction, and tumor-promoting capabilities compared to their FAP− counterparts. These cells significantly increased proliferation and migration of gastric cancer cells through the paracrine secretion of Inhibin Subunit Beta A (INHBA) and activation of the SMAD2/3 signaling pathway. Moreover, FAP+ GCMSCs also induced collagen deposition in ECM and then up-regulated invasion and stemness of GC cells. Mechanistically, this process was mediated by the interaction of collagen with Integrin Subunit Beta 1 (ITGB1), triggering the phosphorylation of Focal Adhesion Kinase (FAK) and Yes Associated Transcriptional Regulator (YAP). Our findings reveal that FAP+ GCSMCs enhanced the GC progression via releasing cytokine INHBA and remodeling ECM providing a theoretical basis for further exploration of tumor stromal-targeting therapy of gastric cancer.

Phase I study of [68Ga]Ga-HX01 for targeting integrin αvβ3 and CD13 in healthy and malignancy subjects.

Noninvasive angiogenesis visualization is essential for evaluating tumor proliferation, progression, invasion, and metastasis. This study aimed to translate the heterodimeric PET tracer [68Ga]Ga-HX01, which targets integrin αvβ3 and CD13 in neovascularization, into phase I clinical study. This study enrolled 12 healthy volunteers (phase Ia) and 10 patients with malignant tumors (phase Ib). The subjects in phase Ia were divided into low-dose (0.05 mCi/kg) and high-dose (0.1 mCi/kg) groups. For phase Ia subjects, PET/CT images, blood and urine samples were collected to analyze the biodistribution, pharmacokinetics, radiation dosimetry, and safety of [68Ga]Ga-HX01. For phase Ib patients, PET/MR scans were performed at 30 ± 5 and 60 ± 5min after injection. The safety and preliminary diagnostic value of [68Ga]Ga-HX01 were assessed. In phase Ia study, [68Ga]Ga-HX01 was distributed and metabolized similarly in two dosage groups as the highest accumulations in kidneys and urine. It possessed quick renal excretion and blood clearance with an elimination half-life (T1/2) of 28.92 ± 3.97min. The total effective dose was 2.14 × 10- 2 mSv/MBq. In phase Ib study, [68Ga]Ga-HX01 clearly detected the lesions per patient, and found a total of 59 lesions with varying uptake levels. For safety evaluation, no serious adverse events were observed during the examination. [68Ga]Ga-HX01 has proved to be a translational radiopharmaceutical with reliable security, favorable pharmacokinetics, and the ability to visualize tumors. The preliminary results in malignancy patients warrant further investigation of [68Ga]Ga-HX01 in monitoring antiangiogenic therapy of patients with malignancies. ClinicalTrials.gov, NCT06416774. Registered 11 May, 2024.

Identification of ETV5 as a prognostic marker related to epigenetic modification in pan-cancer and facilitates tumor progression in hepatocellular carcinoma

ETS variant transcription factor 5 (ETV5), a master transcription factor during development, exerts vital function on the occurrence and progression of various cancers. In order to systematically analyze and explore ETV5 potential specific regulatory mechanisms in pan-cancer, RNA sequencing data and clinicopathological features of patients with various tumors were obtained through the Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases, and an integrated data mining analysis was carried out, including the association of ETV5 expression with patient prognosis, drug sensitivity and epigenetic modification. The results revealed that abnormally highly expressed ETV5 resulted in unfavorable prognosis and differential drug sensitivity in multiple malignancies, and its expression was associated with epigenetic modification modulators including EZH2. ETV5 related genes were enriched in tumorigenesis biological processes and signaling pathways. In hepatocellular carcinoma, ETV5 expression was correlated with patients’ tumor pathological stage and resulted in adverse outcome of patients. Our further experiments evidences indicated that ETV5 facilitated cell proliferation and reduced sensitivity to GSK126 via regulating EZH2. Collectively, this study comprehensively elucidates the carcinogenic effects and molecular mechanisms of ETV5 in tumorigenesis and development, and provides theoretical basis and guidance for tumor diagnosis, targeted therapy for ETV5 and clinical epigenetic drug research.

A hypoxia-activated and microenvironment-remodeling nanoplatform for multifunctional imaging and potentiated immunotherapy of cancer

Activatable theranostic systems combining precise diagnosis and robust immune activation have significant potential in cancer treatment. Herein, we develop a versatile nanoplatform integrating hypoxia-activatable molecular imaging with effective photoimmunotherapy for cancer treatment. Our molecular probe features turn-on near-infrared-II (NIR-II) fluorescence and photoacoustic signals in hypoxic tumor environments. It also induces hypoxia-triggered photodynamic and photothermal effects, promoting immunogenic cell death and activating the STING pathway, engaging both innate and adaptive immunity. The molecular probe is formulated with a vascular disrupting agent to amplify the hypoxia-responsive phototheranostic properties, on which M1-like macrophage membrane is camouflaged to shield against premature release while conferring cancer-targeting affinity. The activatable NIR-II fluorescence and photoacoustic imaging enable precise tumor delineation, while the enhanced phototherapy activates tumor-specific cytotoxic T cells, impeding both primary and distant tumor progression and providing protective immunity against rechallenge in 4T1 tumor-bearing female mice. This work advances activatable theranostic protocols for image-guided immunotherapy.