Available online 8 March 2024

Author links open overlay panel, Abstract

In this chapter, we have made an attempt to elucidate the relevance of hedgehog signaling pathway in tumorigenesis. Here, we have described different types of hedgehog signaling (canonical and non-canonical) with emphasis on the different mechanisms (mutation-driven, autocrine, paracrine and reverse paracrine) it adopts during tumorigenesis. We have discussed the role of hedgehog signaling in regulating cell proliferation, invasion and epithelial-to-mesenchymal transition in both local and advanced cancer types, as reported in different studies based on preclinical and clinical models. We have specifically addressed the role of hedgehog signaling in aggressive neuroendocrine tumors as well. We have also elaborated on the studies showing therapeutic relevance of the inhibitors of hedgehog signaling in cancer. Evidence of the crosstalk of hedgehog signaling components with other signaling pathways and treatment resistance due to tumor heterogeneity have also been briefly discussed. Together, we have tried to put forward a compilation of the studies on therapeutic potential of hedgehog signaling in various cancers, specifically aggressive tumor types with a perspective into what is lacking and demands further investigation.

Section snippetsHedgehog protein

Hedgehog (Hh) gene was discovered as a regulatory gene in the development of embryo in Drosophila by Nusslein-Volhard and Wieschaus in 1980 (Nüsslein-Volhard & Wieschaus, 1980). It was identified as a secretory segment polarity gene which was shown to be essential for the embryonic cuticle pattern in Drosophila (Lee, Von Kessler, Parks, & Beachy, 1992). Later, it was identified as an evolutionarily conserved protein with three mammalian orthologs, Sonic hedgehog (SHH), Indian hedgehog (IHH),

Mechanisms of hedgehog signaling in cancer

Although hedgehog signaling has been widely studied in embryonic development, it has wide implications in stem cell biology and cancer. SHH is also known to induce stem cell and proliferation related genes such as MYC, cyclin D1, IGF2 and BMI1 during cerebellum development (Ng & Curran, 2011; Wechsler-Reya & Scott, 1999). Hedgehog signaling also maintains stem cells in adult brain, hair follicles and involved in the injury-dependent regeneration of organs (Ahn & Joyner, 2005; Beachy, Karhadkar,

Targeting hedgehog signaling components

Targeting hedgehog signaling pathway has been considered as a treatment for multiple cancer types. Hedgehog signaling pathway inhibitors can target at different levels and are broadly classified as Hh ligand inhibitors, SMO antagonists, GLI inhibitors, inhibitors of bromodomain and extra-terminal domain (BET) family of proteins, atypical protein kinase C (aPKC) inhibitors, and phosphodiesterase inhibitors (Xu, Song, Wang, & Ajani, 2019) (Table 3). Hedgehog ligand inhibitors such as neutralizing

Perspective

Both canonical and non-canonical hedgehog signaling pathway have been proven to regulate many cellular processes such as embryonic development, cell differentiation, proliferation, regeneration and maintenance of stem cells. Relevance of hedgehog signaling in tumorigenesis have also been elucidated in many in vitro and in vivo studies. These studies highlight on how hedgehog signaling pathway adopts different mechanisms (mutation-driven, autocrine, paracrine and reverse paracrine) to regulate

References (141)H. Nagao-Kitamoto et al.Ribosomal protein S3 regulates GLI2-mediated osteosarcoma invasion

Cancer Letters

(2015)

A.H. Polizio et al.Heterotrimeric Gi proteins link Hedgehog signaling to activation of Rho small GTPases to promote fibroblast migration

The Journal of Biological Chemistry

(2011)

A.A. Abbasi et al.Evolution and functional diversification of the GLI family of transcription factors in vertebrates

Evolutionary Bioinformatics Online

(2009)

A. Agyeman et al.Mode and specificity of binding of the small molecule GANT61 to GLI determines inhibition of GLI-DNA binding

Oncotarget

(2014)

S. Ahn et al.In vivo analysis of quiescent adult neural stem cells responding to Sonic hedgehog

Nature

(2005)

D. Amakye et al.Unraveling the therapeutic potential of the Hedgehog pathway in cancer

Nature Medicine

(2013)

S.X. Atwood et al.GLI activation by atypical protein kinase C ι/λ regulates the growth of basal cell carcinomas

Nature

(2013)

S. Azoulay et al.Comparative expression of Hedgehog ligands at different stages of prostate carcinoma progression

The Journal of Pathology

(2008)

S. Baek et al.Vitamin D3 regulates cell viability in gastric cancer and cholangiocarcinoma

Anatomy & Cell Biology

(2011)

E.A. Barnes et al.Patched1 interacts with cyclin B1 to regulate cell cycle progression

The EMBO Journal

(2001)

P.A. Beachy et al.Tissue repair and stem cell renewal in carcinogenesis

Nature

(2004)

O.J. Becher et al.Gli activity correlates with tumor grade in platelet-derived growth factor-induced gliomas

Cancer Research

(2008)

Y.H. Belgacem et al.Sonic hedgehog signaling is decoded by calcium spike activity in the developing spinal cord

Proceedings of the National Academy of Sciences of the United States of America

(2011)

M. Benvenuto et al.In vitro and in vivo inhibition of breast cancer cell growth by targeting the Hedgehog/GLI pathway with SMO (GDC-0449) or GLI (GANT-61) inhibitors

Oncotarget

(2016)

D.M. Berman et al.Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours

Nature

(2003)

I. Bièche et al.Molecular profiling of inflammatory breast cancer: Identification of a poor-prognosis gene expression signature

Clinical Cancer Research: An Official Journal of the American Association for Cancer Research

(2004)

J. Briscoe et al.The mechanisms of Hedgehog signalling and its roles in development and disease

Nature Reviews. Molecular Cell Biology

(2013)

S. Buonamici et al.Interfering with resistance to smoothened antagonists by inhibition of the PI3K pathway in medulloblastoma

Science Translational Medicine

(2010)

D. Carpenter et al.Characterization of two patched receptors for the vertebrate hedgehog protein family

Proceedings of the National Academy of Sciences of the United States of America

(1998)

Initial assessment of tumor regrowth after vismodegib in advanced basal cell carcinoma

Archives of Dermatology

(2012)

F. Charron et al.Novel brain wiring functions for classical morphogens: A role as graded positional cues in axon guidance

Development (Cambridge, England)

(2005)

J.K. Chen et al.Inhibition of hedgehog signaling by direct binding of cyclopamine to smoothened

Genes & Development

(2002)

Y. Chen et al.In vivo evidence that patched and smoothened constitute distinct binding and transducing components of a hedgehog receptor complex

Development (Cambridge, England)

(1998)

H.O. Cheung et al.The kinesin protein Kif7 is a critical regulator of Gli transcription factors in mammalian hedgehog signaling

Science Signaling

(2009)

P. Chinchilla et al.Hedgehog proteins activate pro-angiogenic responses in endothelial cells through non-canonical signaling pathways

Cell Cycle (Georgetown, Tex.)

(2010)

J.Y. Choe et al.Sonic hedgehog signalling proteins are frequently expressed in retinoblastoma and are associated with aggressive clinicopathological features

Journal of Clinical Pathology

(2015)

S.G. Chun et al.Targeted inhibition of histone deacetylases and hedgehog signaling suppress tumor growth and homologous recombination in aerodigestive cancers

American Journal of Cancer Research

(2015)

M. Cohen et al.Ptch1 and Gli regulate Shh signalling dynamics via multiple mechanisms

Nature Communications

(2015)

M.K. Cooper et al.Teratogen-mediated inhibition of target tissue response to Shh signaling

Science (New York, N. Y.)

(1998)

C. D’amato et al.Inhibition of Hedgehog signalling by NVP-LDE225 (Erismodegib) interferes with growth and invasion of human renal cell carcinoma cells

British Journal of Cancer

(2014)

C. Danial et al.An investigator-initiated open-label trial of sonidegib in advanced basal cell carcinoma patients resistant to vismodegib

Clinical Cancer Research

(2016)

C. Dierks et al.Essential role of stromally induced hedgehog signaling in B-cell malignancies

Nature Medicine

(2007)

J.M. Donnelly et al.Sonic hedgehog mediates the proliferation and recruitment of transformed mesenchymal stem cells to the stomach

PLoS One

(2013)

Z. Ertao et al.Autocrine Sonic hedgehog signaling promotes gastric cancer proliferation through induction of phospholipase Cγ1 and the ERK1/2 pathway

Journal of Experimental & Clinical Cancer Research: CR

(2016)

F. Fan et al.Macrophage conditioned medium promotes colorectal cancer stem cell phenotype via the hedgehog signaling pathway

PLoS One

(2018)

L. Fan et al.Hedgehog signaling promotes prostate xenograft tumor growth

Endocrinology

(2004)

V. Fendrich et al.Snail and Sonic Hedgehog activation in neuroendocrine tumors of the ileum

Endocrine-Related Cancer

(2007)

N. Garcia et al.Targeting hedgehog pathway and DNA methyltransferases in uterine leiomyosarcoma cells

Cells

(2021)

M. Gerling et al.Stromal Hedgehog signalling is downregulated in colon cancer and its restoration restrains tumour growth

Nature Communications

(2016)

N. Geyer et al.Hedgehog signaling in colorectal cancer: All in the stroma?

International Journal of Molecular Sciences

(2021)

View full text

Copyright © 2024 Published by Elsevier Inc.