We are studying the molecular mechanisms involved in the pathogenesis of rhabdomyosarcoma (RMS), the most common soft tissue sarcoma of childhood, and osteogenic sarcoma (OS), the most common bone tumor of childhood. Several common growth factors are known to play a role in normal growth and maturation of skeletal muscle and bone such as TGFbeta and insulin- like growth factors (IGF'S). In addition, the tumor suppressor gene p53 has been implicated in the progression of both these tumor types. We have focused our attention on the role of IGFs in these tumors. We have identified IGF II as an autocrine growth factor in RMS and are continuing a Phase II study using suramin, an agent that we have demonstrated is capable of interfering with this autocrine growth loop in vitro. We have determined that at least one mechanism leading to overexpression of IGF II in RMS is loss of imprinting and current studies are aimed at determining the mechanisms involved in normal imprinting to identify possible lesions leading to relaxation of imprinting in tumors. In an attempt to determine the precise role of overexpression of IGF II in RMS tumors, we have transfected a human IGF II cDNA expression vector into mouse myoblast cells and have analyzed the effect on differentiation and proliferation potential, as well as tumorigenic potential. To define the molecular events that play a role in the metastatic potential of these cells, we have developed a series of subclones from a human embryonal RMS cell line with differing tumorigenic and metastatic potentials when injected into nude mice. We have completed our descriptive studies of these subclones and ongoing experiments to describe molecular differences between the various subclones include subtraction cDNA cloning and differential display of RNA to isolate genes that may confer metastatic behavior to these cells. We have now demonstrated that OS cell lines require signaling through the IGF I receptor for in vitro growth. Since growth hormone is known to stimulate IGF I secretion and there are data that suggest growth hormone secretion is important in the development of OS, clinical studies with somatostatin analogs are planned.
