Establishment of a normalized revascularization mouse model using tumor transplantation

Tumor blood vessels play an important role in tumor progression and metastasis and have recently been shown to differ in structure from normal blood vessels. Thus, normalization of tumor blood vessels using molecular targeted therapy has been attracting attention as a potential new treatment for cancer. However, some studies have suggested that this therapy is unable to cause significant tumor shrinkage and instead promotes drug resistance. Therefore, we hypothesized that regeneration of normal blood vessels in tumors may lead to improvement of hypoxic conditions in tumors. Furthermore, regeneration of normal blood vessels may contribute to potential improvements in the delivery of anticancer drugs to hypoxic tumors. In this report, we sought to characterize whether transplanting normal endothelial cells into tumor-bearing mice would trigger vascular remodeling. Tumor cells (SAS; human tongue squamous cell carcinoma) were injected into the dorsal subcutis of SCID mice. After 2 weeks, the tumor-bearing mice were injected cisplatin intraperitoneally to regress tumors and tumor vessels as a first step. An additional 2 weeks later, to induce normal angiogenesis in the tumor, human endothelial cells (HMVECs) were transplanted into necrotic regions of the tumor as a second step. Microscopic observations revealed that the transplanted human endothelial cells formed anastomoses with the host mouse vasculature, and perfused vessels were detectable after 7 days. Thus, this regenerated blood vessel mouse model is a useful model for the future development of new cancer therapies, construction of reliable drug delivery systems, and improvement of hypoxic conditions.