The Clinical Implication of Cancer-Associated Microvasculature and Fibroblast in Advanced Colorectal Cancer Patients with Synchronous or Metachronous Metastases

BACKGROUND: We aimed to evaluate the clinical significance of microvessel density (MVD), lymphatic vessel density (LVD), and cancer-associated fibroblasts (CAFs) in relation to tumor location in advanced colorectal cancer (CRC). METHODS: Using immunohistochemistry, we examined 181 advanced CRC patients for CD31 and D2-40 to measure MVD and LVD, respectively, α-smooth muscle actin (SMA) and desmin to identify CAFs, and PTEN to examine genetic changes of CAFs. To evaluate the regional heterogeneity of these properties, we examined tissue from four sites (the center and periphery of the primary cancer, a distant metastasis, and a lymph node metastasis) in each patient. RESULTS: MVD, LVD, and CAFs showed significant heterogeneity with respect to the tumor location. LVD was the greatest in the center of the primary cancers and the amount of CAFs was the lowest in distant metastases. In distant metastases, those from the lung had higher LVD and MVD, but fewer CAFs than those from the liver, peritoneum, or ovary. Patients with low MVD and LVD in the center of the primary cancer had worse outcomes and patients with few CAFs in distant metastases and in the primary tumor had a lower survival rate. PTEN expression in CAFs in distant metastases was lost in 11 of 181 CRC patients (6.1%), which was associated with a worse prognosis. CONCLUSIONS: The microenvironment, including cancer-associated microvasculature and fibroblasts, is heterogeneous with respect to the tumor location in CRC patients. Therefore, heterogeneity of microenvironments should be taken into account when managing CRC patients.