CD99 Triggering in Ewing Sarcoma Delivers a Lethal Signal through p53 Pathway Reactivation and Cooperates with Doxorubicin

Guerzoni, Clara; Fiori, Valentina; Terracciano, Mario; Manara, Maria Cristina; Moricoli, Diego; Pasello, Michela; Sciandra, Marika; Nicoletti, Giordano; Gellini, Mara; Dominici, Sabrina; Chiodoni, Claudia; Fornasari, Pier Maria; Lollini, Pier‐Luigi; Colombo, Mario P.; Picci, Piero; Cianfriglia, Maurizio; Magnani, Mauro; Scotlandi, Katia

doi:10.1158/1078-0432.ccr-14-0492

Cited by 39 publications

(49 citation statements)

References 47 publications

(57 reference statements)

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“…Knockdown of EWS/FLI1 was also coupled to decreases in cyclin D1 and promotion of p53 expression [38, 39] which were observed after EGFR inhibition in our experiments. Thus, activities displayed by an EGFR inhibitor are consistent with other experimental agents that induce antiproliferative effects in ES associated with stimulation of p53 expression [40-42]. The combined actions of inhibiting protein kinase signaling and reducing cyclin D1 expression while promoting expression of p53 highlight the potential of EGFR inhibition to target both growth and cell cycle progression pathways, which are required for EWS/FLI1-induced malignant transformation [43].…”

Section: Discussionsupporting

confidence: 64%

Epidermal Growth Factor Receptor Regulation of Ewing Sarcoma Cell Function

et al. 2018

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Objective: Ewing sarcoma (ES) is a type of childhood cancer probably arising from stem mesenchymal or neural crest cells. The epidermal growth factor receptor (EGFR) acts as a driver oncogene in many types of solid tumors. However, its involvement in ES remains poorly understood. Methods: Human SK-ES-1 and RD-ES ES cells were treated with EGF, the EGFR inhibitor tyrphostin (AG1478), or phosphoinositide 3-kinase (PI3K) or extracellular-regulated kinase (ERK)/mitogen-activated kinase (MAPK) inhibitors. Cell proliferation survival, cycle, and senescence were analyzed. The protein content of possible targets of EGFR manipulation was measured by Western blot. Results: Cell proliferation and survival were increased by EGF and inhibited by AG1478. The EGFR inhibitor also altered the cell cycle, inducing arrest in G1 and increasing the sub-G1 population, reduced polyploidy and increased the population of senescent cells. In addition, AG1478 reduced the levels of phosphorylated AKT (p-AKT), ERK, p-ERK, cyclin D1, and brain-derived neurotrophic factor (BDNF), while enhancing p53 levels. Cell proliferation was also impaired by inhibitors of PI3K or ERK, alone or combined with AG1478. Conclusions: Our findings reveal novel aspects of EGFR regulation of ES cells and provide early evidence for antitumor activities of EGFR inhibitors in ES.

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Section: Discussionsupporting

confidence: 64%

Epidermal Growth Factor Receptor Regulation of Ewing Sarcoma Cell Function

et al. 2018

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“…CD99 promotes cancer cell death when triggered by specific antibodies, such as 0662, O13 murine mAbs or the human single chain fragment variable diabody (dAbd C7) [20]. Engagement of CD99 with antibodies induced fast (within 15 min) and massive annexin V exposition to the outside layer of cell membrane, MDM2 ubiquitination and degradation, reactivation of p53 signaling and mitochondrial depolarization [20, 21].…”

Section: Resultsmentioning

confidence: 99%

“…Engagement of CD99 with antibodies induced fast (within 15 min) and massive annexin V exposition to the outside layer of cell membrane, MDM2 ubiquitination and degradation, reactivation of p53 signaling and mitochondrial depolarization [20, 21]. All EWS cells express CD99 [24] and we found that 13 patient-derived EWS cell lines, including chemotherapy-resistant variants, are all sensitive to CD99-induced cell death (Supplementary Table S1).…”

Section: Resultsmentioning

confidence: 99%

“…We previously reported a marked and rapid decrease of MDM2 protein levels following CD99 engagement [20]. MDM2 is an E3 ubiquitin ligase that antagonizes the tumor suppressor p53 [27].…”

Section: Resultsmentioning

confidence: 99%

“…In this paper, we demonstrate that CD99 engagement by the 0662 anti-CD99 monoclonal antibody (mAb) [20, 21] induces cell death of EWS cells through a non-apoptotic pathway resembling methuosis, which requires the activation of insulin-like growth factor receptor 1 (IGF-1R) [22, 23] and RAS-Rac1 downstream signaling. These data define a novel role for CD99 and the IGF-1R/RAS pathway in methuosis and identify a novel targeting approach for EWS cells, including chemoresistant variants.…”

Section: Introductionmentioning

confidence: 99%

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CD99 triggering induces methuosis of Ewing sarcoma cells through IGF-1R/RAS/Rac1 signaling

et al. 2016

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CD99 is a cell surface molecule that has emerged as a novel target for Ewing sarcoma (EWS), an aggressive pediatric bone cancer. This report provides the first evidence of methuosis in EWS, a non-apoptotic form of cell death induced by an antibody directed against the CD99 molecule. Upon mAb triggering, CD99 induces an IGF-1R/RAS/Rac1 complex, which is internalized into RAB5-positive endocytic vacuoles. This complex is then dissociated, with the IGF-1R recycling to the cell membrane while CD99 and RAS/Rac1 are sorted into immature LAMP-1-positive vacuoles, whose excessive accumulation provokes methuosis. This process, which is not detected in CD99-expressing normal mesenchymal cells, is inhibited by disruption of the IGF-1R signaling, whereas enhanced by IGF-1 stimulation. Induction of IGF-1R/RAS/Rac1 was also observed in the EWS xenografts that respond to anti-CD99 mAb, further supporting the role of the IGF/RAS/Rac1 axis in the hyperstimulation of macropinocytosis and selective death of EWS cells. Thus, we describe a vulnerability of EWS cells, including those resistant to standard chemotherapy, to a treatment with anti-CD99 mAb, which requires IGF-1R/RAS signaling but bypasses the need for their direct targeting. Overall, we propose CD99 targeting as new opportunity to treat EWS patients resistant to canonical apoptosis-inducing agents.

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Molecular Genetics of Ewing Sarcoma

Ordóñez

Amaral

Álava

2015

Encyclopedia of Life Sciences

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Ewing sarcoma (ES) is an aggressive tumour affecting mainly children and young adults. When metastases are detected, the survival rate is compromised as a result of a lack of appropriated treatments. Balanced chromosomal translocations, present in all primary ES, originate gene fusions, such as EWSR1‐FLI1, which act as aberrant transcription factors. Targeting EWSR1 ‐ FLI1 by using RNA interference approaches reduced tumour growth and tumourigenicity of ES cells in vitro and in vivo and is a good tool in order to get knowledge in the ES biology. However, possibility of taking RNA interference into clinic is limited. At present, some drugs affecting gene fusion activity have been reported to reduce tumour growth. In addition, several approaches targeting ES genetic alterations not related to gene fusions or their genetic targets have been recently reported. The use of more appropriated animal models and the study of ES tumour microenvironment and epigenetics will unveil new therapeutic targets. Key Concepts ES is an aggressive developmental tumour. Balanced chromosomal translocation and associated gene fusions are the primary molecular event in ES. Secondary molecular events in ES can define new therapeutic targets and new prognostic markers. The role played by epigenetics in ES and the regulation of chromatin remodelling is beginning to be known. Detection of ES circulating cells or identification of gene expression profiles in peripheral blood cells could become good prognostic markers. Identification of new markers of cancer stem cells could help improve ES therapy. Endoglin could be a relevant therapeutic target in ES. Osteolysis and bone remodelling are important mechanisms of ES tumour growth. ES cells secrete extracellular vesicles, containing aberrant EWSR1‐FLI1 mRNA and other growth factors, which interact with surrounding tumour cells and extracellular matrix components. Combination therapy of a dual inhibitor of IGF1R and IR pathways and a DNA damage agent can avoid resistance to IGF1R inhibitors. At present, there is a lack of appropriate genetically engineered mice (GEM) of ES.

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CD99 Triggering in Ewing Sarcoma Delivers a Lethal Signal through p53 Pathway Reactivation and Cooperates with Doxorubicin

Cited by 39 publications

References 47 publications

Epidermal Growth Factor Receptor Regulation of Ewing Sarcoma Cell Function

Epidermal Growth Factor Receptor Regulation of Ewing Sarcoma Cell Function

CD99 triggering induces methuosis of Ewing sarcoma cells through IGF-1R/RAS/Rac1 signaling

Molecular Genetics of Ewing Sarcoma

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