HIF2α is involved in the expansion of CXCR4-positive cancer stem-like cells in renal cell carcinoma

Micucci, C.; Matacchione, Giulia; Valli, Debora; Orciari, Silvia; Catalano, Alfonso

doi:10.1038/bjc.2015.338

Cited by 44 publications

(32 citation statements)

References 39 publications

(43 reference statements)

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“…A number of differentially expressed genes in the Caki-1 cell line can be found in Supplementary Table S1. For example, chemokine receptor CXCR4 was reported to be 2.01-fold upregulated in the Caki-1 cell line; this was previously reported as a cancer stem cell marker, and CXCR4-positive cells exhibit great resistance to tyrosine kinase inhibitors (27,42,47). In addition, CXCR4 expression has significant prognostic value and therapeutic importance in RCC patients (13).…”

Section: Discussionmentioning

confidence: 90%

Gene set enrichment analysis and ingenuity pathway analysis of metastatic clear cell renal cell carcinoma cell line

Khan

Dębski

Dąbrowski

et al. 2016

American Journal of Physiology-Renal Physiology

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Section: Discussionmentioning

confidence: 90%

Gene set enrichment analysis and ingenuity pathway analysis of metastatic clear cell renal cell carcinoma cell line

Khan

Dębski

Dąbrowski

et al. 2016

American Journal of Physiology-Renal Physiology

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“…Other studies demonstrate CXCR4 to be present only in a subpopulation of RCC cells that were more tumorigenic (42) and to enhance cell migration and wound healing of renal cancer cells (43). In vivo , RCC derived spheres developed into tumors and interestingly, expressed high levels of CXCR4 (44). Taken together, we speculate that VCAN can thus promote ccRCC progression and metastases by supporting a suitable ECM environment where MMP7 is activated leading to proteolytic VCAN fragments and CXCR4 induction.…”

Section: Discussionmentioning

confidence: 99%

Versican Promotes Tumor Progression, Metastasis and Predicts Poor Prognosis in Renal Carcinoma

Mitsui

Shiina

Kato

et al. 2017

Molecular Cancer Research

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The proteoglycan versican (VCAN) promotes tumor progression and enhances metastasis in several cancers; however, its role in clear cell renal cell carcinoma (ccRCC) remains unknown. Recent evidence suggests that VCAN is an important target of chromosomal 5q gain, one of the most prevalent genetic abnormalities in ccRCC. Thus, we investigated whether VCAN expression is associated with the pathogenesis of ccRCC. VCAN expression was analyzed using three RCC and normal kidney cell lines as well as a clinical cohort of 84 matched ccRCC and normal renal tissues. Functional analyses on growth and progression properties were performed using VCAN depleted ccRCC cells. Microarray expression profiling was employed to investigate the target genes and biological pathways involved in VCAN-mediated ccRCC carcinogenesis. ccRCC had elevated VCAN expression in comparison with normal kidney in both cell lines and clinical specimens. The elevated expression of VCAN was significantly correlated with metastasis (P<0.001) and worse 5-year overall survival after radical nephrectomy (P=0.014). In vitro, VCAN knockdown significantly decreased cell proliferation and increased apoptosis in Caki-2 and 786-O cells, and this was associated with alteration of several TNF signaling-related genes such as TNF-α, BID, and BAK. Furthermore, VCAN depletion markedly decreased cell migration and invasion which correlated with reduction of MMP7 and CXCR4. These results demonstrate that VCAN promotes ccRCC tumorigenesis and metastasis and thus, is an attractive target for novel diagnostic, prognostic and therapeutic strategies.

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“…Most of this evidence is based on tumor-tissue-specific SCLCCs, while some are based on RCC cell lines [18–20, 42, 43]. SCLCCs have been identified from RCC cell lines based on chemokine receptor CXCR4 [19, 42] and side population cell selection by aldehyde dehydrogenase activity [18, 20, 43], Hoechst 33342 dye [44] and rhodamine 123 [45]. Previously, Bussolati et al observed renal carcinoma specimens from patients after radical nephrectomy, which showed CD105+ subpopulation is enrich for tumor-initiating cells (TICs) [31] and tumor angiogenesis [46].…”

Section: Discussionmentioning

confidence: 99%

Comparative Gene Expression Profiling of Primary and Metastatic Renal Cell Carcinoma Stem Cell-Like Cancer Cells

et al. 2016

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BackgroundRecent advancement in cancer research has shown that tumors are highly heterogeneous, and multiple phenotypically different cell populations are found in a single tumor. Cancer development and tumor growth are driven by specific types of cells—stem cell-like cancer cells (SCLCCs)—which are also responsible for metastatic spread and drug resistance. This research was designed to verify the presence of SCLCCs in renal cell cancer cell lines. Subsequently, we aimed to characterize phenotype and cell biology of CD105+ cells, defined previously as renal cell carcinoma tumor-initiating cells. The main goal of the project was to describe the gene-expression profile of stem cell-like cancer cells of primary tumor and metastatic origin.Materials and MethodsReal-time PCR analysis of stemness genes (Oct-4, Nanog and Ncam) and soft agar colony formation assay were conducted to check the stemness properties of renal cell carcinoma (RCC) cell lines. FACS analysis of CD105+ and CD133+ cells was performed on RCC cells. Isolated CD105+ cells were verified for expression of mesenchymal markers—CD24, CD146, CD90, CD73, CD44, CD11b, CD19, CD34, CD45, HLA-DR and alkaline phosphatase. Hanging drop assay was used to investigate CD105+ cell-cell cohesion. Analysis of free-floating 3D spheres formed by isolated CD105+ was verified, as spheres have been hypothesized to contain undifferentiated multipotent progenitor cells. Finally, CD105+ cells were sorted from primary (Caki-2) and metastatic (ACHN) renal cell cancer cell lines. Gene-expression profiling of sorted CD105+ cells was performed with Agilent’s human GE 4x44K v2 microarrays. Differentially expressed genes were further categorized into canonical pathways. Network analysis and downstream analysis were performed with Ingenuity Pathway Analysis.ResultsMetastatic RCC cell lines (ACHN and Caki-1) demonstrated higher colony-forming ability in comparison to primary RCC cell lines. Metastatic RCC cell lines harbor numerous CD105+ cell subpopulations and have higher expression of stemness genes (Oct-4 and Nanog). CD105+ cells adopt 3D grape-like floating structures under handing drop conditions. Sorted CD105+ cells are positive for human mesenchymal stem cell (MSC) markers CD90, CD73, CD44, CD146, and alkaline phosphatase activity, but not for CD24 and hematopoietic lineage markers CD34, CD11b, CD19, CD45, and HLA-DR. 1411 genes are commonly differentially expressed in CD105+ cells (both from primary [Caki-2] and metastatic RCC [ACHN] cells) in comparison to a healthy kidney epithelial cell line (ASE-5063). TGF-β, Wnt/β-catenine, epithelial-mesenchymal transition (EMT), Rap1 signaling, PI3K-Akt signaling, and Hippo signaling pathway are deregulated in CD105+ cells. TGFB1, ERBB2, and TNF are the most significant transcriptional regulators activated in these cells.ConclusionsAll together, RCC-CD105+ cells present stemlike properties. These stem cell-like cancer cells may represent a novel target for therapy. A unique gene-expression profile of CD105+ cells could be used as initia...

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HIF2α is involved in the expansion of CXCR4-positive cancer stem-like cells in renal cell carcinoma

Cited by 44 publications

References 39 publications

Gene set enrichment analysis and ingenuity pathway analysis of metastatic clear cell renal cell carcinoma cell line

Gene set enrichment analysis and ingenuity pathway analysis of metastatic clear cell renal cell carcinoma cell line

Versican Promotes Tumor Progression, Metastasis and Predicts Poor Prognosis in Renal Carcinoma

Comparative Gene Expression Profiling of Primary and Metastatic Renal Cell Carcinoma Stem Cell-Like Cancer Cells

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