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PubMed2003

Integrin alpha1beta1 and alpha2beta1 are the key regulators of hepatocarcinoma cell invasion across the fibrotic matrix microenvironment.

As with many types of cancer, cell motility is an important factor in the progression and metastasis of hepatocellular carcinomas (HCC). HCC is associated with significant fibrosis in the liver. The fibrotic microenvironment in the liver is characterized by an altered composition of the extracellular matrix (ECM) and an abundance of growth factors that are likely conducive to migration of HCC cells. The purpose of this study was to delineate promigratory stimuli within the fibrotic microenvironment and to identify specific targets for prevention of HCC cell migration. We used a modified Boyden chamber system that allowed distinction between chemotactic (indirect stimulation) and haptotactic (direct stimulation) migration of two distinct HCC cell lines across the ECM-coated membrane. Fibrotic microenvironment-associated growth factors, such as transforming growth factor beta1 (TGF-beta1), basic fibroblast growth factor (bFGF), and epidermal growth factor (EGF), induced chemotactic and haptotactic migration of HepG2 and Chang cells. Neutralizing antibodies to individual growth factors significantly decreased chemotactic and haptotactic migration. Haptotactic stimulation, but not chemotactic stimulation of HCC cell lines with TGF-beta1, bFGF, and EGF, induced production of matrix metalloproteinase (MMP) 2, a potential mediator of migration. Inhibition of MMPs significantly decreased haptotactic migration induced by individual growth factors but had an insignificant effect on chemotactic migration, suggesting an MMP-independent migration in this setting. Inhibition of cell-ECM interactions with blocking antibodies to alpha1 and alpha2 integrins were sufficient to inhibit both haptotactic and chemotactic migration induced by individual growth factors, strongly suggesting that targeting these integrins to abrogate pathogenic cell-ECM interactions might be a promising tool for inhibiting growth factor-induced invasion and metastasis of HCC.

Carcinoma, Hepatocellular↗

PubMed1992

Temperature and humidity within the clothing microenvironment.

The present study investigates clothing microenvironment conditions that may develop during prolonged exposure of workers to a hot environment. Five subjects were exposed to a linear increase in ambient temperature from 20-40 degrees C over a 90-min period, and then remained at 40 degrees C for an additional 90 min. During the exposures, subjects were clad in four types of helicopter personnel suits (Gore-Tex, Cotton Ventile, Nomex/Insulite, and Nomex/Neoprene), incorporating both dry-suit and wet-suit designs. Continuous assessment was made of skin temperature, rectal temperature, and of microenvironment temperature, relative humidity, and vapor pressure (T mu, RH mu, and VP mu) 8 mm from the surface of the skin. Results indicate that although microenvironment temperatures were similar among suits and slightly lower than that of the environment, the RH mu and VP mu were much greater than those of the ambient air. The Nomex/Insulite and Nomex/Neoprene suits showed the highest VP mu, of which only the Nomex/Insulite resulted in significantly greater increases in rectal temperature, likely due to complete covering of the body with the impermeable insulite component. The present study demonstrates the need to discern between the ambient conditions and the conditions encountered next to the skin when protective clothing is worn.

Adult↗

PubMed2005

Prostate cancer cell survival pathways activated by bone metastasis microenvironment.

The development of resistance to anti-cancer therapies in bones is a major hurdle preventing long-lasting clinical responses to anti-cancer therapies in hormone refractory prostate cancer. Herein, we present the major signal transduction pathways, which are activated in prostate cancer cells residing at bone metastasis microenvironment. These intracellular signal transduction pathways can inhibit anti-cancer therapy-induced apoptosis of metastatic prostate cancer cells, thereby optimizing their survival, locally. Employment of this knowledge in a clinical setting provides the conceptual framework for the development of bone-targeted therapies for advanced prostate cancer. Indeed, bone metastasis microenvironment-targeted therapies illustrate a novel paradigm in cancer treatment: anti-tumor treatment strategies may not only aim at directly inducing cancer cell apoptosis, but can also target the tumor metastasis microenvironment, and neutralize the protection it confers on metastatic cancer cells.

Androgen Antagonists↗

PubMed2005

[Microenvironment effect of APA microcapsule on embryonic stem cell].

We undertook a series of studies to evaluate the role of microenvironment during embryonic stem cell (ESC) proliferation and differentiation. In this paper, cell microencapsulation technology was employed, which allows the free exchange of nutrients, oxygen and biologically active products between the entrapped cell and culture medium. We analyzed the feasibility of mouse ESCs in microcapsules and evaluated the growth, metabolic activity and differentiation of ESCs once enclosed in alginate-Ca(2+) microbead, solid or liquefied core alginate-poly-lysine-alginate (APA) microcapsule, respectively. We found that ESCs grew gradually in both types of microcapsules, but the appearance of cells was distinctive for each type of capsule. In the case of unliquefied microcapsules, cells created multiple spherical or lens-shaped aggregates. In contrast, the liquefied alginate core allowed the enclosed ESCs to grow together in a clump at the periphery of the capsule. Combined with cell viability and activity of glucose/lactic acid metabolism, the liquefied core of APA might provide more suitable culture conditions for the ESC growth in comparison with the unliquefied type or alginate-Ca(2+). For better evaluating the nature of ESC growth in APA microcapsules in vitro (that is whether or not encapsulated ESCs maintained undifferentiated state while they kept the ability for proliferation), the expression of the typical markers for undifferentiated, dividing ESCs, such as the stage specific embryonic antigen (SSEA-1) and alkaline phosphatase (AP), was detected by immunochemistry and immunofluorescence staining. The results showed that cell aggregates formed in the microcapsule still expressed the marker proteins at a higher level on day 22 in vitro. The expression of gene Oct-4, a transcription factor necessary for maintaining ESCs in an undifferentiated state, was also detected when RT-PCR assay was employed (on day 22 in vitro). In addition, cell aggregates were released from the microcapsules by mechanical disruption and induced into insulin-producing cells. These findings further indicate that most of the ESCs in APA microcapsule maintain their multi-potential even though the culture time prolonged as long as 22 d in vitro. Taken together, APA microcapsule provides a suitable microenvironment that promotes ESCs to maintain their stemness. Therefore, the microenvironment plays an important role in the process of ESC proliferation and differentiation.

Alginates↗

PubMed1990

Phenotypic characterization of murine thymic microenvironments.

The thymus provides the necessary microenvironments for the differentiation of T lymphocytes. Thymic non-lymphoid cells, such as epithelial cells, macrophages and interdigitating cells are thought to promote sequential stages in T cell differentiation. However, their specific role in each step of T cell differentiation remains to be established. With the development of new monoclonal antibodies it has now become possible to characterize the different thymic stromal cell types. In this review, various aspects of thymic stromal cells and their functions in T cell differentiation are discussed, such as: (1) phenotypic analysis of stromal cells in situ; (2) the application of new "chimeric' monoclonal antibodies which "link' developing thymocytes and stromal cells; (3) perturbation of thymic microenvironments after cyclosporin-A treatment; (4) perturbation of thymic microenvironments in new transgenic mouse lines; (5) phenotypic analysis of in vitro growing stromal cell lines.

Animals↗

PubMed1991

Stochastic microenvironment models for air pollution exposure.

Exposure assessment is a crucial link in air pollution risk assessment and management. With the recent advances in instrumentation, it has become possible to measure air pollution exposures in the vicinity of the individual human subjects, using either personal monitoring or microenvironment monitoring. For many important pollutants such as CO, NO2, and VOC, the air pollution exposure depends crucially on the location and activity of the individual: indoor versus outdoor, smoking versus not smoking, etc. The stochastic microenvironment models were developed to relate air pollution exposure to the location and activity. We review the two major existing models, the Cartesianization method (Duan, 1980, 1982, 1987) and SHAPE (Ott, 1981, 1982, 1984), and compare their assumptions and implications. We also propose a new model, the variance components model, which includes both Cartesianization and SHAPE as special cases. The variance components model considers both long-term average concentrations and short-term fluctuations. The Cartesianization focuses on long-term averages, while SHAPE focuses on short-term fluctuations. We propose to choose among the three models by examining the variance function which relates variability to averaging time. The theory is applied to the data collected from U.S. EPA's Washington CO Study, with the variance function estimated using Carroll and Ruppert's (1984) transform-both-sides regression model and Duan's (1983) smearing estimate. For the microenvironment in transit, both long-term averages and short-term fluctuations are important.

Air Pollution↗

PubMed1989

Morphology of interactions of the haematopoietic microenvironment with the haematopoietic cells in erythroid spleen colonies.

The morphology of the interactions of the cells of the haematopoietic microenvironment with haematopoietic cells was studied in exogenous erythroid spleen colonies formed in mice, on the fifth and eighth day after their irradiation with a lethal dose of gamma rays and bone marrow transplantation. The characteristic type of stromal cell interacting with less mature cells of the erythroid series was a dark, branching reticular cell. The typical structural interaction of the reticular cells with erythroblasts was the formation of very long, fine cytoplasmic processes by the reticular cells. The processes were in close contact with the erythroblasts and formed a three-dimensional network stretching long distances from the nucleus of the reticular cells. Other cells of the haematopoietic microenvironment, in contact chiefly with poly- and ortochromic erythroblasts, were macrophages and the two together formed typical erythroblastic islands. In places, the macrophages and erythroblasts formed close, firm contacts by means of their cytoplasmic membranes. These morphological observations support the conception that close functional cooperation exists between the cells of the haematopoietic microenvironment and the haematopoietic cells in differentiation and proliferation processes in the haematopoietic tissue of spleen colonies.

Animals↗

PubMed1978

Hematopoiesis on cellulose ester membranes (CEM). I. Functional characteristics of cells comprising the hematopoietic microenvironment.

Cellulose ester membranes (CEM) implanted into the peritoneal cavity of mice rapidly became coated with cells of peritoneal origin. Up to 56% of the cells, at a peak point 3-5 days after implantation, showed cell membrane receptors for complement and cytophilic immunoglobulin. A similar proportion of cells from CEM phagocytized yeast particles in vitro. When studied in situ, rosettes with C3b and IgG coated erythrocytes were formed by 23% of the cells coating CEM. A decreasing percentage of cells with monocyte-macrophage characteristics were detected between 5 and 17 days. CEM removed at 2 or 6 weeks after peritoneal implantation enriched tissue cultured media with colony stimulating factor which supported the growth of granulopoietic colonies in softagar culture. Mice given 59iron and 99technetium sulfur colloid i.v. showed substantial uptake of both isotopes by the CEM but the 59iron uptake could not be suppressed by hypertransfusion. Surface hematopoietic colony formation on CEM was studied 1-14 days after implantation. A peak colony number occurred at 5 days and the fell off slightly by 2 weeks. These studies indicate that the hematopoietic microenvironment of peritoneally implanted CEM contains a major sub-population of cells with monocytemacrophage features. The hematopoietic microenvironment was well-maintained even though the percentage of monocyte-macrophage marked cells decreased indicating that the microenvironment is not solely dependent upon monocyte-macrophages.

Animals↗

PubMedDate not supplied

[Characteristics of the restoration of the hematopoietic microenvironment of the spleen regenerating after partial damage].

The initial stages of restoration of hemopoietic microenvironment in a regenerating spleen were studied functionally and morphologically after its partial damage. The hemopoietic microenvironment is restored locally and this process involves the damaged region only. The stages of restoration of hemopoietic microenvironment in the spleen are determined only by the properties of the spleen stroma itself and do not depend on the conditions of regeneration (in situ damage or ectopic transplantation).

Animals↗

PubMed1983

Progression of mouse thymic leukemias in thymic microenvironments.

Mouse thymic leukemogenesis has been assumed to occur in multiple steps corresponding to the stages of normal T-cell lineage development. One of the roles of the thymus in leukemogenesis is to provide permissive microenvironments for the progression of developing leukemias from thymus-dependent to independent growth. We have devised a method to consistently isolate the symbiotic complex of leukemia cells and thymic epithelium-like stromal cells from primary leukemic thymuses. In such complexes, leukemia cells were able to proliferate in close association with thymic stromal cells in pseudoemperipolesis, i.e., a unique form of cell interaction which we defined. In normal thymus, subcapsular zone blasts, mitotically active early thymic lymphocytes, were able to form similar complexes with thymic stromal cells, but this property was lost as they differentiated into cortical small lymphocytes. These observations indicate that the stage of intrathymic progression of leukemias is critically linked with the stage of subcapsular zone blasts of normal thymic lymphopoiesis. Mechanism and regulation of the complex formation was analyzed by an in vitro assay. We found that many thymic microenvironment-dependent leukemia cells were reversibly stimulated to proliferate by various tumor-promoters sharing a cellular receptor for phorbol esters. Without support by adequate stromal cells or a tumor promoter, leukemia cells rapidly ceased to grow and died. The degree of growth stimulation was well correlated with their tumor-promoting activity in mouse skin. Action of tumor promoters on microenvironment-dependent leukemias seemed to be direct rather than mediated by lymphokines. Another remarkable effect of tumor promoters was their inhibition of complex formation, presumably by affecting the cytoskeleton.

Animals↗

PubMed1994

Role of marrow microenvironment in engraftment and maintenance of allogeneic hematopoietic stem cells.

Following allogeneic marrow transplantation a competent marrow microenvironment consists of a complex mixture of both donor and host derived cells. Clearly some forms of genetic disparity between donor and host can compromise appropriate interactions and function of these cells. The competency of the microenvironment can also be compromised by viral infections, and the underlying disease process as in rare cases of aplastic anemia. As we come to precisely define each component of the microenvironment, it will become possible to accurately diagnose causes of poor marrow function and develop methods for prevention and treatment.

Adipose Tissue↗

PubMed1996

Composition and function of the hemopoietic microenvironment in human myeloid leukemia.

In normal adult mammals, blood cell production, hemopoiesis, takes place within the medullary cavity. There, hemopoietic cell proliferation and differentiation are regulated by a network of stromal/accessory cells and their products (ie cytokines and extracellular matrix molecules), known as the hemopoietic microenvironment. Recent in vitro studies indicate that both cell composition and functional abnormalities of the hemopoletic microenvironment are present in a proportion of patients with myeloid leukemia, both chronic (CML) and acute (AML). Cell composition abnormalities have been primarily observed in a subset of patients with AML; these abnormalities include reduced numbers of fibroblast progenitors and, in some cases, reduced numbers of macrophages and adipocytes. In terms of function, it has been shown that the marrow stromal cells from a significant number of both CML and AML patients, possess a deficient hemopoletic supportive capacity in vitro. This seems to be related to the presence of functionally abnormal, malignant macrophages. The mechanisms by which these macrophages alter the hemopoietic function of the marrow stroma, as a whole, are still not fully understood. Whereas in AML, a macrophage-derived soluble inhibitory activity (containing tumor necrosis factor alpha) has been described; in CML, a direct, macrophage-mediated cell-to-cell contact mechanism for hemopoietic inhibition seems to be involved. To date, however, it is not clear whether the abnormalities in the hemopoietic microenvironment are secondary to myeloid leukemia or if they precede clinical CML/AML. Furthermore, it is not known to what extent the functional abnormalities observed in vitro contribute to the hematologic dysfunction that characterizes myeloid leukemia and to the in vivo progression of the disease.

Adipocytes↗

PubMedDate not supplied

Identification of neural crest derived cells within the cellular microenvironment of the human thymus employing a library of monoclonal antibodies raised against neuronal tissues.

The organization of optimal microenvironmental conditions within the developing thymus for lymphatic stem cell migration and their further maturation requires cellular and humoral participation of the neural crest. Recently, the immunophenotypical (IP) heterogeneity of lymphatic cells has become a scientific fact. Monoclonal antibodies (MoABs) produced against the various subpopulations of the reticulo-epithelial cells (RE) demonstrated their heterogeneity. We suggest that with a library of MoABs, raised against normal neuronal tissues, neural tumors, and a medulloblastoma cell line, including UJ13/A, UJ127.11, UJ167.11, UJ223.8, UJ308, J1153, A2B5, 215.D11, 275.G7, 282.1, antineurofilament (NF - med. m.w.), and anti-Thy-1 it is possible to recognize cells of neural crest origin within the postnatal thymic cellular microenvironment. Evidence has been collected concerning such connections between the nervous system and the thymus, such as the production of neuropeptides, oxytocin, and neurophysin by the thymus. Our immunohistochemical study was carried out on quick-frozen sections of human postnatal thymuses removed during open heart surgery, employing an indirect, alkaline phosphatase conjugated streptavidin-biotin technique. The employed MoABs reacted with the subcapsular (outer cortex) thymic nurse cells (TNCs) and with medullary RE cells, in close contact with already mature, immunocompetent T lymphocytes ready to leave the thymic microenvironment and enter the peripheral blood. The thymic medulla's strong immunoreactivity with A2B5, which binds to the GQ ganglioside, is typical for peptide secreting cells often migrated from the neural crest. A2B5+, Thy-1+ IP was demonstrated on the large TNCs. Cortical RE cells showed reactivity with UJ127.11, UJ223.8, and UJ308. Dense expression of neural crest antigens was detected in the Hassall's bodies (HBs) employing MoABs UJ223.8, UJ308, 215.D11, and 275.G7. These results suggest a neural crest origin for TNCs and for 20% to 30% of the cells of thymic microenvironment. The outer (peripheral) part of the HBs contained functionally very active RE cells. These RE cells also expressed antigens characteristic of the neural crest, detectable with MoABs UJ127.11, UJ223.8, UJ308, J1153, 215.D11, 275.G7 and A2B5.

Animals↗

PubMed2026

Effect of Tertiary Lymphoid Structures on Immune Cell Infiltration in the Tumor Microenvironment and Prognosis in Lung Adenocarcinoma.

Tertiary lymphoid structures (TLSs) modulate immune responses in various solid tumors, but their comprehensive role in lung adenocarcinoma (LUAD) remains unclear. In this study, we analyzed RNA-seq data from 539 LUAD patients in The Cancer Genome Atlas (TCGA) and microarray data from 223 samples from the Gene Expression Omnibus (GEO, GSE13213, and GSE37745). TLS signatures were evaluated via unsupervised consensus clustering based on 12 chemokine transcriptome signatures. The relationships between TLS and clinical characteristics, tumor microenvironment (TME) cell infiltration, and prognosis were assessed using ESTIMATE and CIBERSORT. A prognostic model was established using LASSO regression and validated with external datasets. Additionally, H&E and IHC analyses were performed to explore associations between intratumoral TLS density, immune-related molecular expression, and patient prognosis in LUAD. Consensus clustering of the TCGA cohort revealed two distinct LUAD patient clusters according to TLS abundance. Cluster 1 exhibited greater immune cell infiltration, more favorable prognosis, and increased expression of immune checkpoint molecules. We developed a prognostic model comprising eight survival-associated genes that act as independent prognostic factors for patient survival. H&E/IHC analyses revealed that TLS density-regardless of pathological stage-was associated with better prognosis; higher intratumoral TLS density/proportion was also related to more favorable outcomes. IHC confirmed that survival-associated genes (CD5, HLA-DMB, and P2RY13) are independent prognostic indicators in LUAD. Our study demonstrated the close relationship between TLS signatures and an active immune microenvironment, highlighting their potential as independent prognostic indicators in LUAD.

Humans↗

PubMed2025

Digital Immunophenotyping of Lung Atypical Carcinoids and Large Cell Neuroendocrine Carcinomas Identifies Three Subtypes With Specific Tumor-Immune Microenvironment Features.

Atypical carcinoids (ACs) and large cell neuroendocrine carcinomas (LCNECs) are defined by the WHO as intermediate- and high-grade lung neuroendocrine neoplasms, respectively, based on morphological criteria; however, treatment strategies remain debated. Given the emerging role of the tumor microenvironment (TME) and tumor-infiltrating lymphocytes (TILs) in cancer prognosis and therapy response, this study aimed to characterize the immune landscape of ACs and LCNECs comprehensively. Immunohistochemistry for T-cell markers (CD3, CD8), immune checkpoints (PD-1, PD-L1), HLA molecules (HLA-DR, HLA-I), and fibroblasts (α-SMA) was performed on a re-evaluated cohort of 56 ACs and 104 LCNECs. Digital image analysis quantified intra-tumor (iTILs) and stromal (sTILs) CD3 and CD8 TILs in the whole slide and in specific tumor regions (invasive margin [IM] and central tumor [CT]). LCNECs exhibited significantly higher stromal T-cell infiltration, immune checkpoint expression, and HLA compared to ACs (p < 0.001), while α-SMA was more prominent in ACs. No ACs showed PD-L1 tumor expression. Digital quantification confirmed greater iTILs and sTILs in LCNECs across all regions, with moderate concordance to manual counts. Interestingly, TIL parameters were higher at the IM than in the CT (p < 0.001). Using Boruta feature selection algorithm, Principal Component Analysis and Hierarchical Clustering, three patient clusters were identified: Cluster 1 (mainly ACs, low TILs, favorable prognosis), Cluster 2 (mixed histology, intermediate TILs, moderate prognosis), and Cluster 3 (mostly LCNECs, high TILs, poor prognosis), with distinct TME marker profiles. PD-L1 tumor expression was strongly linked to Cluster 3. These findings suggest that ACs and LCNECs may be stratified into three distinct immune clusters, highlighting the heterogeneity of their tumor microenvironment and providing a rationale for further translational studies.

Humans↗

PubMed2025

Integrative multi-omics profiling deciphers tumor microenvironment heterogeneity and immunotherapy vulnerabilities in lung neuroendocrine carcinomas.

INTRODUCTION: Lung neuroendocrine carcinomas (Lu-NECs) are rare, highly aggressive lung tumors with poor prognosis and limited therapeutic options. Understanding the tumor immune microenvironment (TIME) is crucial towards personalized therapeutic strategies. OBJECTIVES: This study aims to systematically characterize the heterogeneity and complexity of the TIME in Lu-NECs by integrating proteomic, transcriptomic, and genomic data. METHODS: We performed comprehensive immune-proteomic profiling of 76 Lu-NECs across diverse histopathological subtypes to elucidate intra-tumoral TIME heterogeneity at the proteomic level. Validation was conducted in multiple independent cohorts, including 112 Lu-NECs using immunohistochemistry, 147 Lu-NECs, and 17 small cell lung carcinoma samples using transcriptomics. We integrated proteomic, transcriptomic, genomic, and clinical data to assess molecular, immunological, and clinical features, as well as therapeutic vulnerabilities across different immune subtypes. RESULTS: We delineated the immuno-proteomic landscape of Lu-NECs and identified two major immuno-proteomic clusters with distinct immunological, molecular, and clinical characteristics. IPC1 was characterized by high immune cell infiltration, while IPC2 exhibited sparse immune cell presence. Genomic analysis revealed distinct mutational patterns, with IPC1 showing a higher incidence of APOBEC-associated mutation signatures and IPC2 being enriched for mutations associated with defective DNA mismatch repair and tobacco-related mutagens. Functional analyses indicated that IPC1 was related to immune and oncogenic signaling activity, whereas IPC2 was associated with cancer stemness and proliferation-related features. Furthermore, IPC1 and IPC2 demonstrated histological subtype-specific clinical benefits from postoperative chemotherapy. Finally, we developed a machine learning model (iPROM) to predict Lu-NECs immune classification and improve risk stratification, which was validated across multiple independent cohorts. CONCLUSIONS: This study advances the understanding of the tumor immune microenvironment in Lu-NECs through multi-omics characterization and highlights potential personalized therapeutic vulnerabilities tailored to the specific immune landscapes of Lu-NECs.

Humans↗

PubMed2025

A novel glycogene-related signature for prognostic prediction and immune microenvironment assessment in kidney renal clear cell carcinoma.

BACKGROUND: Kidney Renal Clear Cell Carcinoma (KIRC) is a prevalent urinary malignancies worldwide. Glycosylation is a key post-translational modification that is essential in cancer progression. However, its relationship with prognosis, tumour microenvironment (TME), and treatment response in KIRC remains unclear. METHOD: Expression profiles and clinical data were retrieved from The Cancer Genome Atlas and Gene Expression Omnibus databases. Consensus clustering, Cox regression, and LASSO regression analyses were conducted to develop an optimal glycogene-related signature. The prognostic relevance of this molecular signature was rigorously analyzed, along with its connections to tumour microenvironment (TME), tumour mutation burden, immune checkpoint activity, cancer-immunity cycle regulation, immunomodulatory gene expression patterns, and therapeutic response profiles. Validation was performed using real-world clinical specimens, quantitative PCR (qPCR), and immunohistochemistry (IHC), supported by cohort analyses from the Human Protein Atlas (HPA) database. RESULTS: A glycogene-associated prognostic scoring system was established to categorize patients into risk-stratified subgroups. Patients in the high-risk cohort exhibited significantly poorer survival outcomes (p < 0.001). By incorporating clinicopathological variables into this framework, we established a predictive nomogram demonstrating strong calibration and a concordance index (C-index) of 0.78. The high-risk subgroup displayed elevated immune infiltration scores (p < 0.001), upregulated expression of immune checkpoint-related genes (p < 0.05), and an increased frequency of somatic mutations (p = 0.043). The risk score positively correlated with cancer-immunity cycle activation and immunotherapy-related signals. The high-risk groups also showed associations with T cell exhaustion, immune-activating genes, chemokines, and receptors. Drug sensitivity analysis revealed that low-risk patients were more sensitive to sorafenib, pazopanib, and erlotinib, whereas high-risk individuals responded better to temsirolimus (p < 0.01). qPCR and IHC analyses consistently revealed distinct expression patterns of MX2 and other key genes across the risk groups, further corroborated by the HPA findings. CONCLUSION: This glycogene-based signature provides a robust tool for predicting prognosis, TME characteristics, and therapeutic responses in KIRC, offering potential clinical utility in patient management.

Humans↗

PubMed2025

Development and validation of a novel risk stratification signature derived from migrasome and tumor microenvironment-related genes for molecular subtyping and improving clinical outcomes in head and neck squamous cell carcinoma.

BACKGROUND: The tumor microenvironment (TME) and migrasomes released by tumor cells significantly influence carcinogenesis and immune evasion. However, our understanding of the prognostic and therapeutic implications of migrasome and tumor microenvironment-related genes (mtmRGs) in head and neck squamous cell carcinoma (HNSCC) remains limited. METHODS: We explored the relationship between mtmRGs and HNSCC prognosis by utilizing The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. Subsequently, we developed an innovative prognostic signature, and assessed its prognostic significance using the Kaplan-Meier method, time-dependent receiver operating characteristic (ROC), and Cox regression analyses. To explore the underlying mechanisms, we conducted gene set variation analysis (GSVA), gene set enrichment analysis (GESA), and immune infiltration analysis. A nomogram was developed to estimate the overall survival (OS) rates for HNSCC patients. Lastly, we chose P4HA1, which was part of the signature, for additional experimental validation in vitro and in vivo. RESULTS: The mtmRGs signature effectively classifies HNSCC patients into two distinct risk subgroups, with the high-risk cohort demonstrating significantly poorer OS. The risk score serves as an independent prognostic factor for HNSCC patients; those with lower risk scores are more likely to exhibit favorable responses to immunotherapy, particularly with CTLA4 inhibitors. Furthermore, a lower risk score is significantly correlated with the sensitivity of HNSCC patients to cyclophosphamide, gemcitabine, and axitinib. CONCLUSION: This study presents an innovative gene signature associated with mtmRGs, which may be utilized both for predicting survival and directing personalized chemotherapy and immunotherapy regiments for patients with HNSCC.

Humans↗