Signaling pathways in Rhabdomyosarcoma invasion and metastasis

Abstract

Rhabdomyosarcoma (RMS) is an aggressive childhood mesenchymal tumor with two major molecular and histopathologic subtypes: fusion-positive (FP)RMS, characterized by the PAX3-FOXO1 fusion protein and largely of alveolar histology, and fusion-negative (FN)RMS, the majority of which exhibit embryonal tumor histology. Metastatic disease continues to be associated with poor overall survival despite intensive treatment strategies. Studies on RMS biology have provided some insight into autocrine as well as paracrine signaling pathways that contribute to invasion and metastatic propensity. Such pathways include those driven by the PAX3-FOXO1 fusion oncoprotein in FPRMS and signaling pathways such as IGF/RAS/MEK/ERK, PI3K/AKT/mTOR, cMET, FGFR4, and PDGFR in both FP and FNRMS. In addition, specific cytoskeletal proteins, G protein coupled receptors, Hedgehog, Notch, Wnt, Hippo, and p53 pathways play a role, as do specific microRNA. Paracrine factors, including secreted proteins and RMS-derived exosomes that carry cargo of protein and miRNA, have also recently emerged as potentially important players in RMS biology. This review summarizes the known factors contributing to RMS invasion and metastasis and their implications on identifying targets for treatment and a better understanding of metastatic RMS.

Anticancer effect of myristicin on hepatic carcinoma and related molecular mechanism

“… 2014 ; Ramadan et al. 2020 ). PI3K/Akt/mTOR signalling pathway inhibition has been shown to be used to inhibit HCC (Kudo 2011 ; Ye et al.…”

Unraveling the IGF System Interactome in Sarcomas Exploits Novel Therapeutic Options

“…Rhabdomyosarcoma is the most common pediatric soft tissue sarcoma of the muscle [173]. Two major histopathological subtypes exist: alveolar and embryonal [173].…”

“…Rhabdomyosarcoma is the most common pediatric soft tissue sarcoma of the muscle [173]. Two major histopathological subtypes exist: alveolar and embryonal [173]. The alveolar subtype is characterized by a recurrent t(2;13) translocation genereting a fusion between the PAX3 and FKHR (FOXO1) genes.…”

“…Constitutive downregulation of IGFBP2, which inhibits IGF1R phosphorylation and signaling, was identified as a possible mechanism for resistance to IGF1R antibody [185]. It is important to mention that, in addition to the IGF axis, several autocrine and paracrine signaling pathways might contribute to the malignant propensity of rhabdomyosarcoma histologic subtypes inlcuding the cMET, FGFR4 and PDGFR cascades, which all activate Akt signaling [173]. Accordingly, progression of rhabdomyosarcoma tumors and resistance to IGF1R inhibition were associated with reactivation of Akt in spite of suppression of IGF1R action [186].…”

A bioengineering method for modeling alveolar Rhabdomyosarcoma and assessing chemotherapy responses

“…Despite being the most common pediatric soft tissue tumor, the rarity of RMS increases the difficultly of recruiting patients for clinical studies and, in many cases, their results are limited by small samples sizes. The most common subtype is embryonal RMS which accounts for over 60% of all RMS diagnoses and has a 5-year survival rate of 73.4% [ 4 , 5 ]. This is a favorable diagnosis in comparison with alveolar RMS (ARMS), a less common pediatric subtype with significantly poorer outcomes and a 5 year survival rate of only 47.7% [4] .…”