interleukin-8 and Hypopharyngeal-Neoplasms

It has been shown that fibroblasts within the stroma of malignant tumours can affect the tumour's biological character, influencing such properties as local aggressiveness and metastasis potential. This influence is asserted via paracrine secretion of multiple cell factors, including chemokines. This study demonstrates that both normal keratinocytes and cancer cells can stimulate the secretion of chemokines IL-8 and CXCL-1 from normal dermal fibroblasts and stromal fibroblasts from squamous cell carcinoma. The effect of epithelia on normal fibroblasts leads to a transient secretory change, in contrast to stromal fibroblasts which generate a more prolonged one. This observation demonstrates that stimulated expression of both IL-8 and CXCL-1 is not specific to cancer, supporting the hypothesis that similar mechanisms exist between wound healing and oncogenesis. It also shows that stromal fibroblasts isolated from a tumour have significantly different features from normal fibroblasts.

Topics: Carcinoma, Squamous Cell; Cells, Cultured; Chemokine CXCL1; Coculture Techniques; Culture Media, Conditioned; Dermis; Fibroblasts; Humans; Hypopharyngeal Neoplasms; Interleukin-8; Keratinocytes; Neoplasm Proteins; Secretory Rate; Skin Neoplasms; Stromal Cells; Up-Regulation; Wound Healing

Stromal cell-derived factor-1 (SDF-1) (CXCL12) has been observed to promote laryngeal and hypopharyngeal squamous cell carcinomas (LHSCCs) invasion through cooperation with its receptor CXCR4. Here, we further explore the angiogenesis mechanism induced by SDF-1/CXCR4 interaction in LHSCCs. Immunohistochemistry (IHC) reveals the significant correlation between CXCR4 and angiogenesis in tumors. After blocking the function of CXCR4 by specific inhibitor AMD3100 and neutralized antibody 12G5 or inhibiting the expression by siRNA, we were able to disrupt the HUVECs tube formation, demonstrating that SDF-1/CXCR4 indeed regulated the angiogenesis mechanism. The angiogenesis profiling from angiogenesis array and reverse transcription polymerase chain reaction indicates that IL-8 can be significantly triggered by SDF-1/CXCR4 interaction in LHSCCs. We also demonstrate that IL-8 secretion mechanism is regulated by Akt phosphorylation after SDF-1 stimulation. These results point out the importance of SDF-1/CXCR4 interaction in LHSCCs angiogenesis. The angiogenic factor IL-8 would be triggered by the cooperation of SDF-1 and CXCR4 through an Akt-dependent pathway. This provides a new targeting therapy utility, disrupting SDF-1/CXCR4 interaction combined with downstream-induced angiogenic factors in LHSCCs would be beneficial to improve clinical outcome.

Topics: Blotting, Western; Carcinoma, Squamous Cell; Cell Line, Tumor; Chemokine CXCL12; Humans; Hypopharyngeal Neoplasms; Interleukin-8; Laryngeal Neoplasms; Phosphorylation; Proto-Oncogene Proteins c-akt; Real-Time Polymerase Chain Reaction; Receptors, CXCR4; Reverse Transcriptase Polymerase Chain Reaction

The transcriptional activation of NF-κB signalling has been identified as a major pathway involved in inflammation and tumor aggressiveness in a number of human cancers. Here we identify the impact of miscellaneous known and so far unknown NF-κB inhibitors originating from different drug classes on the function and proliferation of HNSCC. In detail: HNSCC cell lines were exposed to Acetylsalicylic Acid (ASA), Celecoxib, Dexamethasone, Curcumin and EPs 7630. Our major interest was to detect upstream alterations in cell signalling after applying NF-κB inhibiting substances. The inhibition of NF-κB signalling leads to an upstream regulation of Toll-like-receptor 3 (TLR3), a predominant receptor driving cell expansion. We find a marked downregulation of TLR3 and IKK complex, documenting upstream responses to NF-κB inhibition by every agent tested. In a second step we further analyse proliferation, cytokine production and alterations in the expression of downstream proteins such as cyclin D1 and c-Myc. Our data demonstrate decreased proliferation in response to incubation with aforementioned agents. Modulation of TLR3 and NF-κB expression is accompanied by altered profiles of IL-6 and IL-8 which are relevant cytokines in HNSCC progression. Proto-oncogenes cyclin D1 and c-myc are downregulated by all substances. Apart from the interplay of cytokines and TLR3, we substantiated EPs 7630 as a new and natural NF-κB inhibitor.

Topics: Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Proliferation; Cyclin D; Cyclooxygenase Inhibitors; Cytokines; Humans; Hypopharyngeal Neoplasms; I-kappa B Kinase; Interleukin-6; Interleukin-8; Male; Middle Aged; NF-kappa B; Proto-Oncogene Proteins c-myc; Signal Transduction; Toll-Like Receptor 3