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  • Introduction Hedgehog HH signaling regulates development cel

    2022-01-21

    Introduction Hedgehog (HH) signaling regulates development, cell proliferation, and tissue repair [1], [2], [3]. In mammals, HH signaling is activated by 3 ligands: Sonic hedgehog (SHH), Indian hedgehog (IHH), or Desert hedgehog; SHH is the most widely expressed in adult tissues [3]. The primary receptor for these ligands is Patched-1 (Ptch1). In the absence of ligand, Ptch1 inhibits Smoothened (Smo) (Figure 1A); and upon ligand binding, Ptch1 inhibition is released, activating Smo, leading to activation of the glioma-associated oncogene (Gli) transcription factors Gli1, Gli2, and Gli3 (Figure 1B) [2]. Gli1 activates target genes related to tumorigenesis (eg, cyclin-D1, Myc, Bcl-2), and angiogenesis factor genes [3]. Normal HH signaling is important for morphogenesis, from embryonic development to adult tissue homeostasis [4]; and plays a specific role in latrunculin development, especially that of the cerebellum [5], [6]. In postnatal bone remodeling [7], IHH is expressed at bone growth plates by chondrocytes and osteoblasts, and HH signaling is active [8]. After embryogenesis, HH signaling is quiescent, although SHH-mediated signaling is active in hair follicles, reprograms energy metabolism in adipocytes, and plays a role in multiple organ homeostasis [4], [9], [10], [11], [12]. This review discusses the pharmacology of HHIs and the preclinical and clinical evidence for HHI therapies for hematological cancer and solid tumors beyond advanced basal cell carcinoma (BCC).
    Dysregulated Hedgehog Signaling and the Development of Cancer The HH signaling pathway is normally tightly regulated; however, dysregulation due to mutations in Smo or Ptch1 plays a major role in oncogenesis [3]. In normal tissue, SHH activation of the HH pathway increases DNA synthesis by stem cells [13]. In human cancer, the role of HH signaling was first described in patients with basal cell carcinoma nevus syndrome (BCCNS) and sporadic BCC [14]. Evidence shows that HH ligand binding to Ptch1 controls the cell cycle by promoting transition from Gap 2 to mitosis via binding to a complex of cyclin B1 and cyclin-dependent kinase 1. In BCCNS, Ptch1 acts like a tumor suppressor [1]. Aberrant activation of HH signaling underlies the pathogenesis of a variety of cancers in addition to BCC, including medulloblastoma, breast, lung, pancreatic, prostate, and hematological malignancies [15], [16], [17], [18], [19]. Unlike BCC and medulloblastoma, these solid tumors demonstrate ligand-dependent HH pathway activation [20] and a variety of mechanisms of aberrant HH signaling have been implicated in the development of these different cancer types [4] (Figure 2). Ligand-independent signaling (Figure 2A) occurs in BCC and medulloblastoma [15], [16], and results from loss-of-function mutations in Ptch or Suppressor of fused (Sufu), or gain-of-function mutations in Smo [4], [21], [22], [23]. Autocrine ligand-dependent activation (eg, in breast, lung, pancreatic, and prostate cancer), occurs when the tumor cell produces HH ligand, leading to activation of HH signaling within the same tumor cell (Figure 2B) [4], [15]. Paracrine ligand-dependent activation (eg, in colon, pancreas, and prostate) occurs when the tumor cell produces HH ligand, which then activates HH signaling (eg, vascular endothelial growth factor, interleukin 6, insulin-like growth factor, and wingless/integrated) in a nearby stromal cell, leading to stimulation of tumor growth (Figure 2C) [4], [15]. Inverse paracrine (reverse paracrine), ligand-dependent activation (eg, in lymphoma and multiple myeloma) occurs when HH ligand produced by the stroma cell activates tumor HH signaling (Figure 2D) [4]. In prostate cancer, SHH, PTCH1, GLI1, GLI2, and GLI3 expression increased (range, 1.5- to 300-fold) in microdissected tumor samples compared with normal tissue [24]. Intratumor expression was variable, likely relating to the heterogeneous nature of prostate cancer [24]. GLI1 expression was consistently observed in prostate tumor cell lines and primary tumors, indicating an important role in prostate tumor cell proliferation and tumorigenesis [24]. Additionally, GLI1 gene and protein were also overexpressed in patient-derived human breast cancer tissue compared with normal breast tissue [25]. A positive association was noted between increased GLI1 expression, tumor stage, and lymph node status, correlating with an unfavorable overall survival (OS) [25]. A subsequent meta-analysis confirmed that GLI1 overexpression in breast cancer is associated with reduced disease-free survival, 3- and 5-year survival, and OS [26].