Rhabdomyosarcoma: Advances in Molecular and Cellular Biology

Abstract

Rhabdomyosarcoma (RMS) is the most common soft tissue malignancy in childhood and adolescence. The two major histological subtypes of RMS are alveolar RMS, driven by the fusion protein PAX3-FKHR or PAX7-FKHR, and embryonic RMS, which is usually genetically heterogeneous. The prognosis of RMS has improved in the past several decades due to multidisciplinary care. However, in recent years, the treatment of patients with metastatic or refractory RMS has reached a plateau. Thus, to improve the survival rate of RMS patients and their overall well-being, further understanding of the molecular and cellular biology of RMS and identification of novel therapeutic targets are imperative. In this review, we describe the most recent discoveries in the molecular and cellular biology of RMS, including alterations in oncogenic pathways, miRNA (miR), in vivo models, stem cells, and important signal transduction cascades implicated in the development and progression of RMS. Furthermore, we discuss novel potential targeted therapies that may improve the current treatment of RMS.

Figure 1

The chromosomal rearrangements in ARMS. 80% of ARMS classified as translocation-positive ARMS carry characteristic chromosomal translocations demonstrated as t(2;13)(q35;q14), t(1;13)(p36;q14), and (2;2)(q35;p23). In (a) and (b), the translocations fuse the FKHR (a member of the forkhead/HNF-3 transcription factor family) locus on chromosome 13 to either PAX3 on chromosome 2 or PAX7 on chromosome 1. In (c), the translocation generated a fusion protein composed of PAX3 and the nuclear receptor coactivator NCOA1, having similar transactivation properties as PAX3/FKHR.

Figure 2

Myogenic pathways in the tumorigenesis of RMS. In aberrant neoplastic condition, progenitor cells residing in muscle result in aberrant pathways, which lead to malignant transformation and fail to differentiate, proliferate uncontrollably, and form RMS. Sharp arrows (→) indicate upregulation/activation and blunt arrows (⊥) indicate downregulation/inhibition.

Figure 3

Genetic analyses of RMS have pinpointed several common alterations, including inactivation of a master regulator of p53 and Rb pathways, CDKN2A/B, and activation of FGFR4, RAS, and Hedgehog (Hh) signaling. The modifications of these pathways influence oncogenesis and metastatic potential.

Figure 4

The DNA repair systems in RMS. There are two pathways repairing the DNA lesions, directly without affecting DNA structure and indirectly by DNA phosphodiester backbone cleavage. The modifications in DNA repair enzymes expression or activity lead to resistance to chemotherapy and radiation in RMS tumor cells. MGMT, O⁶-methylguanine-DNA methyltransferase; BER, base excision repair; NER, nucleotide excision repair; HR, homologous recombination; NHEJ, nonhomologous end-joining; MMEJ, microhomology-mediated end-joining.