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CD146 is a novel marker for highly tumorigenic cells and a potential therapeutic target in malignant rhabdoid tumor.

ABSTRACT: Malignant rhabdoid tumor (MRT) is a rare, highly aggressive pediatric malignancy that primarily develops during infancy and early childhood. Despite the existing standard of intensive multimodal therapy, the prognosis of patients with MRT is dismal; therefore, a greater understanding of the biology of this disease is required to establish novel therapies. In this study, we identified a highly tumorigenic sub-population in MRT, based on the expression of CD146 (also known as melanoma cell adhesion molecule), a cell adhesion molecule expressed by neural crest cells and various derivatives. CD146⁺ cells isolated from four MRT cell lines by cell sorting exhibited enhanced self-renewal and invasive potential in vitro. In a xenograft model using immunodeficient NOD/Shi-scid IL-2R?-null mice, purified CD146⁺ cells obtained from MRT cell lines or a primary tumor exhibited the exclusive ability to form tumors in vivo. Blocking of CD146-related mechanisms, either by short hairpin RNA knockdown or treatment with a polyclonal antibody against CD146, effectively suppressed tumor growth of MRT cells both in vitro and in vivo via induction of apoptosis by inactivating Akt. Furthermore, CD146 positivity in immunohistological analysis of 11 MRT patient samples was associated with poor patient outcomes. These results suggest that CD146 defines a distinct sub-population in MRT with high tumorigenic capacity and that this marker represents a promising therapeutic target.

SUBMITTER: Nodomi S

PROVIDER: S-EPMC5057042 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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CD146 is a novel marker for highly tumorigenic cells and a potential therapeutic target in malignant rhabdoid tumor.

Nodomi S S Umeda K K Saida S S Kinehara T T Hamabata T T Daifu T T Kato I I Hiramatsu H H Watanabe K-I KI Kuwahara Y Y Iehara T T Adachi S S Konishi E E Nakahata T T Hosoi H H Heike T T

Oncogene 20160404 40

Malignant rhabdoid tumor (MRT) is a rare, highly aggressive pediatric malignancy that primarily develops during infancy and early childhood. Despite the existing standard of intensive multimodal therapy, the prognosis of patients with MRT is dismal; therefore, a greater understanding of the biology of this disease is required to establish novel therapies. In this study, we identified a highly tumorigenic sub-population in MRT, based on the expression of CD146 (also known as melanoma cell adhesio ...[more]

PMID: 27041577

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Project description:Rhabdoid tumors (RT) are aggressive tumors characterized by genetic loss of SMARCB1 (SNF5, INI-1), a component of the SWI/SNF chromatin remodeling complex. No effective treatment is currently available. This study seeks to shed light on the SMARCB1-mediated pathogenesis of RT and to discover potential therapeutic targets. Global gene expression of 10 RT was compared with 12 cellular mesoblastic nephromas, 16 clear cell sarcomas of the kidney, and 15 Wilms tumors. 114 top genes were differentially expressed in RT (p<0.001, fold change >2 or <0.5). Among these were down-regulation of SMARCB1 and genes previously associated with SMARCB1 (ATP1B1, PTN, DOCK4, NQO1, PLOD1, PTP4A2, PTPRK). 28/114 top differentially expressed genes were involved with neural or neural crest development and were all sharply down-regulated. This was confirmed by Gene Set Enrichment Analysis (GSEA). Neural and neural crest stem cell marker proteins SOX10, ID3, CD133 and Musashi were negative by immunohistochemistry, whereas Nestin was positive. Decreased expression of CDKN1A, CDKN1B, CDKN1C, CDKN2A, and CCND1 was identified, while MYC-C was upregulated. GSEA of independent gene sets associated with bivalent histone modification and polycomb group targets in embryonic stem cells demonstrated significant negative enrichment in RT. Several differentially expressed genes were associated with tumor suppression, invasion and metastasis, including SPP1 (osteopontin), COL18A1 (endostatin), PTPRK, and DOCK4. We conclude that RTs arise within early progenitor cells during a critical developmental window in which loss of SMARCB1 directly results in repression of neural development, loss of cyclin dependent kinase inhibition, and trithorax/polycomb dysregulation. Keywords: Gene expression; rhabdoid tumor; pediatric renal tumors; neural crest The goal of this study is to identify genetic pathways that will clarify the nature of RT and enable the identification of therapeutic targets. Experimental Design: Frozen tissue samples were obtained from the Renal Tumor Bank of the Children's Oncology Group (COG). A total of 53 tumors were hybridized to Affymetrix U133A arrays and analyzed including 10 RT, 12 cellular mesoblastic nephromas (CMN), also known as infantile fibrosarcomas, 16 clear cell sarcomas of the kidney (CCSK) and 15 Wilms tumors (WT). Quality control steps taken: 1. Samples were snap frozen immediately following surgery and were mailed on dry ice to the Tumor Bank and retained at -80Â°C. 2. Frozen sections were evaluated histologically and tumors with less than 80% viable tumor cellularity were excluded. 3. Array images were assessed by eye to confirm scanner alignment and the absence of significant bubbles or scratches. 4. Samples for which the 3'/5' ratios for GAPDH were greater than 3.4 were excluded. 5. The BioB spike controls were confirmed as present 90% of the time; BioC, BioD and cre were confirmed as increasing intensity in all samples. 6. When scaled to a target intensity of 2500, scaling factors were between 13 and 52; background levels were 34-115: Raw Q values were 1.3-3.7 and mean intensities were within acceptable limits. 7. The range of percent present calls was from 30% to 52%. Statistical Analysis: Positional-dependent-nearest-neighbor model (PDNN) software was used to translate the scanned images into expression analysis files and to normalize the data across all arrays (http://odin.mdacc.tmc.edu/~zhangli/PerfectMatch/). To establish a broad list of probesets containing the majority of genes significant in the pathogenesis of RT, the expression of 10 RT was compared with the 43 other tumor types combined (non-RT) using the two-sample t-test, resulting in 2921 probesets with p-value <0.005 and false discovery rate of <1%. This data is provided in the attached supplementary file 'Supplemental Table 1'. To define probesets more uniquely expressed in RT, the gene expression of RT was compared with each of the other tumor types separately (CCSK, CMN, and WT) using the two-sample t-test, and genes present in each one of the resulting four comparisons (RT vs. CCSK, RT vs. CMN, RT vs. WT and RT vs non-RT) with a p-value of <0.001 are provided in the attached supplementary file 'Supplemental Table 2'. Lastly, the 766 genes differentially expressed between RT and non-RT (p<0.0001) were analyzed in PANTHER (Protein ANalysis THrough Evolutionary Relationships), and those groups within the biologic process category over-represented with a Bonferoni corrected p value<0.05 are listed in the attached file labelled âSupplemental Table 3â.

Dataset Information

CD146 is a novel marker for highly tumorigenic cells and a potential therapeutic target in malignant rhabdoid tumor.

Publications

CD146 is a novel marker for highly tumorigenic cells and a potential therapeutic target in malignant rhabdoid tumor.

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