Is Xenotransplantability of Human Colon Cancers in SCID Mice Affected by Angiogenic Factors?

Extract

Human malignant tumors transplanted in SCID (severe combined immunodeficiency) mice retain their original characteristics, such as histology (1), cytokine production (2,3), karyotype, and sensitivity to anticancer agents. This in vivo system has provided an opportunity to study viable human malignant cells without limitations on material supply. Since Rygaard and Povlsen (4) reported the successful transplantation of human malignant tumors into nude mice, various types of human tumors have been maintained in these animals. Although this system has enabled us to establish certain human malignant tumors as xenografts, only transferable tumors are serially maintained as xenograft tumors. It is not clearly understood what key properties and molecules of donor tumor lead to successful establishment of xenografts.

Vascular endothelial growth factor (VEGF) has been studied as a strong inducer of angiogenesis (5). VEGF plays an important role in neovascularization of various kinds of neoplasms. Four different isoforms of VEGF transcripts encoding polypeptides of 206, 189, 165, and 121 amino acids have been reported, and these isoforms possess different biologic activities. In our previous study, the cell-associated isoform VEGF189 was shown to be strongly associated with distant metastasis in human colon cancer (6). The factors that modulate angiogenesis are also probably associated with xenotransplantability. It has not been well defined how various angiogenic factors affect the xenotransplantability of human malignant tumors. We analyzed levels of expression of such factors as VEGF, thrombospondin 1 (TSP1), and TSP2 in human primary colon cancers in relation to their xenotransplantability in SCID mice. We also studied gene expression of VEGF receptor flt-1, KDR, TSP1 receptor (TSP1R)/CD36, and transforming growth factor-β (TGFβ). Activated K-ras oncogene and p53 accumulation were coevaluated.