Inflammatory mast cells play a critical role in promoting angiogenesis during squamous epithelial carcinogenesis. In a mouse model expressing human papillomavirus type 16 (HPV16) under the control of the keratin 14 (K14) promoter, mast cells infiltrate premalignant lesions and activate the matrix metalloproteinase-9 (MMP-9)/gelatinase B pathway, which is essential for angiogenesis. Mast cells release serine proteases, such as MCP-4 (chymase) and MCP-6 (tryptase), which contribute to stromal remodeling and angiogenesis. MCP-6 acts as a mitogen for dermal fibroblasts, promoting collagen deposition and angiogenesis, while MCP-4 activates progelatinase B, leading to ECM remodeling and angiogenesis. In the core of solid tumors, angiogenesis is self-sustaining due to upregulation of angiogenic factors by tumor cells, whereas in premalignant lesions, mast cells are required to initiate angiogenesis. Mast cell deficiency in the KIT^W/KIT^Wv mouse model significantly reduces neoplastic progression, indicating that mast cells are essential for early stages of carcinogenesis. The study highlights the biphasic regulation of angiogenesis during squamous carcinogenesis, with mast cells playing a key role in the initial stages by promoting angiogenesis and stromal remodeling, and tumor cells taking over angiogenic control in later stages. The findings suggest that targeting mast cell-derived factors could be a potential therapeutic strategy for preventing the progression of epithelial cancers.Inflammatory mast cells play a critical role in promoting angiogenesis during squamous epithelial carcinogenesis. In a mouse model expressing human papillomavirus type 16 (HPV16) under the control of the keratin 14 (K14) promoter, mast cells infiltrate premalignant lesions and activate the matrix metalloproteinase-9 (MMP-9)/gelatinase B pathway, which is essential for angiogenesis. Mast cells release serine proteases, such as MCP-4 (chymase) and MCP-6 (tryptase), which contribute to stromal remodeling and angiogenesis. MCP-6 acts as a mitogen for dermal fibroblasts, promoting collagen deposition and angiogenesis, while MCP-4 activates progelatinase B, leading to ECM remodeling and angiogenesis. In the core of solid tumors, angiogenesis is self-sustaining due to upregulation of angiogenic factors by tumor cells, whereas in premalignant lesions, mast cells are required to initiate angiogenesis. Mast cell deficiency in the KIT^W/KIT^Wv mouse model significantly reduces neoplastic progression, indicating that mast cells are essential for early stages of carcinogenesis. The study highlights the biphasic regulation of angiogenesis during squamous carcinogenesis, with mast cells playing a key role in the initial stages by promoting angiogenesis and stromal remodeling, and tumor cells taking over angiogenic control in later stages. The findings suggest that targeting mast cell-derived factors could be a potential therapeutic strategy for preventing the progression of epithelial cancers.