Redundancy of autocrine loops in human rhabdomyosarcoma cells: induction of differentiation by suramin

Abstract

Smmay Three human rhabdomyosarcoma cell lines were used to investigate the presence of autocrine loops based on the production of insulin-like growth factor (IGF)-II, basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF)jtransforming growth factor (TGF)-a and of their corresponding receptors, and whether these loops affect cell proliferation and myogenic differentiation.

Oncogenic Ras-induced secretion of a novel inhibitor of skeletal myoblast differentiation

“…Blocking these pathways individually or in combination through the use of speci®c neutralizing antibodies inhibited proliferation but did not restore a myogenic phenotype. Blocking essentially all autocrine growth loops with suramin, a general growth factor antagonist, however, inhibited both proliferation and restored the myogenic phenotype (Giovanni et al, 1995). The ®nding that the degree of proliferation is not inversely proportional to the degree of di erentiation is not surprising since it is well documented that the inhibition of di erentiation by growth factors or by oncogenic Ras is independent of their mitogenicity Olson et al, 1987;Payne et al, 1987;Gossett et al, 1988;Lathrop et al, 1985;Rosenthal and Cheng, 1995;Weyman et al, 1997).…”

Rhabdomyosarcoma – working out the pathways

“…For example: c-MET ampli®cation and overexpression has been detected in RMS, as discussed above (Ferracini et al, 1996;Takayama et al, 1997); basic ®broblast growth factor (bFGF)-FGF receptor (FGFR) autocrine signaling has been reported in human RMS cells (Schweigerer et al, 1987;De Giovanni et al, 1995); and IGF2 is consistently overexpressed in both embryonal and alveolar RMS, where it can induce autocrine signaling through the IGF1 RTK, and cooperate with PAX3-FKHR (ElBadry et al, 1990;Minniti et al, 1994;Wang et al, 1998). Insights gained through analysis of satellite cells and skeletal muscle regeneration provide a rational hypothesis for how constitutive activation of speci®c growth factor receptor signaling pathways can disrupt the delicate balance between proliferation and differentiation, creating an expanded pool of cycling myogenic progenitors that become targets of further mutagenesis and seeds of future RMS.…”

“…This LOI can lead to a twofold gene dosage e ect, and may contribute to the characteristic overexpression of IGF2 observed in these tumors (Zhan et al, 1994). LOH studies have Barr et al, 1993;Galili et al, 1993Davis et al, 1994Besnard-Gue rin et al, 1996Visser et al, 1997Stratton et al, 1990Mulligan et al, 1990;Felix et al, 1992El-Badry et al, 1990Zhan et al, 1994Meddeb et al, 1996Keleti et al, 1996;Fiddler et al, 1996Khatib et al, 1993Knudsen et al, 1998Ferracini et al, 1996Garson et al, 1986Mitani et al, 1986;Bayani et al, 1995Weber-Hall et al, 1996Smith et al, 1998Iolascon et al, 1996Schweigerer et al, 1987De Giovanni et al, 1995Chardin et al, 1985Stratton et al, 1989 *Denotes alterations seen commonly in both RMS cell lines and tumor tissue; other lesions occur occasionally, and/or have been infrequently reported. LOH, loss of heterozygosity; LOI, loss of imprinting also suggested the existence of putative RMSassociated tumor suppressor genes residing at 11q and 16q (Loh et al, 1992;Visser et al, 1997).…”

Wild-type p53-mediated down-modulation of interleukin 15 and interleukin 15 receptors in human rhabdomyosarcoma cells

“…Cells transduced and cultured as above were utilized for RNA extraction, cDNA synthesis and RT-PCR, as reported previously (De Giovanni et al, 1995;Lollini et al, 1997). RNA was extracted from at least three independent experinments in which control and non-biding site.…”

“…the most frequent softtissue sarcoma in childhood (Pappo et al 1995). frequently shows impaired p53 function (Felix et al 1992: Diller et al 1995: Keleti et al 1996 and produces a variety of growth factors (Schweigerer et al 1987;El-Badry et al 1990: De Giovanni et al 1995 that could be subject to transcription control by p53 (Fujiwara et al 1994: Shin et al 1995: Zhang et al 1996. We recently found that rhabdomyosarcoma cell lines express and secrete interleukin 15 (IL-15) (Lollini et al 1997).…”