Oral Squamous Cell Carcinoma-derived Sonic Hedgehog Promotes Angiogenesis

Kuroda, Hiromasa; Kurio, Naito; Shimo, Tsuyoshi; Matsumoto, K.; Masui, Masanori; Takabatake, Kiyofumi; Okui, Tatsuo; Ibaragi, Soichiro; Kunisada, Yuki; Obata, Kyoichi; Yoshioka, Norie; Kishimoto, Kenji; Nagatsuka, Hitoshi; Sasaki, Akira

doi:10.21873/anticanres.12132

Cited by 13 publications

(17 citation statements)

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“…Angiogenesis of tumors has critical effects on development of the tumor. Some studies have reported the details of the contribution of SHH to tumor angiogenesis [59] and also reported the contribution of SHH to angiogenesis of OSCC [33,34]. PTCH expression was not expressed in blood vessels observed in the connective tissue adjacent to the normal epithelium.…”

Section: Discussionmentioning

confidence: 99%

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The Role of Sonic Hedgehog Signaling in the Tumor Microenvironment of Oral Squamous Cell Carcinoma

Takabatake

Shimo

Murakami

et al. 2019

IJMS

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Sonic hedgehog (SHH) and its signaling have been identified in several human cancers, and increased levels of SHH expression appear to correlate with cancer progression. However, the role of SHH in the tumor microenvironment (TME) of oral squamous cell carcinoma (OSCC) is still unclear. No studies have compared the expression of SHH in different subtypes of OSCC and focused on the relationship between the tumor parenchyma and stroma. In this study, we analyzed SHH and expression of its receptor, Patched-1 (PTCH), in the TME of different subtypes of OSCC. Fifteen endophytic-type cases (ED type) and 15 exophytic-type cases (EX type) of OSCC were used. H&E staining, immunohistochemistry (IHC), double IHC, and double-fluorescent IHC were performed on these samples. ED-type parenchyma more strongly expressed both SHH and PTCH than EX-type parenchyma. In OSCC stroma, CD31-positive cancer blood vessels, CD68- and CD11b-positive macrophages, and α-smooth muscle actin-positive cancer-associated fibroblasts partially expressed PTCH. On the other hand, in EX-type stroma, almost no double-positive cells were observed. These results suggest that autocrine effects of SHH induce cancer invasion, and paracrine effects of SHH govern parenchyma-stromal interactions of OSCC. The role of the SHH pathway is to promote growth and invasion.

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Section: Discussionmentioning

confidence: 99%

“…Hedgehog signaling contributes to the development and progression of many cancers [24,25,26,27,28,29,30,31,32]. In OSCC, reactivation and overexpression of the Hedgehog pathway plays a key role in development and progression [33,34,35,36], and SHH signal activation is associated with worse prognosis in OSCC [37,38].…”

Section: Introductionmentioning

confidence: 99%

The Role of Sonic Hedgehog Signaling in the Tumor Microenvironment of Oral Squamous Cell Carcinoma

Takabatake

Shimo

Murakami

et al. 2019

IJMS

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“…Hyperactivation of the Hh signaling observed in tumors is suggested to promote tumor angiogenesis. In detail, the Hh signaling blockade with Smo antagonists, including GDC-0449 and Cyclopamine, reduces the vascular density of Hh-producing colon cancer xenografts [60] and oral squamous cell carcinoma [83] or melanoma [84]. Conversely, ectopic expression of Shh in low-Hh-expressing DLD-1 xenografts increases tumor vascular density and augments angiogenesis [60] and the tumors implanted in Hhip+/− mice exhibit increased tumor angiogenesis [85].…”

Section: Postnatal Angiogenesismentioning

confidence: 99%

“…Shh produced by cancer cells is proposed as an alternative to promote Vegfa expression in stromal fibroblasts [60,85], which subsequently induces EC proliferation. Moreover, Hh ligands produced by cancer cells are also proposed to modulate EC function directly: Shh is highly expressed in human tongue oral squamous cell carcinoma (OSCC) whereas Ptch1, Gli1 and Gli2 proteins are expressed in the microvascular cells in the tumor invasive front [83,93]. In cultured HUVEC, Shh is reported to promote cell proliferation [84], while tGli1 promotes Vegfr2 expression [87] and Hhip, which is highly expressed in ECs, and is downregulated in ECs undergoing angiogenesis.…”

Section: Postnatal Angiogenesismentioning

confidence: 99%

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

Chapouly

Guimbal

Hollier

et al. 2019

IJMS

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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.

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“…The Hedgehog (Hh) signaling plays an important role in tissue homeostasis, control of cell polarity, and regulation of embryonic development [63]. Uncontrolled activation of the Hedgehog pathway is associated with many cancers [64–66], and it was recently involved in the chemoresistance phenotype due to the accumulation of CSC [67, 68]. Small Hh inhibitors, such as vismodegib (antagonist of smoothened receptor), can suppress cell proliferation and tumor growth [69].…”

Section: Strategies To Target Cancer Stem Cellsmentioning

confidence: 99%

Cancer Stem Cells: Powerful Targets to Improve Current Anticancer Therapeutics

Bighetti‐Trevisan

Sousa

Castilho

et al. 2019

Stem Cells International

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A frequent observation in several malignancies is the development of resistance to therapy that results in frequent tumor relapse and metastasis. Much of the tumor resistance phenotype comes from its heterogeneity that halts the ability of therapeutic agents to eliminate all cancer cells effectively. Tumor heterogeneity is, in part, controlled by cancer stem cells (CSC). CSC may be considered the reservoir of cancer cells as they exhibit properties of self-renewal and plasticity and the capability of reestablishing a heterogeneous tumor cell population. The endowed resistance mechanisms of CSC are mainly attributed to several factors including cellular quiescence, accumulation of ABC transporters, disruption of apoptosis, epigenetic reprogramming, and metabolism. There is a current need to develop new therapeutic drugs capable of targeting CSC to overcome tumor resistance. Emerging in vitro and in vivo studies strongly support the potential benefits of combination therapies capable of targeting cancer stem cell-targeting agents. Clinical trials are still underway to address the pharmacokinetics, safety, and efficacy of combination treatment. This review will address the main characteristics, therapeutic implications, and perspectives of targeting CSC to improve current anticancer therapeutics.

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Oral Squamous Cell Carcinoma-derived Sonic Hedgehog Promotes Angiogenesis

Abstract: These findings suggest that OSCC-derived SHH stimulates angiogenesis at the tumor invasive front.

Cited by 13 publications

References 0 publications

The Role of Sonic Hedgehog Signaling in the Tumor Microenvironment of Oral Squamous Cell Carcinoma

The Role of Sonic Hedgehog Signaling in the Tumor Microenvironment of Oral Squamous Cell Carcinoma

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

Cancer Stem Cells: Powerful Targets to Improve Current Anticancer Therapeutics

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