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.

Keywords: Ewing sarcoma; Gli; Sonic Hedgehog; osteosarcoma; skeletal development.

Figure 1

Off state (left): In the absence of Sonic Hedgehog (SHH) ligand, Ptch inhibits signal transduction by SMO. Gli canonical SHH signaling pathway proteins are sequestered in the cytoplasm by interaction with Sufu. Therefore, the expression of SHH signaling targets turns off. On state (right): In the presence of ligand, SHH binds to Ptch and, therefore, induces the translocation of SMO to the primary cilium, a subcellular compartment essential for signal transduction to the positive forms of Gli proteins. Gli proteins accumulate into the nucleus and activate target genes transcription.

Figure 2

Origins of appendicular, axial and craniofacial skeletons. The axial and appendicular skeletons derive from cells of the paraxial mesoderm following a proximal-distal migration of cells from the lateral and intermediary mesoderm or the segmentation of cells from the somatic mesoderm. The craniofacial skeleton derives from the ectoderm cells of the neural crests following a dorsal-ventral migration, enabling the formation of the branchial arches and a posterior-anterior migration.

Figure 3

Sonic Hedgehog (SHH) implications in the craniofacial and limb morphogenesis. (A) SHH expression pattern in the first branchial arch determines the Meckel cartilage initiation site on mouse embryonic day 9.5 (E9.5). (B) SHH expression on mouse embryonic day 10.5 mandible determines the tooth initiation site. (C) SHH expression in the frontonasal prominences of the mouse embryonic day 10.5 governs the morphogenesis of the upper facial structures. (D–E) In the mouse limb bud at embryonic day 10.5, SHH expression in the zone of polarizing activity (ZPA) determines the posterior region of the limb bud, where distal growth is controlled by the apical ectodermal ridge (AER) visualized by Dlx2/LacZ expression in (D) and the subjacent progression zone. The cells determined by the SHH signaling will give rise to the posterior bones of the autopod and zeugopod (E).

Figure 4

Role of SHH/Gli cascade in Ewing sarcoma development. Upper panels: EWS-Fli1 protein regulates Gli1 gene expression at the transcriptional level and, therefore, promotes the expression of Gli gene targets implicated in various cellular events, such as cell proliferation and migration. Lower panels: progression of Ewing sarcoma development. During primary tumor growth, cancer cells produce soluble factors, such as growth factors or cytokines, that activate osteoclastogenesis and, in turn, bone degradation. This bone resorption then allows the release of trapped growth factors into the bone matrix able to stimulate tumor growth, “EMT-like” (epithelial mesenchymal transition) angiogenesis and, therefore, the metastatic process.