Molecular Analysis on Tumor Invasion and Metastasis of CD44 Variant Forms

点击翻译按钮获取中文摘要

CD44 is a major receptor for hyaluronan and is involved in many biological processes, including cell migration, tumor invasion, and metastasis. To examine how CD44 variant molecules contribute to the tumor cell invasion and metastasis, standard CD44s (82s), CD44v8-10 (82E) and mock (82pCI) transfectants of a CD44-negative human lung cancer cell line were subcutaneously injected into SCID mice. In 82pCI- and 82s-derived tumors, multiple irregular foci of necrosis were prominent, while necrosis was scant in 82E tumors. We found the increased small vessels in the stroma of 82E tumors compared to those of 82s and 82pCI tumors. 82E cells showed the enhanced production of vascular endothelial growth factor (VEGF) in both mRNA and protein levels. The levels of the VEGF mRNA from 82E cells increased in a cell-density dependent manner, and this induced production was abolished by the treatment with hyaluronidase as the cells carried hyaluronan on their surface. Furthermore, the addition of stimulatory anti-CD44 antibody also increased the production of VEGF. These suggest that a homotypic cell-cell contact stimulates the CD44v8-10 through the engagement of cell surface hyaluronan and resulted in the enhanced production of VEGF. Accordingly, our study indicates that CD44v8-10 positive cancer may have an advantage to grow by the induced angiogenesis through the VEGF production.