The Extracellular Matrix Environment of Clear Cell Renal Cell Carcinoma

Oxburgh, Leif

doi:10.3390/cancers14174072

Cited by 11 publications

(5 citation statements)

References 117 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…ECM proteins are important molecular components that are involved in cellular architectures and have several signaling properties [36][37][38]. Thus, the composition of these ECM compositions within a tumor type is a useful predictor for determining the various pathological aspects of these tumors.…”

Section: Discussionmentioning

confidence: 99%

Three-Dimensional Spheroid Configurations and Cellular Metabolic Properties of Oral Squamous Carcinomas Are Possible Pharmacological and Pathological Indicators

Miyamoto

Nishikiori

Sato

et al. 2023

Cancers

View full text Add to dashboard Cite

The objective of the current study was to elucidate the clinicopathological significance and appearance of in vitro three-dimension (3D) spheroid models of oral malignant tumors that were prepared from four pathologically different squamous cell carcinoma (OSCC; low-grade; SSYP and MO-1000, intermediate-grade; LEM2) and oral adenosquamous carcinoma (OASC; high-grade; Mesimo) obtained from patients with different malignant stages. To characterize the biological significance of these cell lines themselves, two-dimensional (2D) cultured cells were subjected to cellular metabolic analysis by a Seahorse bioanalyzer alongside the measurement of the cytotoxicity of cisplatin (CDDP). The appearance of their 3D spheroids was then observed by phase contrast microscopy, and both 2D and 3D cultured cells were subject to trypsin digestion and qPCR analysis of factors related to oncogenic signaling and other related analyses. ATP-linked respiration and proton leaking were significantly different among the four cell lines, and the malignant stages of these cultures were significantly associated with increased ATP-linked respiration and decreased proton leakage. Alternatively, the appearances of these 3D spheroids were also significantly diverse among them, and their differences increased in the order of LEM2, MO-1000, SSYP, and Mesimo. Interestingly, these orders were exactly the same in that the efficacies of CDDP-induced cytotoxicity increased in the same order. qPCR analysis indicated that the levels of expression of oncogenic signaling-related factors varied among these four cell lines, and the values for fibronectin and a key regulator of mitochondrial biogenesis, PGC-1α, were prominently elevated in cultures of the worst malignant Mesimo cells. In addition, although 0.25% trypsin-induced destruction was comparable among all four 2D cultured cells, the values for the 3D spheroids were also substantially varied among these cultures. The findings reported herein indicate that cellular metabolic functions and 3D spheroid architectures may be valuable and useful indicators for estimating the pathological and drug-sensitive aspects of OSCC and OASC malignancies.

show abstract

Section: Discussionmentioning

confidence: 99%

Three-Dimensional Spheroid Configurations and Cellular Metabolic Properties of Oral Squamous Carcinomas Are Possible Pharmacological and Pathological Indicators

Miyamoto

Nishikiori

Sato

et al. 2023

Cancers

View full text Add to dashboard Cite

show abstract

“…53 Collagen IV specifically is a known VHL interaction partner, and found in abundance in ccRCC. 54 Yet the majority of ECM is produced not by cancer cells but other stromal cell types such as fibroblasts. This fibrotic overproduction of collagen and other ECM proteins appears to be present in multiple kidney-specific pathologies, as validated in recent spot based spatial transcriptomics.…”

Section: Discussionmentioning

confidence: 99%

Increased spatial coupling of integrin and collagen IV in the immunoresistant clear cell renal cell carcinoma tumor microenvironment

Soupir,

Hayes,

Peak

et al. 2023

Preprint

View full text Add to dashboard Cite

BackgroundImmunotherapy (IO) has improved survival for patients with advanced clear cell renal cell carcinoma (ccRCC), but resistance to therapy develops in most patients. We use cellular-resolution spatial transcriptomics in patients with IO naïve and IO exposed primary ccRCC tumors to better understand IO resistance. Spatial molecular imaging (SMI) was obtained for tumor and adjacent stroma samples. Spatial gene set enrichment analysis (GSEA) and autocorrelation (coupling with high expression) of ligand-receptor transcript pairs were assessed. Multiplex immunofluorescence (mIF) validation was used for significant autocorrelative findings and the cancer genome atlas (TCGA) and the clinical proteomic tumor analysis consortium (CPTAC) databases were queried to assess bulk RNA expression and proteomic correlates.Results21 patient samples underwent SMI. Viable tumors following IO harbored more stromal CD8+ T cells and neutrophils than IO naïve tumors.YES1was significantly upregulated in IO exposed tumor cells. The epithelial-mesenchymal transition pathway was enriched on spatial GSEA and the associated transcript pairCOL4A1-ITGAVhad significantly higher autocorrelation in the stroma. Fibroblasts, tumor cells, and endothelium had the relative highest expression. More integrin αV+ cells were seen in IO exposed stroma on mIF validation. Compared to other cancers in TCGA, ccRCC tumors have the highest expression of bothCOL4A1andITGAV. In CPTAC, collagen IV protein was more abundant in advanced stages of disease.ConclusionsOn spatial transcriptomics,COL4A1andITGAVwere more autocorrelated in IO-exposed stroma compared to IO-naïve tumors, with high expression amongst fibroblasts, tumor cells, and endothelium. Integrin represents a potential therapeutic target in IO treated ccRCC.

show abstract

“…The most prevalent genetic mutations in KIRC inactivate the VHL gene, which plays a direct role in ECM organization. Therefore, therapeutic approaches to control ECM are currently being investigated and an advanced understanding of KIRC ECM will determine if ECM-modifying drugs are appropriate for KIRC (Oxburgh, 2022). An additional BP enrichment was macrophages that are highly enriched in RCC, and the RCC survival rate is strongly correlated with the inflammatory cytokines secreted by macrophages (Xie et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

Assessment of the progression of kidney renal clear cell carcinoma using transcriptional profiles revealed new cancer subtypes with variable prognosis

Livesey,

Eshibona,

Bendou

2023

Front. Genet.

View full text Add to dashboard Cite

Background: Kidney renal clear cell carcinoma is the most prevalent subtype of renal cell carcinoma encompassing a heterogeneous group of malignancies. Accurate subtype identification and an understanding of the variables influencing prognosis are critical for personalized treatment, but currently limited. To facilitate the sub-classification of KIRC patients and improve prognosis, this study implemented a normalization method to track cancer progression by detecting the accumulation of genetic changes that occur throughout the multi-stage of cancer development.Objective: To reveal KIRC patients with different progression based on gene expression profiles using a normalization method. The aim is to refine molecular subtyping of KIRC patients associated with survival outcomes.Methods: RNA-sequenced gene expression of eighty-two KIRC patients were downloaded from UCSC Xena database. Advanced-stage samples were normalized with early-stage to account for differences in the multi-stage cancer progression’s heterogeneity. Hierarchical clustering was performed to reveal clusters that progress differently. Two techniques were applied to screen for significant genes within the clusters. First, differentially expressed genes (DEGs) were discovered by Limma, thereafter, an optimal gene subset was selected using Recursive Feature Elimination (RFE). The gene subset was subjected to Random Forest Classifier to evaluate the cluster prediction performance. Genes strongly associated with survival were identified utilizing Cox regression analysis. The model’s accuracy was assessed with Kaplan-Meier (K-M). Finally, a Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed.Results: Three clusters were revealed and categorized based on patients’ overall survival into short, intermediate, and long. A total of 231 DEGs were discovered of which RFE selected 48 genes. Random Forest Classifier revealed a 100% cluster prediction performance of the genes. Five genes were identified with significant diagnostic capacity. The downregulation of genes SALL4 and KRT15 were associated with favorable prognosis, while the upregulation of genes OSBPL11, SPATA18, and TAL2 were associated with favorable prognosis.Conclusion: The normalization method based on tumour progression from early to late stages of cancer development revealed the heterogeneity of KIRC and identified three potential new subtypes with different prognoses. This could be of great importance for the development of new targeted therapies for each subtype.

show abstract

The Extracellular Matrix Environment of Clear Cell Renal Cell Carcinoma

Cited by 11 publications

References 117 publications

Three-Dimensional Spheroid Configurations and Cellular Metabolic Properties of Oral Squamous Carcinomas Are Possible Pharmacological and Pathological Indicators

Three-Dimensional Spheroid Configurations and Cellular Metabolic Properties of Oral Squamous Carcinomas Are Possible Pharmacological and Pathological Indicators

Increased spatial coupling of integrin and collagen IV in the immunoresistant clear cell renal cell carcinoma tumor microenvironment

Assessment of the progression of kidney renal clear cell carcinoma using transcriptional profiles revealed new cancer subtypes with variable prognosis

Contact Info

Product

Resources

About