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A role for p38 MAPK in head and neck cancer cell growth and tumor-induced angiogenesis and lymphangiogenesis.

ABSTRACT: We have recently gained a remarkable understanding of the mutational landscape of head and neck squamous cell carcinoma (HNSCC). However, the nature of the dysregulated signaling networks contributing to HNSCC progression is still poorly defined. Here, we have focused on the role of the family of mitogen activated kinases (MAPKs), extracellular regulated kinase (ERK), c-Jun terminal kinase (JNK) and p38 MAPK in HNSCC. Immunohistochemical analysis of a large collection of human HNSCC tissues revealed that the levels of the phosphorylated active form of ERK1/2 and JNK were elevated in less than 33% and 16% of the cases, respectively. Strikingly, however, high levels of active phospho-p38 were observed in most (79%) of hundreds of tissues analyzed. We explored the biological role of p38 in HNSCC cell lines using three independent approaches: treatment with a specific p38 inhibitor, SB203580; a retro-inhibition strategy consisting in the use of SB203580 combined with the expression of an inhibitor-insensitive mutant form of p38α; and short-hairpin RNAs (shRNAs) targeting p38α. We found that specific blockade of p38 signaling significantly inhibited the proliferation of HNSCC cells both in vitro and in vivo. Indeed, we observed that p38 inhibition in HNSCC cancer cells reduces cancer growth in tumor xenografts and a remarkable decrease in intratumoral blood and lymphatic vessels. We conclude that p38α functions as a positive regulator of HNSCC in the context of the tumor microenvironment, controlling cancer cell growth as well as tumor-induced angiogenesis and lymphangiogenesis.

SUBMITTER: Leelahavanichkul K

PROVIDER: S-EPMC3946852 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Metastatic melanoma is an aggressive tumor and can constitute a real therapeutic challenge despite the significant progress achieved with targeted therapies and immunotherapies, thus highlighting the need for the identification of new therapeutic targets. Adrenomedullin (AM) is a peptide with significant expression in multiple types of tumors and is multifunctional. AM impacts angiogenesis and tumor growth and binds to calcitonin receptor-like receptor/receptor activity-modifying protein 2 or 3 (CLR/RAMP2; CLR/RAMP3). In vitro and in vivo studies were performed to determine the functional role of AM in melanoma growth and tumor-associated angiogenesis and lymphangiogenesis. In this study, AM and AM receptors were immunohistochemically localized in the tumoral compartment of melanoma tissue, suggesting that the AM system plays a role in melanoma growth. We used A375, SK-MEL-28, and MeWo cells, for which we demonstrate an expression of AM and its receptors; hypoxia induces the expression of AM in melanoma cells. The proliferation of A375 and SK-MEL-28 cells is decreased by anti-AM antibody (αAM) and anti-AMR antibodies (αAMR), supporting the fact that AM may function as a potent autocrine/paracrine growth factor for melanoma cells. Furthermore, migration and invasion of melanoma cells increased after treatment with AM and decreased after treatment with αAMR, thus indicating that melanoma cells are regulated by AM. Systemic administration of αAMR reduced neovascularization of in vivo Matrigel plugs containing melanoma cells, as demonstrated by reduced numbers of vessel structures, which suggests that AM is one of the melanoma cells-derived factors responsible for endothelial cell-like and pericyte recruitment in the construction of neovascularization. In vivo, αAMR therapy blocked angiogenesis and lymphangiogenesis and decreased proliferation in MeWo xenografts, thereby resulting in tumor regression. Histological examination of αAMR-treated tumors showed evidence of the disruption of tumor vascularity, with depletion of vascular endothelial cells and a significant decrease in lymphatic endothelial cells. The expression of AM by melanoma cells promotes tumor growth and neovascularization by supplying/amplifying signals for neoangiogenesis and lymphangiogenesis.

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A role for p38 MAPK in head and neck cancer cell growth and tumor-induced angiogenesis and lymphangiogenesis.

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