Hedgehog signaling: modulation of cancer properies and tumor mircroenvironment

Abstract

Cancer poses a serious health problem in society and is increasingly surpassing cardiovascular disease as the leading cause of mortality in the United States. Current therapeutic strategies for cancer are extreme and harsh to patients and often have limited success; the danger of cancer is intensified as it metastasizes to secondary locations such as lung, bone, and liver, posing a dire threat to patient treatment and survival. Hedgehog signaling is an important pathway for normal development. Initially identified in Drosophila, the vertebrate and mammalian equivalent of the pathway has been studied extensively for its role in cancer development and progression. As this pathway regulates key target genes involved in development, its action also allows for the modulation of the microenvironment to prepare a tumor-suitable niche by manipulating tumor cell growth, differentiation, and immune regulation, thus creating an enabling environment for progression and metastasis. In this review, we will summarize recent scientific discoveries reporting the impact of the Hedgehog signaling pathway on the tumor initiation process and metastatic cascade, shedding light on the ability of the tumor to take over a mechanism crucially intended for development and normal function.

Cancer Stem Cells in Prostate Cancer: Implications for Targeted Therapy

“…In a xenograft mouse model of PCa, GANT-61 reduced tumor growth and proliferation and strongly reduced the expression of PTCH1 mRNA [66,67] . These inhibitors are currently in preclinical development in numerous tumor types including PCa [68,69] .…”

Neoplastic Multifocal Skin Lesions: Biology, Etiology, and Targeted Therapies for Nonmelanoma Skin Cancers

“…The inhibition of the hedgehog pathway has been explored for local treatment of advanced and metastatic SCCs [63], giving rise to a new generation of pharmaceuticals, in particular vismodegib and sonedegib. Vismodegib is an inhibitor of the hedgehog pathway that blocks the effects of SMO homologues, which was the first to be approved, under a priority review program by the FDA and the European Medicines Agency.…”

“…Vismodegib is an inhibitor of the hedgehog pathway that blocks the effects of SMO homologues, which was the first to be approved, under a priority review program by the FDA and the European Medicines Agency. It is indicated for local treatment of advanced and metastatic BCC that has reappeared following surgery or which is incurable by surgery or radiation due to the considerable deformity or loss of function [63]. However, further studies are needed in order to discriminate the differences in tumor response between locally invasive and metastatic BCCs.…”

“…Sonidegib, also known as erismodegib, is another SMO homologue antagonist that was, recently, the second to receive FDA approval for cases of locally advanced BCC with recurrent disease, or for patients who do not qualify for radiation therapy or surgical removal [63]. It has demonstrated comparative results to vismodegib for locally advanced BCC [64].…”

“…Besides the promising results of all hedgehog pathway inhibitors, their failure is also evident for resistant tumors limiting their use [63,64]. Alternative strategies, as combined therapies, are needed to overcome the drug resistance of distinct advanced BCCs.…”