SHH Signaling Pathway Drives Pediatric Bone Sarcoma Progression

Abstract

Primary bone tumors can be divided into two classes, benign and malignant. Among the latter group, osteosarcoma and Ewing sarcoma are the most prevalent malignant primary bone tumors in children and adolescents. Despite intensive efforts to improve treatments, almost 40% of patients succumb to the disease. Specifically, the clinical outcome for metastatic osteosarcoma or Ewing sarcoma remains poor; less than 30% of patients who present metastases will survive 5 years after initial diagnosis. One common and specific point of these bone tumors is their ability to deregulate bone homeostasis and remodeling and divert them to their benefit. Over the past years, considerable interest in the Sonic Hedgehog (SHH) pathway has taken place within the cancer research community. The activation of this SHH cascade can be done through different ways and, schematically, two pathways can be described, the canonical and the non-canonical. This review discusses the current knowledge about the involvement of the SHH signaling pathway in skeletal development, pediatric bone sarcoma progression and the related therapeutic options that may be possible for these tumors.

The YAP/TEAD Axis as a New Therapeutic Target in Osteosarcoma: Effect of Verteporfin and CA3 on Primary Tumor Growth

“…In several cancers, it has been demonstrated that YAP stimulates cell proliferation largely by controlling the expression of a broad number of cell cycle regulators or the expression of oncogenes, for example MYC and AP-1 family members [ 19 ]. In this work, we identify genes directly involved in the control of cell cycle, such as CDC25B, or involved in the regulation of oncogene expression, such as Gli1 previously described as a pro-proliferation factor and thus as a potential therapeutic target in OS [ 31 ]. Furthermore, using overexpression of a mutant YAP protein unable to interact with TEAD1–4 (YAPS94A), we clearly demonstrate that the TEADs transcriptional factors are crucial in YAP-driven OS growth both in vitro and in vivo as previously described in other cancers [ 21 ].…”

Crucial Role of the YAP/TEAD Axis in Osteosarcoma Tumor Growth: Effects of YAP Inhibitors Verteporfin and CA3 on Tumor Growth in vivo

“…In several cancers, it has been demonstrated that YAP stimulates cell proliferation largely by controlling the expression of a broad number of cell cycle regulators or the expression of oncogenes, for example MYC and AP-1 family members [19]. In this work, we identify genes directly involved in the control of cell cycle, such as CDC25B, or involved in the regulation of oncogene expression, such as Gli1 previously described as a pro-proliferation factor and thus as a potential therapeutic target in OS [30]. Furthermore, using overexpression of a mutant YAP protein unable to interact with TEAD1-4 (YAPS94A), we clearly demonstrate that the TEADs transcriptional factors are crucial in YAP-driven OS growth both in vitro and in vivo as previously described in other cancers [21].…”

Recent Insights into Therapy Resistance in Osteosarcoma

“…Aberrant activation of the Sonic Hedgehog (SHH) pathway is another signal transduction pathway that has implications in osteosarcoma development, progression, and metastasis [ 33 ]. A study by Shu et al implicated a role for this pathway in stemness and chemotherapy resistance and observed that by inhibiting heat shock protein 90 (Hsp90) with the small molecule 17-AAG, they suppressed the SHH pathway and reversed chemoresistance [ 34 ].…”