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

Nodomi, Seishiro; Umeda, Katsutsugu; Saida, Satoshi; Kinehara, T; Hamabata, Takayuki; Daifu, Tomoo; Kato, Ikunoshin; Hiramatsu, Hidefumi; Watanabe, Kinuyo; Kuwahara, Yasumichi; Iehara, Tomoko; Adachi, Souichi; Konishi, Eiichi; Nakahata, Tatsutoshi; Hosoi, Hajime; Heike, Toshio

doi:10.1038/onc.2016.72

Cited by 18 publications

(24 citation statements)

References 50 publications

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“…CD146 plays a crucial role in vascular development and angiogenesis, acting as a coreceptor of VEGFR2 in endothelial cells (Jiang et al, 2012). Notably, VEGF-induced Akt1 (hereafter referred to as Akt) signaling via phosphorylation of Akt-S473, a well-established mTORC2 phosphorylation event, is an important component in this process (Li et al, 2003;Nodomi et al, 2016;Xu et al, 2003). Elimination of CD146 reduces Akt activity, resulting in decreased proliferation and cell survival (Kang et al, 2006;Zeng et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

CD146 Regulates Growth Factor-Induced mTORC2 Activity Independent of the PI3K and mTORC1 Pathways

Hua

Chiu

et al. 2019

Cell Reports

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Section: Introductionmentioning

confidence: 99%

CD146 Regulates Growth Factor-Induced mTORC2 Activity Independent of the PI3K and mTORC1 Pathways

Hua

Chiu

et al. 2019

Cell Reports

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“…Notably, the cell spheroids also expressed EpCAM, an epithelial cell adhesion molecule associated with epithelial tumor phenotype and cancer spreading (Additional file 2 : Figure S1e). Since advanced renal cancer oftentimes express mesenchymal markers, we extended the phenotypic characterization to CD146, a stem-cell marker, expressed by mesenchymal cells with marked plasticity and associated with cancer aggressiveness [ 33 , 34 ]. In RCC-derived stem-like cell lines, CD146 levels are elevated a substantial fraction of the cell population and, since most of the cells are EpCAM positive, it is likely that both markers are co-expressed (Additional file 2 : Figure S1E).…”

Section: Resultsmentioning

confidence: 99%

Renal cancer: new models and approach for personalizing therapy

Martino

Luca

Grassi

et al. 2018

J Exp Clin Cancer Res

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BackgroundClear cell RCC (ccRCC) accounts for approximately 75% of the renal cancer cases. Surgery treatment seems to be the best efficacious approach for the majority of patients. However, a consistent fraction (30%) of cases progress after surgery with curative intent. It is currently largely debated the use of adjuvant therapy for high-risk patients and the clinical and molecular parameters for stratifying beneficiary categories. In addition, the treatment of advanced forms lacks reliable driver biomarkers for the appropriated therapeutic choice. Thus, renal cancer patient management urges predictive molecular indicators and models for therapy-decision making.MethodsHere, we developed and optimized new models and tools for ameliorating renal cancer patient management. We isolated from fresh tumor specimens heterogeneous multi-clonal populations showing epithelial and mesenchymal characteristics coupled to stem cell phenotype. These cells retained long lasting-tumor-propagating capacity provided a therapy monitoring approach in vitro and in vivo while being able to form parental tumors when orthotopically injected and serially transplanted in immunocompromised murine hosts.ResultsIn line with recent evidence of multiclonal cancer composition, we optimized in vitro cultures enriched of multiple tumor-propagating populations. Orthotopic xenograft masses recapitulated morphology, grading and malignancy of parental cancers. High-grade but not the low-grade neoplasias, resulted in efficient serial transplantation in mice. Engraftment capacity paralleled grading and recurrence frequency advocating for a prognostic value of our developed model system. Therefore, in search of novel molecular indicators for therapy decision-making, we used Reverse-Phase Protein Arrays (RPPA) to analyze a panel of total and phosphorylated proteins in the isolated populations. Tumor-propagating cells showed several deregulated kinase cascades associated with grading, including angiogenesis and m-TOR pathways.ConclusionsIn the era of personalized therapy, the analysis of tumor propagating cells may help improve prediction of disease progression and therapy assignment. The possibility to test pharmacological response of ccRCC stem-like cells in vitro and in orthotopic models may help define a pharmacological profiling for future development of more effective therapies. Likewise, RPPA screening on patient-derived populations offers innovative approach for possible prediction of therapy response.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0874-4) contains supplementary material, which is available to authorized users.

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“…In a xenograft model using immunodeficient NOD/Shi-scid IL-2Rγ-null mice, CD146 + cells purified from malignant rhabdoid tumor (MRT) cell lines or a primary tumor displayed the unique ability to form tumors in vivo. Blocking CD146-associated mechanisms, including short hairpin RNA knockdown or treatment with a polyclonal antibody against CD146, effectively suppressed the tumor growth of MRT cells in vitro and in vivo, via the induction of apoptosis by inactivating Akt (50).…”

Section: Discussionmentioning

confidence: 99%

Clinical significance of melanoma cell adhesion molecule CD146 and VEGFA expression in epithelial ovarian cancer

et al. 2018

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Ovarian cancer is the fifth most common type of cancer in females; however, its asymptomatic progression and the lack of an efficient screening strategy leads to late diagnosis. The present study aimed to investigate the expression levels of cluster of differentiation (CD)146 and vascular endothelial growth factor A (VEGFA) in epithelial ovarian cancer, and their clinical significance. A total of 52 ovarian samples were tested, of which 22 were from patients with epithelial ovarian cancer and 30 were from non-cancer patients. The relative gene expression of CD146 and VEGFA was quantified using reverse transcription-quantitative polymerase chain reaction analysis. Western blotting was used to determine the protein expression levels. The relative gene expression levels of CD146 and VEGFA in tumor tissues were significantly increased compared with the control (4.92±0.44 vs. 1.05±0.06 and 3.08±0.17 vs. 1.06±0.07, P<0.01). The protein expression levels of CD146 and VEGFA in tumor tissue were also significantly increased compared with the control (0.70±0.02 vs. 0.41±0.07 and 0.54±0.01 vs. 0.26±0.01, P<0.01). There was a positive correlation between the expression levels of CD146 and VEGFA genes (r=0.78) and between the two proteins (r=0.69). Dot density frequency analysis indicated that CD146 and VEGFA were specifically present in tumor tissues. In conclusion, CD146 and VEGFA are co-overexpressed in ovarian cancer; their potential as tumor biomarkers or therapeutic targets for the treatment of ovarian cancer requires further investigation.

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

Cited by 18 publications

References 50 publications

CD146 Regulates Growth Factor-Induced mTORC2 Activity Independent of the PI3K and mTORC1 Pathways

CD146 Regulates Growth Factor-Induced mTORC2 Activity Independent of the PI3K and mTORC1 Pathways

Renal cancer: new models and approach for personalizing therapy

Clinical significance of melanoma cell adhesion molecule CD146 and VEGFA expression in epithelial ovarian cancer

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