Radioresistance in rhabdomyosarcomas: Much more than a question of dose

Abstract

Management of rhabdomyosarcoma (RMS), the most common soft tissue sarcoma in children, frequently accounting the genitourinary tract is complex and requires a multimodal therapy. In particular, as a consequence of the advancement in dose conformity technology, radiation therapy (RT) has now become the standard therapeutic option for patients with RMS. In the clinical practice, dose and timing of RT are adjusted on the basis of patients' risk stratification to reduce late toxicity and side effects on normal tissues. However, despite the substantial improvement in cure rates, local failure and recurrence frequently occur. In this review, we summarize the general principles of the treatment of RMS, focusing on RT, and the main molecular pathways and specific proteins involved into radioresistance in RMS tumors. Specifically, we focused on DNA damage/repair, reactive oxygen species, cancer stem cells, and epigenetic modifications that have been reported in the context of RMS neoplasia in both in vitro and in vivo studies. The precise elucidation of the radioresistance-related molecular mechanisms is of pivotal importance to set up new more effective and tolerable combined therapeutic approaches that can radiosensitize cancer cells to finally ameliorate the overall survival of patients with RMS, especially for the most aggressive subtypes.

Keywords: radiation therapy; radioresistance; radiosensitizers; radiotherapy; rhabdomyosarcoma.

Figure 1

Distribution of primary sites for rhabdomyosarcoma. The head and neck site may be subdivided as 7% orbit, 8% other head, 23% parameningeal, and 9% non-parameningeal. The pelvic sites may be subdivided as 11% bladder and prostate, and 5% female genital or 12% male non-bladder/prostate.

Figure 2

The role of molecular analysis for differential diagnosis and classification of RMS. Molecular analysis helps to identify the subtypes and classify RMS.

Figure 3

Molecular mechanisms responsible of radioresistance. Several key cellular and molecular factors, including DNA damage and repair, oxidative stress, tumor microenvironment, cancer stem cells (CSCs), and tumor heterogeneity, are implied in RMS radioresistance.

Figure 4

Effects of the combined treatment with DNMT3A/3B silencing and radiotherapy. Visual representation of the different radiosensitizing mechanisms observed upon (A) DNMT3A and (B) DNMT3B knocking down and RT co-treatment.