Dataset Information

Cellular and Molecular Players in the Tumor Microenvironment of Renal Cell Carcinoma.

ABSTRACT: Globally, clear-cell renal cell carcinoma (ccRCC) represents the most prevalent type of kidney cancer. Surgery plays a key role in the treatment of this cancer, although one third of patients are diagnosed with metastatic ccRCC and about 25% of patients will develop a recurrence after nephrectomy with curative intent. Molecular-target-based agents, such as tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs), are recommended for advanced cancers. In addition to cancer cells, the tumor microenvironment (TME) includes non-malignant cell types embedded in an altered extracellular matrix (ECM). The evidence confirms that interactions among cancer cells and TME elements exist and are thought to play crucial roles in the development of cancer, making them promising therapeutic targets. In the TME, an unfavorable pH, waste product accumulation, and competition for nutrients between cancer and immune cells may be regarded as further possible mechanisms of immune escape. To enhance immunotherapies and reduce resistance, it is crucial first to understand how the immune cells work and interact with cancer and other cancer-associated cells in such a complex tumor microenvironment.

SUBMITTER: Lasorsa F

PROVIDER: S-EPMC10299533 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Cellular and Molecular Players in the Tumor Microenvironment of Renal Cell Carcinoma.

Lasorsa Francesco F Rutigliano Monica M Milella Martina M Ferro Matteo M Pandolfo Savio Domenico SD Crocetto Felice F Tataru Octavian Sabin OS Autorino Riccardo R Battaglia Michele M Ditonno Pasquale P Lucarelli Giuseppe G

Journal of clinical medicine 20230607 12

Globally, clear-cell renal cell carcinoma (ccRCC) represents the most prevalent type of kidney cancer. Surgery plays a key role in the treatment of this cancer, although one third of patients are diagnosed with metastatic ccRCC and about 25% of patients will develop a recurrence after nephrectomy with curative intent. Molecular-target-based agents, such as tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs), are recommended for advanced cancers. In addition to cancer cells, ...[more]

PMID: 37373581

Similar Datasets

Project description:Background: RNA methylation modification plays an important role in immune regulation. m7G RNA methylation is an emerging research hotspot in the RNA methylation field. However, its role in the tumor immune microenvironment of kidney renal clear cell carcinoma (KIRC) is still unclear. Methods: We analyzed the expression profiles of 29 m7G regulators in KIRC, integrated multiple datasets to identify a novel m7G regulator-mediated molecular subtype, and developed the m7G score. We evaluated the immune tumor microenvironments in m7G clusters and analyzed the correlation of the m7G score with immune cells and drug sensitivity. We tested the predictive power of the m7G score for prognosis of patients with KIRC and verified the predictive accuracy of the m7G score by using the GSE40912 and E-MTAB-1980 datasets. The genes used to develop the m7G score were verified by qRT-PCR. Finally, we experimentally analyzed the effects of WDR4 knockdown on KIRC proliferation, migration, invasion, and drug sensitivity. Results: We identified three m7G clusters. The expression of m7G regulators was higher in cluster C than in other clusters. m7G cluster C was related to immune activation, low tumor purity, good prognosis, and low m7G score. Cluster B was related to drug metabolism, high tumor purity, poor survival, and high m7G score. Cluster A was related to purine metabolism. The m7G score can well-predict the prognosis of patients with KIRC, and its prediction accuracy based on the m7G score nomogram was very high. Patients with high m7G scores were more sensitive to rapamycin, gefitinib, sunitinib, and vinblastine than other patients. Knocking down WDR4 can inhibit the proliferation, migration, and invasion of 786-0 and Caki-1 cells and increase sensitivity to sorafenib and sunitinib. Conclusion: We proposed a novel molecular subtype related to m7G modification and revealed the immune cell infiltration characteristics of different subtypes. The developed m7G score can well-predict the prognosis of patients with KIRC, and our research provides a basis for personalized treatment of patients with KIRC.

Project description:Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer and has strong immunogenicity. A systematically investigation of the tumor microenvironment (TME) in ccRCC could contribute to help clinicians develop personalized treatment and facilitate clinical decision-making. In this study, we analyzed the immune-related subtype of ccRCC on the basis of immune-related gene expression data in The Cancer Genome Atlas (TCGA, N = 512) and E-MTAB-1980 (N = 101) dataset, respectively. As a result, two subtypes (C1 and C2) were identified by performing non-negative matrix factorization clustering. Subtype C1 was characterized by increased advance ccRCC cases and immune-related pathways. A higher immune score, stromal score, TMB value, Tumor Immune Dysfunction and Exclusion (TIDE) prediction score, and immune checkpoint genes expression level were also observed in C1. In addition, the C1 subtype might benefit from chemotherapy and immunotherapy. The patients in subtype C2 had more metabolism-related pathways, higher tumor purity, and a better prognosis. Moreover, some small molecular compounds for the treatment of ccRCC were identified between the two subtypes by using the Connectivity Map (CMap) database. Finally, we constructed and validated an immune-related (IR) score to evaluate immune modification individually. A high IR score corresponded to a favorable prognosis compared to a low IR score, while more advanced tumor stage and grade cases were enriched in the low IR score group. The two IR score groups also showed a distinct divergence among immune status, TME, and chemotherapy. The external validation dataset (E-MTAB-1980) and another immunotherapy cohort (IMvigor 210) demonstrated that patients in the high IR score group had a significantly prolonged survival time and clinical benefits compared to the low IR score group. Together, characterization of molecular heterogeneity and IR signature may help develop new insights into the TME of ccRCC and provide new strategies for personalized treatment.

Project description:BackgroundThe transcriptome public database and advances in biological discoveries contributed to significant progresses in identifying the drivers of cancer progression. Cellular senescence (CS) is considered as a leading factor resulting in cancer development. The purpose of this study was to explore the significance of CS-related genes in the molecular classification and survival outcome of clear cell renal cell carcinoma (ccRCC).MethodsCS-related genes were obtained from the CellAge database, and patients from TCGA-KIRC dataset and ICGC dataset were clustered by ConsesusClusterPlus. The characteristics of overall survival (OS), genomic variation, and tumor microenvironment (TME) of each cluster were analyzed. Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression analysis was conducted to develop a CS-related risk model to score ccRCC patients and assess the risk scores in predicting patients' response to immunotherapy and chemotherapy. A nomogram based on the risk model was established to improve the risk stratification of patients.ResultsCcRCC was divided into three molecular subtypes based on CS-related genes. The three molecular phenotypes showed different OS and clinical manifestations, mutation patterns, and TME states. Five genes were obtained from nine differentially expressed CS-related genes in the three molecular subtypes to develop a risk model. Patients with ccRCC were divided into high- and low-risk subgroups. The former showed an unfavorable OS, with a significantly higher genomic variation rate, TME score, and numerous immune checkpoint expressions when compared to the low-risk subgroup. Risk score reflected the response of patients to axitinib, bortezomib, sorafenib, sunitinib, and temsirolimus.ConclusionsIn general, CS-related genes divided ccRCC into three molecular subtypes with distinct OS, mutation patterns, and TME states. The risk model based on the five CS-related genes can predict the prognosis and therapeutic outcome of ccRCC patients, providing a theoretical basis for further study on the molecular mechanism of CS-related ccRCC.

Project description:BackgroundIt is well known that chronic inflammation can promote the occurrence and progression of cancer. As a type of proinflammatory death, pyroptosis can recast a suitable microenvironment to promote tumor growth. However, the potential role of pyroptosis in clear cell renal cell carcinoma (ccRCC) remains unclear.MethodsThe transcriptome expression profile and mutation profile data of ccRCC with clinical characteristics included in this study were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Consensus clustering was used for clustering. Gene set enrichment analysis (GSEA) analysis were applied to evaluate the biological mechanisms. Single sample gene set enrichment analysis (ssGSEA) was applied for evaluating the proportion of various immune infiltrating cells. The ESTIMATE algorithm was involved to compute the immune microenvironment scores.ResultsAmong the 17 pyroptosis regulators, a total of 15 pyroptosis regulators were differential expressed between tumor and normal tissues, in which 12 of them emerged strong correlations with prognoses. According to the pyroptosis components, the ccRCC patients were divided into four pyroptosis subtypes with different clinical, molecular, and pathway characteristics. Compared with other clusters, cluster B showed the pyroptosis heat phenotype, while cluster D represented the pyroptosis cold phenotype with poor overall survival. In addition, we performed principal component analysis (PCA) on the differential genes between clusters to construct the pyroptosis index. Furthermore, the pyroptosis index was significantly correlated with survival in different tumor mutation statuses and different grades and stages. Besides, the expression of pyroptosis-related regulators was related to the infiltration of immune cells and the expression of immune checkpoints, among which AIM2 was considered as the most significant immune-related pyroptosis regulator. Ultimately, we found that AIM2 was related to the immune activation pathway and was significantly overexpressed in tumor tissues.ConclusionThis study revealed that pyroptosis regulators and pyroptosis index played an important role in the development and prognoses of ccRCC. Moreover, AIM2 can be used as a predictor of the response of immunotherapy. Assessing the pyroptosis patterns may help evaluate the tumor status and guide immunotherapy strategies.

Project description:Previous studies have demonstrated that direct targeting of interstitial cancer-associated fibroblasts (CAF) and tumor fibrosis alone seemed to be an unpromising treatment option for malignant tumors. Therefore, it is necessary to further explore the mechanism of the influence of collagen and tumor fibrosis on the biological behavior of malignant tumors. The current study aimed to explore the effect of intratumor fibrosis on the prognosis of renal clear cell carcinoma (ccRCC) and its mechanism. With the bioinformatic analysis of The Cancer Genome Atlas (TCGA) database (n = 537), the study showed that high Collagen type I α 1 (COL1A1) mRNA expression indicated the poor prognosis of ccRCC patients compared with low expression ones. We further used the Two-photon-excited fluorescence (TPEF)/second harmonic generation (SHG) microscopy to determine the intratumor fibrosis of 68 patients with surgical resection of ccRCC and confirmed that a high fibrosis level in the tumor was associated with a poor prognosis compared with patients with low expression (Progression-Free Survival: p = 0.030). We further measured the protein chips of 640 cytokines in ccRCC specimens and found that several cytokines, including prolactin (PRL), were associated with the degree of fibrosis in the tumor, as confirmed by the prolactin receptor (PRLR) immunohistochemical method. In addition, the study showed that PRLR expression decreased significantly in the ccRCC compared with adjacent normal tissue (p < 0.05). Our research shows that low expression of PRLR predicted the poor survival of the patient. We used the Cell Counting Kit-8 experiment, the transwell and the plate clone formation assay to evaluate the role of PRL in the 7860 and the ACHN cell lines. We found that PRL promoted ccRCC cell proliferation and migration. JAK-STAT3 activation was found in the high prolactin expression group by mass spectrum analysis. This study delineated the fibrosis-based tumor microenvironment characteristics of ccRCC. PRL/PRLR may be involved in the fibrosis process and are essential prognostic risk factors for ccRCC.

Dataset Information

Cellular and Molecular Players in the Tumor Microenvironment of Renal Cell Carcinoma.

Publications

Cellular and Molecular Players in the Tumor Microenvironment of Renal Cell Carcinoma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets