The Hedgehog signaling pathway HH pathway hereafter is vital

The Hedgehog signaling pathway (HH pathway hereafter) is vital for development and tissue homeostasis. [4] In recent years, studying the role of the HH pathway in carcinogenesis and cancer stemness has highlighted the HH inhibitors as putative cancer therapeutics [5]. However, clinical application of HH inhibition in cancer improves outcomes only for patients with basal cell carcinoma [6] and a subgroup of patients with medulloblastoma with active HH signaling [7]. Both these tumor types harbor oncogenic mutations in key molecules of the HH pathway. In contrast, clinical trials have largely yielded negative results for unselected populations of patients with solid tumors of epithelial origin despite preclinical rationale [8,9]. Herein, we review the preclinical and clinical data on the use of HH inhibitors with respective to the major histologic types of lung cancer, including small-cell lung cancer (SCLC), lung adenocarcinoma and squamous cell lung carcinoma. The goal of this review is to highlight areas of uncertainty and guide future research for HH pathway inhibition in lung cancer.
Hedgehog pathway overview Stem Adox are capable for both self-renewal and evolution to more differentiated states, a feature known as asymmetric cell division. [10] The identification of stem cells originated from the observation that a limited number of bone marrow cells are able to reconstitute the entire hematopoietic system when transplanted in syngeneic mice [11]. Since then, a number of stem cell populations have been characterized both in normal adult and embryonic tissues including the hematopoietic stem cells [12], the neural stem cells (NSCs) [13], the embryonic stem cells [14] and others [15,16]. Likewise to stem cells in normal tissues, the stem cell theory of cancer introduces the concept of the cancer initiating cell (CIC) sitting at the top of cancer cell hierarchy [17]. According to this theory, a limited number of CICs can form a tumor xenograft when implanted in mice [18]; CICs are responsible for resistance to drug therapy, disease relapse and metastasis [17]. Importantly, both normal stem cells and CICs activate common molecular pathways including morphogens WNT, NOTCH and HH [19]. Especially the HH pathway activation follows a concentration HH ligand gradient during the development of the normal lung and is also important for the maintenance of adult stem cells in many tissues [20,21]. The HH pathway (illustrated in Fig. 1) was initially described in Drosophila melanogaster where it was found to be required for segment polarity and ventral-dorsal differentiation. [22] In vertebrates, the SHH, IHH and DHH (Sonic, Indian and Desert Hedgehog respectively) ligands bind to the 12-pass transmembrane receptors Patched1 and Patched2 (PTCH1 and PTCH2 respectively). [23] In the absence of ligands, the PTCH receptors suppress the 7-pass transmembrane G-protein coupled receptor (GPCR)-like protein Smoothened (SMO) [24]. The binding of lipid modified SHH, IHH and DHH ligands to the PTCH receptors [25,26], activates SMO in the primary cilium, a solitary organelle with sensory function in most mammalian cells [[27], [28], [29]]. The exact interaction of PTCH with SMO is not fully elucidated but involves control of cholesterol availability [30,31]. This process inhibits the processing of the zinc finger transcription factors GLI. Following SMO activation, full length GLI enters the cilia in the form of a complex with the HH negative regulator Suppressor of Fused (SUFU) [32]. The complex accumulates at the cilia tip where GLI disassociates [32] and exits the cilia in a Kinesin Family Member 7 (KIF7) dependent process to function as a transcriptional activator for HH pathway target genes [4]. There are currently three identified GLI transcription factors in vertebrates, GLI1, GLI2 and GLI3. GLI3 functions mainly as a pathway repressor in its truncated form. GLI1 lacks the N-terminal repressor sequence and has activating effect only, whereas GLI2 is the main pathway activator [[33], [34], [35]].