gw-799388 and Carcinoma--Squamous-Cell

While immune suppression is a hallmark of head and neck squamous cell carcinoma (HSNCC), the immunological impact of premalignant oral lesions, which often precedes development of HNSCC, is unknown. The present study assessed the changes in splenic and draining lymph node CD4(+) cell populations and their production of select cytokines that occur in mice with carcinogen-induced premalignant oral lesions and the changes that occur as lesions progress to oral cancer. These studies found skewing toward Th1 and Th17-type phenotypes in the spleen and lymph nodes of mice with premalignant oral lesions and a shift to Treg as lesions progress to cancer. Since the role of Th17 cells in the progression from premalignant lesions to cancer is not clear, studies determined the immunological and clinical effect of treating mice bearing premalignant oral lesions with a TGF-β type 1 receptor inhibitor plus IL-23 as an approach to sustain the Th17 phenotype. These studies showed that the treatment approach not only sustained the Th17 phenotype, but also increased distal spleen cell and regional lymph node cell production of other stimulatory/inflammatory mediators and slowed premalignant lesion progression to cancer.

Topics: Animals; Antigens, Surface; Benzamides; Biomarkers; Carcinogens; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Cytokines; Disease Progression; Female; Head and Neck Neoplasms; Humans; Immunophenotyping; Interleukin-23; Lymph Nodes; Mice; Mouth Neoplasms; Neoplasms; Phenotype; Precancerous Conditions; Pyrazoles; Spleen; Squamous Cell Carcinoma of Head and Neck; T-Lymphocytes, Regulatory; Th17 Cells

Esophageal squamous cell carcinoma (ESCC) is known to be a highly angiogenic tumor. Here, we investigated the role of the stromal fibroblasts in the ESCC-induced angiogenic response using a novel 3-dimensional model.. A novel assay was developed where cocultures of ESCC and esophageal fibroblasts induced human microvascular endothelial cell (HMVEC) vascular network formation in a 3-dimensional collagen gel. Biochemical studies showed that the ESCC-induced activation of the fibroblasts was required to induce vascular network formation via a transforming growth factor (TGF)-beta and vascular endothelial growth factor (VEGF)-dependent pathway.. Conditioned media from a panel of 4 ESCC lines transdifferentiated normal esophageal fibroblasts into myofibroblasts via TGF-beta signaling. The presence of fibroblasts was essential for efficient HMVEC network formation, and the addition of ESCC cells to these cultures greatly enhanced the angiogenic process. The role of TGF-beta in this process was shown by the complete inhibition of network formation following TGF-beta inhibitor treatment. Finally, we showed that ESCC-derived TGF-beta regulates angiogenesis through the release of VEGF from the fibroblasts and that the VEGF release was blocked following TGF-beta inhibition.. This study shows the essential role of fibroblasts in the ESCC angiogenic-induced response and suggests that the pharmacologic targeting of the TGF-beta signaling axis could be of therapeutic benefit in this deadly disease.

Topics: Benzamides; Benzodioxoles; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Transdifferentiation; Coculture Techniques; Collagen; Culture Media, Conditioned; Dose-Response Relationship, Drug; Endothelial Cells; Esophageal Neoplasms; Esophagus; Fibroblasts; Gels; Humans; Imidazoles; Microcirculation; Neovascularization, Pathologic; Paracrine Communication; Pyrazoles; Pyridines; Transfection; Transforming Growth Factor beta1; Transforming Growth Factor beta2; Vascular Endothelial Growth Factor A