Phorbol ester-induced neutrophilic inflammatory responses selectively promote metastatic spread of melanoma in a TLR4-dependent manner

Increased neutrophil counts both in tumor tissue and peripheral blood correlate with poor clinical outcome in melanoma patients suggesting a pro-tumorigenic role of neutrophils for the pathogenesis of malignant melanoma. Recently, we discovered that neutrophilic skin inflammatory responses induced by UV exposure promote metastatic spread of primary cutaneous melanomas in genetically engineered Hgf-Cdk4(R24C) mice. We hypothesized that other pro-inflammatory stimuli that induce neutrophilic inflammatory responses also promote the development and progression of melanomas. In the current study, we therefore investigated how the most potent and frequently used tumor promoter 12-O-Tetradecanoylphorbol-13-acetate (TPA) affects the development and progression of carcinogen-induced melanomas in Hgf-Cdk4(R24C) mice. Local and systemic neutrophilic inflammatory responses induced by TPA also selectively increase the metastatic spread of melanoma cells to draining lymph nodes and lungs. Using a highly metastatic Hgf-Cdk4(R24C) melanoma skin transplant we could show that TPA enhances systemic spread of melanoma cells which was depended on intact TLR4 signaling in recipient mice and on the presence of neutrophils. Altogether, our experimental results support an important mechanistic role of TLR4-driven neutrophilic inflammation for melanoma progression.