Targeting the Insulin-Like Growth Factor Pathway in Rhabdomyosarcomas: Rationale and Future Perspectives

Abstract

Rhabdomyosarcomas (RMS) are a heterogeneous group of tumors that share features of skeletal myogenesis and represent the most common pediatric soft tissue sarcoma. Even though significant advances have been achieved in RMS treatment, prognosis remains very poor for many patients. Several elements of the Insulin-like Growth Factor (IGF) pathway are involved in sarcomas, including RMS. The IGF2 ligand is highly expressed in most, if not all, RMS, and frequent overexpression of the receptor IGF1R is also found. This is confirmed here through mining expression profiling data of a large series of RMS samples. IGF signaling is implicated in the genesis, growth, proliferation, and metastasis of RMS. Blockade of this pathway is therefore a potential therapeutic strategy for the treatment of RMS. In this paper we examine the biological rationale for targeting the IGF pathway in RMS as well as the current associated preclinical and clinical experience.

Prohibitin-2 Binding Modulates Insulin-like Growth Factor-binding Protein-6 (IGFBP-6)-induced Rhabdomyosarcoma Cell Migration

“…IGF-II is an autocrine growth factor for RMS (3,25), and IGFBP-6 inhibited proliferation and survival of RMS cells in vitro (26). Further, IGFBP-6 overexpression inhibited RMS xenograft growth in vivo (26).…”

5-Azacytidine inhibits human rhabdomyosarcoma cell growth by downregulating insulin-like growth factor 2 expression and reactivating the H19 gene product miR-675, which negatively affects insulin-like growth factors and insulin signaling

“…as mentioned above, H19-derived mir-675 downregulates the expression of igf1r in murine placental cells (24). to address whether mir-675 is involved in regulation of igf1r expression in human rMS cells, we measured the expression of two isoforms of this mirna (mir-675-3p and -5p) in rH30 and rD cells, unexposed and exposed to azac ( fig.…”

“…Encoded by the insulin-like growth factor 2 (IGF2) gene, igf2 is a growth factor essential for normal embryonic and neonatal growth and development, while H19 gives rise to a non-coding mrna that has the opposite effect on cell proliferation. igf2 signals through the tyrosine kinase insulin-like growth factor 1 receptor (igf1r), which is frequently overexpressed in human rMS (19)(20)(21)(22)(23)(24)(25) and a number of other cancers (25). the 5-Azacytidine inhibits human rhabdomyosarcoma cell growth by downregulating insulin-like growth factor 2 expression and reactivating the H19 gene product miR-675, which negatively affects insulin-like growth factors and insulin signaling Maciej tarnoWSKi 1 , Marta tKacz function of H19-derived non-coding rna (ncrna) is largely unknown and still under debate.…”

From fever to immunity: A new role for IGFBP‐6?

“…IGFs in general and IGF‐II in particular are involved in promoting tumour growth in situ in an autocrine or paracrine fashion once the tumour has been established. Many cancers overexpress IGF2 59 by mechanisms including loss of imprinting (LOI) and loss of heterozygosity (LOH) 60, 61. Interestingly, other observations indicate that the IGF system might be important also for tumour cell death.…”