What’s the sonic hedgehog protein(Shh)?
Human Recombinant Sonic Hedgehog (Shh) is a member of a tiny group of secreted proteins and the most well-known function is crucial for embryonic development, including cell differentiation, proliferation, and selection of T cells. It controls the destiny of neural and hematopoietic stem cells as well. Moreover, Shh is connected to cancer formation and tissue reorganization after injury in adult tissue.
 
Why do researchers target the Shh pathway in cancer?
Numerous cancers development, including basal cell carcinoma, medulloblastoma, and acute promyelocytic leukemia (APL), are closely connected with the Shh pathway. Abnormal activation of this pathway is also seen in several different human malignancies, including those of the brain, gastrointestinal system, lungs, breast, and prostate.^[1]
There are three unique ligands, Sonic Hedgehog (Shh), Indian hedgehog, and Desert hedgehog[2], which can trigger the hedgehog(HH) pathway in mammals. Of these ligands, the Shh is the most frequently expressed and powerful. The Shh is produced as a full-length which is an inactive form. The Shh can autolyze to generate the sonic hedgehog protein C-terminal fragment (Shh-C) and the Shh N-terminal fragment (Shh-N). The active Shh ligand is called Shh-N. ^[3] Patched1 (PTCH1), a 12-transmembrane protein that binds Shh ligand, is the receptor for this active Shh ligand. When Shh binds to PTCH1, Smoothed (SMO) is no longer suppressed by PTCH1, which activates SMO signaling activity. In the end, SMO activation weakens the link between the inhibitor of fused homolog (SUFU) and GLI proteins, allowing GLI proteins to reach the nucleus and activate transcriptional targets to control cellular gene expression. The Shh signaling pathway's end effectors, the GLI proteins, control genes that influence cellular and tissue patterning and development. Numerous GLI protein-regulated genes are used by cancer cells as they control several cancer-related activities, such as neovascularization, proliferation, migration, and invasion. ^{[4, 5, 6]}




How does the sonic hedgehog protein connect with organ development and tumor immunity?
♦ Organ development - Lung
As we mentioned above, the canonical hedgehog (HH) signaling pathway plays a crucial role during embryonic development. HH is an important morphogen that controls a variety of cellular functions. It has the ability to elicit tissue-specific reactions that eventually aid in the development of a fully developed organism. Sonic Hedgehog (SHH), one of the three HH proteins, is essential for lung development. Our lung appears to have a branching, tree-like structure in vertebrates. This structure, which is formed by repeated tip splitting, is known as branching morphogenesis. The epithelium is chemoattracted to the pleura by a cluster of mesenchymal cells that are expressing fibroblast growth factor 10 (FGF10). Low levels of sonic hedgehog (SHH) expression enable FGF10 to serve as a chemotactic factor. Additionally essential to bud growth is the bone morphogenetic protein 4 (BMP4). ^{[7, 8]}




♦ Cancer development
There is more and more evidence showing that the Shh signaling affects the immunological microenvironment of both malignant and non-malignant tissues in a variety of intricate and interesting ways. HH/GLI signaling involves multiple mechanisms which modulate cancer and inflammation circumstances. Such as, tumor-associated macrophages (TAMs) and immunosuppressive Myeloid-derived suppressor cells (MDSCs) are recruited by cancer cells when oncogenic HH/GLI signaling causes the release of CCL2 and CCL3 from the cancer cells. ^{[9, 10, 11]} Dendritic cells and cancer cells are stimulated by HH/GLI to express PD-L1, which suppresses tumor-specific cytotoxic T-cells by binding to PD-1 and further weakens the ability against cancer cells. ^{[12, 13]} The immunosuppressive cytokines and growth factors, like IL-10 and TGFβ, produced by GLI2 from TAMs and Tregs lead to the inactivation of tumor-specific CD8+ T-cells. HH/GLI signaling interacts with pro-inflammatory signals like IL-6/STAT3. As a result, autocrine HH/GLI-induced IL-6 signaling and/or pro-inflammatory IL-6 from TAM and stromal cells enhance STAT3 signaling in cancer cells, supporting the development of malignant tumors. ^{[14, 15]}



Related Products:
→ Human Sonic Hedgehog (C24II), His-SUMO Tag
→ BMP-4 (Bone morphogenetic protein-4), Human
→ FGF-10 (Fibroblast growth factor-10), Human
→ CCL2 (C-C motif chemokine ligand 2), Human
→ CCL3 (C-C motif chemokine ligand 3), Human
→ IL-10 (Interleukin-10), Human
→ TGF beta 1 (Transforming growth factor β1), Human
→ IL-6 (Interleukin-6), Human

---

Ref.

1. Carpenter RL, Ray H. Safety and Tolerability of Sonic Hedgehog Pathway Inhibitors in Cancer. Drug Saf. 2019 Feb;42(2):263-279.
2. Echelard Y, Epstein DJ, St-Jacques B, Shen L, Mohler J, McMahon JA, McMahon AP. Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell. 1993 Dec 31;75(7):1417-30.
   Porter JA, von Kessler DP, Ekker SC, Young KE, Lee JJ, Moses K, Beachy PA. The product of hedgehog autoproteolytic cleavage active in local and long-range signaling. Nature. 1995 Mar 23;374(6520):363-6.
3. Bailey JM, Mohr AM, Hollingsworth MA. Sonic hedgehog paracrine signaling regulates metastasis and lymphangiogenesis in pancreatic cancer. Oncogene. 2009 Oct 8;28(40):3513-25.
4. Gupta S, Takebe N, Lorusso P. Targeting the Hedgehog pathway in cancer. Ther Adv Med Oncol. 2010 Jul;2(4):237-50.
   Carpenter RL, Lo HW. Identification, functional characterization, and pathobiological significance of GLI1 isoforms in human cancers. Vitam Horm. 2012;88:115-40.
5. Warburton D, Bellusci S, Del Moral PM, Kaartinen V, Lee M, Tefft D, Shi W. Growth factor signaling in lung morphogenetic centers: automaticity, stereotypy and symmetry. Respir Res. 2003;4(1):5.
6. Miura T. Models of lung branching morphogenesis. J Biochem. 2015 Mar;157(3):121-7.
7. Fan Q, Gu D, Liu H, Yang L, Zhang X, Yoder MC, Kaplan MH, Xie J. Defective TGF-β signaling in bone marrow-derived cells prevents hedgehog-induced skin tumors. Cancer Res. 2014 Jan 15;74(2):471-483.
8. Fan Q, He M, Sheng T, Zhang X, Sinha M, Luxon B, Zhao X, Xie J. Requirement of TGFbeta signaling for SMO-mediated carcinogenesis. J Biol Chem. 2010 Nov 19;285(47):36570-6.
9. Hanna A, Metge BJ, Bailey SK, Chen D, Chandrashekar DS, Varambally S, Samant RS, Shevde LA. Inhibition of Hedgehog signaling reprograms the dysfunctional immune microenvironment in breast cancer. Oncoimmunology. 2018 Dec 12;8(3):1548241.
10. Chakrabarti J, Holokai L, Syu L, Steele NG, Chang J, Wang J, Ahmed S, Dlugosz A, Zavros Y. Hedgehog signaling induces PD-L1 expression and tumor cell proliferation in gastric cancer. Oncotarget. 2018 Dec 21;9(100):37439-37457.
11. Lipson EJ, Lilo MT, Ogurtsova A, Esandrio J, Xu H, Brothers P, Schollenberger M, Sharfman WH, Taube JM. Basal cell carcinoma: PD-L1/PD-1 checkpoint expression and tumor regression after PD-1 blockade. J Immunother Cancer. 2017 Mar 21;5:23.
12. Mills LD, Zhang Y, Marler RJ, Herreros-Villanueva M, Zhang L, Almada LL, Couch F, Wetmore C, Pasca di Magliano M, Fernandez-Zapico ME. Loss of the transcription factor GLI1 identifies a signaling network in the tumor microenvironment mediating KRAS oncogene-induced transformation. J Biol Chem. 2013 Apr 26;288(17):11786-94.
13. Grund-Gröschke S, Stockmaier G, Aberger F. Hedgehog/GLI signaling in tumor immunity - new therapeutic opportunities and clinical implications. Cell Commun Signal. 2019 Dec 26;17(1):172.