Myogenic Tumors in Children and Adolescents

Parham, David M.; Alaggio, Rita; Coffin, Cheryl M.

doi:10.2350/10-12-0953-pb.1

Cited by 43 publications

(59 citation statements)

References 253 publications

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“…eRMS and aRMS cells were seeded in 24-well plates at a density of 10x10 3 and 15x10 3 , respectively. After 24, 48 and 72 h of melatonin treatment, the cells were harvested, fixed in paraformaldehyde (F8775) and stained for 10 min with crystal violet (C0075) solution [0.2% in phosphate-buffered saline (PBS) (D8537) with 20% methanol (32213)].…”

Section: Methodsmentioning

confidence: 99%

“…A neutral red assay was employed to determine the percentage of viable cells that incorporated the neutral red dye in lysosomes, as initially described by Borenfreund and Puerner (42), a protocol subsequently modified by Repetto et al (43). Briefly, the cells were seeded in 96-well plates at a density of 1.5x10 3 . After 24, 48 and 72 h of melatonin treatment, the cells were incubated for 2 h with neutral red dye (40 µg/ml) (N7005) dissolved in DMEM with 5% FBS.…”

Section: Methodsmentioning

confidence: 99%

“…Rhabdomyosarcoma (RMS) is considered a myogenic tumor and is classified as the most frequent sarcoma affecting children and adolescents (1). The current classification defines five different histotypes, with embryonal (eRMS) and alveolar (aRMS) subsets being the most frequently observed in children <5 years and in adolescents, respectively (2,3). The eRMS variant is the most treatable and most common subtype representing ~80% of RMS, while aRMS is more aggressive and characterized by a poorer prognosis.…”

Section: Introductionmentioning

confidence: 99%

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Melatonin decreases cell proliferation, impairs myogenic differentiation and triggers apoptotic cell death in rhabdomyosarcoma cell lines

et al. 2015

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Abstract. Melatonin is a small indole produced by the pineal gland and other tissues, and has numerous functions that aid in the maintenance of the whole body homeostasis, ranging from the regulation of circadian rhythms and sleep to protection from oxidative stress. Melatonin has also been reported to counteract cell growth and chemoresistance in different types of cancer. In the present study, we investigated the effects of exogenous melatonin administration on different human cell lines and primary mouse tumor cultures of rhabdomyosarcoma (RMS), the most frequent soft tissue sarcoma affecting childhood. The results showed that melatonin significantly affected the behavior of RMS cells, leading to inhibition of cell proliferation and impairment of myogenic differentiation followed by increased apoptotic cell death, as observed by immunoblotting analysis of apoptosis-related markers including Bax, Bcl-2 and caspase-3. Similar findings were observed using a combination of microscopy techniques, including scanning/transmission electron and confocal microscopy. Furthermore, melatonin in combination with doxorubicin or cisplatin, two compounds commonly used for the treatment of solid tumors, increased the sensitivity of RMS cells to apoptosis. These data indicated that melatonin may be effective in counteracting RMS tumor growth and chemoresistance. IntroductionSoft tissue sarcomas are tumors arising from mesenchymal cell precursors that are committed towards the morpho genesis of soft tissues such as fat, muscle and deep skin tissues. Rhabdomyosarcoma (RMS) is considered a myogenic tumor and is classified as the most frequent sarcoma affecting children and adolescents (1). The current classification defines five different histotypes, with embryonal (eRMS) and alveolar (aRMS) subsets being the most frequently observed in children <5 years and in adolescents, respectively (2,3). The eRMS variant is the most treatable and most common subtype representing ~80% of RMS, while aRMS is more aggressive and characterized by a poorer prognosis. The genetic alterations characterizing eRMS commonly involve the loss of heterozygosis on chromosome region 11p15.5 (4), gain of chromosomes (5,6) and mutations on genes involved with growth factor signaling pathways (7)(8)(9)(10)(11)(12)(13)(14)(15). This leads to uncontrolled cell growth and the interruption of proper myogenic differentiation. Conversely, the aRMS subset is commonly characterized by the expression of Pax3-forkhead box O1 (FOXO1), a fused transcription factor derived from the chromosomal translocation t(2;13)(q35;q14), which juxtaposes the DNA-binding domain of Pax3 to the potent transactivation domain of FOXO1 (16). In the absence of the original Pax3 transactivation domain, the chimeric protein drives in a constitutive manner the transcription of numerous genes involved in muscle embryogenesis, such as c-MET and FGFR4, essentially maintaining the muscle precursors in a long-lasting proliferative state and thereby facilitating tumor initiation, aggressiveness and me...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Melatonin decreases cell proliferation, impairs myogenic differentiation and triggers apoptotic cell death in rhabdomyosarcoma cell lines

et al. 2015

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“…20 Rhabdomyosarcoma (RMS) is a tumor showing distinctive traits of skeletal muscle lineage that, with about 350 new diagnoses in the United States per year, is classified as the most common STS in children and adolescents. 21,22 Patients who have localized RMS have a 5-year survival greater than 70% following a multimodal approach that includes chemotherapy, radiation therapy, and surgery; yet, overall survival of patients with metastasis remains poor. 23,24 Cells mainly deriving from myogenic lineages have been shown to contribute to RMS development in mouse [25][26][27][28] and zebrafish models, 29 yet even nonmyogenic lineages could participate in the formation of RMS.…”

Section: Rhabdomyosarcomamentioning

confidence: 99%

Uncovering metabolism in rhabdomyosarcoma

Monti

Fanzani

2016

Cell Cycle

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Rhabdomyosarcoma (RMS) is a myogenic tumor classified as the most frequent soft tissue sarcoma affecting children and adolescents. The histopathological classification includes five different histotypes, with two most predominant referred as to embryonal and alveolar, the latter being characterized by adverse outcome. The current molecular classification identifies two major subsets, those harboring the fused Pax3-Foxo1 transcription factor generating from a recurrent specific translocation (fusion-positive RMS), and those lacking this signature but harboring mutations in the RAS/PI3K/AKT signalling axis (fusion-negative RMS). Since little attention has been devoted to RMS metabolism until now, in this review we summarize the “state of art” of metabolism and discuss how some of the molecular signatures found in this cancer, as observed in other more common tumors, can predict important metabolic challenges underlying continuous cell growth, oxidative stress resistance and metastasis, which could be the subject of future targeted therapies

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“…Rhabdomyosarcoma (RMS) is a childhood soft tissue sarcoma exhibiting broad expression of skeletal muscle markers, [1][2][3] such as Pax7, MyoD, Myogenin, desmin and muscle-specific actin. 4,5 Cells of origin in RMS may be different muscular and non-muscular cell precursors, [6][7][8] such as muscle satellite cells (SCs), [9][10][11] and myoblasts 9,10,[12][13][14] or adipocytes, 15 which are responsible of two major histological subtypes known as embryonal (ERMS) and alveolar (ARMS).…”

mentioning

confidence: 99%

Cavin-1 and Caveolin-1 are both required to support cell proliferation, migration and anchorage-independent cell growth in rhabdomyosarcoma

Faggi

Chiarelli

Colombi

et al. 2015

Laboratory Investigation

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Rhabdomyosarcoma (RMS) is a childhood soft tissue tumor with broad expression of markers that are typically found in skeletal muscle. Cavin-1 is a recently discovered protein actively cooperating with Caveolin-1 (Cav-1) in the morphogenesis of caveolae and whose role in cancer is drawing increasing attention. Using a combined in silico and in vitro analysis here we show that Cavin-1 is expressed in myogenic RMS tumors as well as in human and primary mouse RMS cultures, exhibiting a broad subcellular localization, ranging from nuclei and cytosol to plasma membrane. In particular, the coexpression and plasma membrane interaction between Cavin-1 and Cav-1 characterized the proliferation of human and mouse RMS cell cultures, while a downregulation of their expression levels was observed during the myogenic differentiation. Knockdown of Cavin-1 or Cav-1 in the human RD and RH30 cells led to impairment of cell proliferation and migration. Moreover, loss of Cavin-1 in RD cells impaired the anchorage-independent cell growth in soft agar. While the loss of Cavin-1 did not affect the Cav-1 protein levels in RMS cells, Cav-1 overexpression and knockdown triggered a rise or depletion of Cavin-1 protein levels in RD cells, respectively, in turn reflecting on increased or decreased cell proliferation, migration and anchorage-independent cell growth. Collectively, these data indicate that the interaction between Cavin-1 and Cav-1 underlies the cell growth and migration in myogenic tumors. Rhabdomyosarcoma (RMS) is a childhood soft tissue sarcoma exhibiting broad expression of skeletal muscle markers, 1-3 such as Pax7, MyoD, Myogenin, desmin and muscle-specific actin. 4,5 Cells of origin in RMS may be different muscular and non-muscular cell precursors, 6-8 such as muscle satellite cells (SCs), 9-11 and myoblasts 9,10,12-14 or adipocytes, 15 which are responsible of two major histological subtypes known as embryonal (ERMS) and alveolar (ARMS). The most common ERMS variant arises in children usually o5 years on distinct body sites, such as head, neck and genitourinary regions, while ARMS typically arises in the muscular limb extremities of adolescents and is characterized by poorer prognosis. 16 The genomic landscape causative of ERMS is characterized by a number of genetic lesions and/or somatic mutations that deliberately sustain the activity of different receptors, such as IGF1R, FGFR4 and Patched, 17-21 and related downstream pathways (i.e., RAS/ERK, PI3K/AKT and Sonic Hedgehog signaling). 11,22 In addition, defects in tumor suppressors (i.e., p53), 23 cell cycle regulatory genes (i.e., N-Myc, Rb1) 21,24 and structural proteins involved in muscular integrity (i.e., dystrophin, alpha-sarcoglycan and dysferlin) have been reported. [25][26][27][28][29][30] Conversely, ARMS is dominated by the presence of specific chromosomal translocations leading to expression of the fused Pax3-Foxo1 and Pax7-Foxo1 factors, that driving in a cell cycle manner the transcription of several genes normally restricted to the embryonal development f...

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Myogenic Tumors in Children and Adolescents

Cited by 43 publications

References 253 publications

Melatonin decreases cell proliferation, impairs myogenic differentiation and triggers apoptotic cell death in rhabdomyosarcoma cell lines

Melatonin decreases cell proliferation, impairs myogenic differentiation and triggers apoptotic cell death in rhabdomyosarcoma cell lines

Uncovering metabolism in rhabdomyosarcoma

Cavin-1 and Caveolin-1 are both required to support cell proliferation, migration and anchorage-independent cell growth in rhabdomyosarcoma

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