Accelerated Tumor Growth and Lymphatic Spread of Transplantable Melanomas in Tumor Necrosis Factor(TNF)-Transgenic Mice

Melanoma is the fifth most common cancer among American adults, with significant morbidity and mortality at 5 years remaining >60% for patients with stage IV disease. The malignancy is due to the transformation of melanocytes, with one of the major risk factors being ultraviolet light exposure. Although as many as one in five human cancers have been linked to chronic inflammation, the role of inflammatory signals in melanoma growth and metastasis remains poorly understood. Tumor necrosis factor (TNF)-transgenic (TNFtg) mice are a well-established model of chronic systemic inflammation, with involvement of joints and other organ systems. To assess the effect of TNF overexpression on melanoma in vivo, we investigated the growth of transplantable B16 melanomas (F1 and F10 sublines) in TNFtg mice (3647 strain). The B16 cell line and its derivatives originated from a spontaneous melanoma of C57BL/6 mouse. B16 cells were injected into the hind paws of TNFtg mice and non-transgenic (NT) littermates at 8-12 weeks of age. At this age, the mice have begun to exhibit early arthritis, creating a localized area of inflammation in the paw. TNFtg mice displayed highly accelerated B16 primary tumor growth compared to NT littermates (tumor area 43.7±15.2mm2 vs 15.0±15.5mm2 at week 2, p To test whether the observed effects were linked to systemic TNF overexpression or to the localized inflamed microenvironment in the arthritic paws we also compared growth of tumors injected in the lower flank, and observed no primary tumor growth differences in this area (251±155mm3 vs 319±178mm3 tumor volume in TNFtg vs NT, p=0.3). Finally, in order to establish whether the observed differences were specific to B16 cells or are relevant for melanoma growth more broadly, we compared growth in TNFtg vs NT mice of an independently derived melanoma line, YUMM1.1. Again, TNFtg mice showed accelerated paw melanoma growth compared to NT mice (32.6±14.0mm2 vs 19.1±20.8mm2 at week 5, p<0.01). Overall, these results highlight a significant effect of TNF, and specifically of the TNF-driven inflammatory microenvironment, in transplantable melanoma growth in mice.