Lymphangiogenesis in the Deepest Invasive Areas of Human Early-Stage Colorectal Cancer

Tumor-associated macrophages (TAMs) are known to induce epithelial-mesenchymal transition (EMT) and angiogenesis in areas with a high density of accumulation in the submucosal (SM) layer. However, lymphatic vessels, which are important routes for lymph node metastasis, have rarely been analyzed, and their relationship to TAM accumulation is unknown. In this study, paraffin-embedded sections from 11 cases of human early-stage colorectal cancer (SM invasive carcinoma) were stained with CD34 antibody for vascular endothelium and podoplanin antibody for lymphatic endothelium at the deepest, central, and marginal sites of tumor invasion. Tumor blood vessels increased in the deepest invasive areas, and a positive correlation was observed between the number of TAMs and tumor blood vessels. Interestingly, lymphatic vessels with CD34-positive endothelial cells (CD34-positive lymphatic vessels) were observed within the tumor. The number of CD34-positive lymphatic vessels was significantly higher in the metastasis-positive group. These results suggest that abnormalities in the vascular and lymphatic systems are observed from the early stage of colorectal cancer development and that VEGF-A derived from TAMs is important for tumor angiogenesis. In addition, CD34-positive lymphatic vessels observed in the deepest areas of tumor invasion have not been reported in Japan, with initial reports indicating that they are neoplastic lymphatic vessels.