ABSTRACT
BACKGROUND: Recent technical progress makes sophisticated noninvasive imaging methods available for murine models. For the first time, in this study, we applied fluorodeoxyglucose (FDG)-positron emission tomography (PET)-CT and FDG-PET-MRI to a murine orthotopic model of head and neck cancer immunotherapy. METHODS: Tumor growth of floor of the mouth tumors was evaluated by multimodal small-animal imaging using FDG-PET-CT and FDG-PET-MRI. The immunotherapeutic effects of anti-CD137 antibody therapy were examined on body weight, tumor growth, and tumor-infiltrating immune cells in longitudinal imaging studies and immunohistochemical analyses. RESULTS: Imaging revealed aggressive, fast-growing tumors without evidence of local or distant metastases. CD137 immunotherapy decreased tumor take and growth and stabilized body weight over time. A clear case of tumor regression was demonstrated by longitudinal PET-CT. CONCLUSION: The murine model mimics the characteristics of head and neck cancer in humans and offers excellent opportunities to investigate immunomodulatory anticancer drugs. The CD137 antibody showed antitumor effects in some therapy-responsive mice.
Subject(s)
4-1BB Ligand/antagonists & inhibitors , Carcinoma, Squamous Cell/diagnostic imaging , Disease Models, Animal , Head and Neck Neoplasms/diagnostic imaging , Immunotherapy/methods , Mouth Neoplasms/diagnostic imaging , Mouth Neoplasms/therapy , Multimodal Imaging/methods , Animals , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/therapy , Cell Line, Tumor , Female , Fluorodeoxyglucose F18 , Head and Neck Neoplasms/pathology , Head and Neck Neoplasms/therapy , Immunohistochemistry , Longitudinal Studies , Magnetic Resonance Imaging/methods , Mice , Mice, Inbred C3H , Positron Emission Tomography Computed Tomography/methods , Squamous Cell Carcinoma of Head and NeckABSTRACT
For preclinical studies of immune-modulating anticancer drugs a murine model that attempts to parallel the clinical nature of head and neck cancer in fully immunocompetent mice is required. In this study we compared features of the squamous cell carcinoma (SCC) VII model after subcutaneous (back, flank) and orthotopic (floor of mouth) injection both in fully immunocompetent C3H/HeN and in previously studied C3H/HeJ mice, which harbor a functional toll-like receptor 4 (TLR-4) deficiency. As C3H/HeN mice do not harbor this deficiency, the presented murine model is an optimization of previously described C3H/HeJ models, which, because of the TLR-4-deficiency, have inherent drawbacks for tumor immunologic studies. We found that tumor growth was accelerated and tumor incidence was increased by about 20% after s.c. injection in TLR-4-deficient mice. Strikingly, tumor-related weight loss (cachexia) was more pronounced in fully immunocompetent C3H/HeN mice (26%) versus TLR-4-deficient C3H/HeJ mice (7.9% weight loss) at high tumor dose. Orthotopic tumors were biologically distinct from subcutaneous tumors as they showed accelerated growth and a distinct immune cell infiltrate. We conclude that a model of orthotopic implantation of SCC VII tumor cells into fully immunocompetent syngeneic C3H/HeN mice reflects features of human head and neck cancer and provides a valuable experimental model for immunological studies in this tumor entity. Our data suggest that TLR-4 expressed by host cells is involved in the regulation of tumor-related cachexia and tumor control.
Subject(s)
Carcinoma, Squamous Cell/pathology , Head and Neck Neoplasms/pathology , Immunocompetence , Toll-Like Receptor 4/physiology , Animals , CD4-Positive T-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/pathology , Cachexia/genetics , Cachexia/metabolism , Cachexia/pathology , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/metabolism , Cell Line, Tumor , Disease Models, Animal , Head and Neck Neoplasms/genetics , Head and Neck Neoplasms/metabolism , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Mice , Mice, Inbred C3H , Mice, Knockout , Neoplasm Transplantation , Receptors, Chemokine/metabolism , Time Factors , Toll-Like Receptor 4/deficiency , Toll-Like Receptor 4/genetics , Tumor BurdenABSTRACT
OBJECTIVE: To investigate whether the insertion/deletion polymorphism (-94ins/delATTG) in the promoter of NF kappa B1 is associated with the risk of bleeding after tonsillectomy. DESIGN AND SETTING: Retrospective study with genotyping performed from tonsillar tissue or blood. PATIENTS: One hundred forty-eight patients having undergone tonsillectomy due to chronic tonsillitis, with or without posttonsillectomy hemorrhage. MEASUREMENTS AND RESULTS: DNA-extraction from paraffin-embedded tonsillectomy tissue or blood was followed by genotyping for the insertion/deletion (-94ins/delATTG) promoter NF kappa B1 polymorphism. Genotypes differed significantly between patients with (n = 56) and without (n = 92) posttonsillectomy hemorrhage, with the frequency of the homozygous deletion genotype carriers (DD) significantly increased in those with posttonsillectomy bleeding with an odds ratio (OR) for bleeding of 3.78 (95% confidence interval [CI] 1.2-11.7, P = .023) but not in homozygous (II) insertion and heterozygous (ID) genotype carriers (II/ID). Genotype distribution in patients was compatible with the Hardy Weinberg equilibrium. In contrast, there were no statistically significant differences between patients with or without posttonsillectomy hemorrhage with regard to demographic characteristics, different surgeons, postoperative medications like analgesics, antibiotics, anticoagulation therapy, or values of variables of pre- and postoperative coagulation studies. Likewise, these variables revealed no differences between genotypes. CONCLUSIONS: Carriers of the homozygous deletion allele were at an almost fourfold risk to develop posttonsillectomy hemorrhage compared to homozygous and heterozygous insertion allele carriers, independent of other risk factors.
