Macrophages and endothelial cells orchestrate tumor-associated angiogenesis in oral cancer via hedgehog pathway activation

• Published in: Tumor biology Vol. 37; no. 7; pp. 9233 - 9241
• Main Authors: Valverde, Ludmila de Faro, Pereira, Thiago de Almeida, Dias, Rosane Borges, Guimarães, Vanessa Sousa Nazaré, Ramos, Eduardo Antônio Gonçalves, Santos, Jean Nunes, Gurgel Rocha, Clarissa Araújo
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01-07-2016; Springer Nature B.V
• Subjects: Angiogenesis; Antigens, CD - metabolism; Antigens, Differentiation, Myelomonocytic - metabolism; Biomedical and Life Sciences; Biomedicine; Cancer Research; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Cell Line, Tumor; Endoglin - metabolism; Endothelial Cells - metabolism; Endothelial Cells - pathology; Female; Gene Expression Regulation, Neoplastic - genetics; Hedgehog Proteins - metabolism; Humans; Immunohistochemistry; Macrophages - metabolism; Macrophages - pathology; Male; Mouth Mucosa - metabolism; Mouth Mucosa - pathology; Mouth Neoplasms - genetics; Mouth Neoplasms - metabolism; Mouth Neoplasms - pathology; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - pathology; Oral cancer; Original Article; Protein expression; Receptors, Cell Surface - metabolism; Signal transduction; Signal Transduction - genetics; Zinc Finger Protein GLI1 - metabolism; Immunohistochemistry; Squamous cell carcinoma; Oral cancer; Hedgehog proteins
• ISSN: 1010-4283; 1423-0380
• DOI: 10.1007/s13277-015-4763-6

The present study aimed to evaluate the role of Hedgehog (Hh) molecule expression in association with the clinical aspects of oral squamous cell carcinoma (OSCC), as well as angiogenesis and CD163+ macrophages. Twenty-eight cases of OSCC, nine cases of tumor-free resection margins (TM), and four cases of non-neoplastic oral mucosa (NNM) were submitted to immunohistochemistry to detect proteins Sonic Hedgehog (SHH), Indian Hedgehog (IHH), GLI1, CD163, and CD105. Protein colocalization with respect to SHH/CD163, IHH/CD163, GLI1/CD163, and GLI1/CD105 was assessed by immunohistochemical double staining. In tumor parenchyma, SHH and IHH were present in the cytoplasm of neoplastic cells, while GLI1 was observed in cytoplasm and nucleus. Endothelial cells were found to express SHH, IHH, and GLI1 within CD105+ vessels, and a positive correlation between infiltrating macrophage density (IMD) and microvascular density (MVD) was observed in cases of OSCC and TM. When compared to TM and NNM, the OSCC cases demonstrated higher immunoreactivity for SHH (
p
 = 0.01), IHH (
p
 = 0.39), GLI1 (
p
 = 0.03), IMD (
p
 = 0.0002), and MVD (
p
 = 0.0002). Our results suggest the participation of the Hh pathway in OSCC by way of autocrine and paracrine signaling, in addition to the participation of both SHH and IHH ligands. Endothelial cells were also found to exhibit positivity with respect to Hh pathway components and we surmise that these molecules may play a role in tumor angiogenesis. CD163+ macrophages were also observed to express IHH, a ligand of this pathway, in addition to being associated with tumor neovascularization.