The role of Hedgehog (Hh) signaling in vascular biology has first been highlighted in embryos by Pepicelli et al. in 1998 and Rowitch et al. in 1999. Since then, the proangiogenic role of the Hh ligands has been confirmed in adults, especially under pathologic conditions. More recently, the Hh signaling has been proposed to improve vascular integrity especially at the blood–brain barrier (BBB). However, molecular and cellular mechanisms underlying the role of the Hh signaling in vascular biology remain poorly understood and conflicting results have been reported. As a matter of fact, in several settings, it is currently not clear whether Hh ligands promote vessel integrity and quiescence or destabilize vessels to promote angiogenesis. The present review relates the current knowledge regarding the role of the Hh signaling in vasculature development, maturation and maintenance, discusses the underlying proposed mechanisms and highlights controversial data which may serve as a guideline for future research. Most importantly, fully understanding such mechanisms is critical for the development of safe and efficient therapies to target the Hh signaling in both cancer and cardiovascular/cerebrovascular diseases.

https://www.mdpi.com/1422-0067/20/12/3076/pdf

Role of Hedgehog Signaling in Vasculature Development, Differentiation, and Maintenance.

Abstract Notch and Hedgehog signaling are involved in cancer biology and pathology, including the maintenance of tumor cell proliferation, cancer stem-like cells, and the tumor microenvironment. Given the complexity of Notch signaling in tumors, its role as both a tumor promoter and suppressor, and the crosstalk between pathways, the goal of developing clinically safe, effective, tumor-specific Notch-targeted drugs has remained intractable. Drugs developed against the Hedgehog signaling pathway have affirmed definitive therapeutic effects in basal cell carcinoma; however, in some contexts, the challenges of tumor resistance and recurrence leap to the forefront. The efficacy is very limited for other tumor types. In recent years, we have witnessed an exponential increase in the investigation and recognition of the critical roles of the Notch and Hedgehog signaling pathways in cancers, and the crosstalk between these pathways has vast space and value to explore. A series of clinical trials targeting signaling have been launched continually. In this review, we introduce current advances in the understanding of Notch and Hedgehog signaling and the crosstalk between pathways in specific tumor cell populations and microenvironments. Moreover, we also discuss the potential of targeting Notch and Hedgehog for cancer therapy, intending to promote the leap from bench to bedside. 

/pdf/the-role-of-hedgehog-and-notch-signaling-pathway-in-cancer-313vc3p9.pdf

The role of Hedgehog and Notch signaling pathway in cancer

Hedgehog (Hh) proteins are prototypical morphogens known to regulate epithelial/mesenchymal interactions during embryonic development. In addition to its pivotal role in embryogenesis, the Hh signaling pathway may be recapitulated in post-natal life in a number of physiological and pathological conditions, including ischemia. This review highlights the involvement of Hh signaling in ischemic tissue regeneration and angiogenesis, with particular attention to the heart, the brain, and the skeletal muscle. Updated information on the potential role of the Hh pathway as a therapeutic target in the ischemic condition is also presented.

https://www.mdpi.com/1422-0067/20/21/5270/pdf

The Hedgehog Signaling Pathway in Ischemic Tissues.

The Hedgehog pathway was recently shown to be involved in vascular development and neovascularization in human embryogenesis and disease. However, the role of Hedgehog pathway in modulating tumor angiogenesis is still unexplored. In the current study, we investigated the expression of Indian Hedgehog (Ihh) and vascular endothelial cell growth factor (VEGF) in human hepatocellular carcinomas (HCCs) with immunohistochemical staining and compared the immunoreaction data with various clinicopathologic characteristics. Immunoreactivity of Ihh and VEGF proteins was observed in 61.5% (56/91) and 64.5% (59/91) cases of HCC tumor tissues, respectively, which was considerably higher than the adjacent nonmalignant tissues. Ihh protein was observed predominantly in the cytoplasm of the tumor cells with a staining pattern of which was sparse and dot-like, or circular around the cell membrane. VEGF protein was expressed heterogenously in the cytoplasm in tumor cells and was negative in peritumoral areas in all cases. CD34 showed diffuse staining in the tumor parenchyma in most HCC specimens. The association of expression of Ihh and VEGF with tumor size was statistically significant (P<0.05), but there was no significant association with other clinicopathologic parameters. Moreover, there was a significant association of the expressions of Ihh and VEGF proteins in HCC (r=0.6, P<0.0001), and of Ihh and CD34 staining (r=0.261, P=0.012). Our findings suggest that Ihh is involved in the development of HCC. These findings are also consistent with the concept that cooperation of Ihh and VEGF modulate HCC tumor angiogenesis and growth.

Cooperation of Indian Hedgehog and Vascular Endothelial Growth Factor in Tumor Angiogenesis and Growth in Human Hepatocellular Carcinomas, an Immunohistochemical Study.

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Cooperation of Indian Hedgehog and Vascular Endothelial Growth Factor in Tumor Angiogenesis and Growth in Human Hepatocellular Carcinomas, an Immunohistochemical Study.