Targeting tumor metastasis---SRC inhibition.

摘要

Src is a non-receptor tyrosine kinase that is frequently over-expressed in malignances and increased Src activation/phosphorylation has been associated with a poor patient prognosis. Src signaling pathways are known to affect critical cellular processes of metastases. This project examined the impact of Src inhibition on tumor metastases by using a specific Src tyrosine kinase inhibitor (AZD0530). In the first part of this project the effect of AZD0530 on tumor cell functions related to metastases were evaluated. AZD0530 was found to inhibit tumor cell proliferation, migration, invasion, adhesion, and to induce tumor cells to accumulate in the G1 phase of cell cycle in several mouse and human cancer models. These results suggested that AZD0530 treatment could inhibit tumor cell functions related to metastasis. The second part of this project was to study the effect of AZD0530 on metastatic process in vivo. A single dose treatment immediately after tumor cell injection via tail vein effectively blocked formation of lung nodules in mice. AZD0530 was also found to inhibit tumor cell induced angiogenesis. However, AZD0530 had no major effect on endothelial cell growth, tube formation and migration. The level of secreted VEGF from KHT cells was found to decrease after AZD0530 treatment. This suggested that the effect on angiogenesis may be caused by inhibiting the secretion of angiogenic factors by tumor cells. The third part was to establish the KHT mouse sarcoma and 4A4 breast tumor models to non-invasively assess tumor growth as well as metastases using the Xenogen imaging system. In both the KHT-Luc and 4A4-Luc spontaneous metastases models, bioluminescent signals from the primary tumors were detected and the intensity was found to increase with tumor growth. In the KHT-Luc experimental metastasis model, bioluminescent signals were observed from lung metastases, and the signal intensity increased with time. These tumor models may allow us to study the effect of Src inhibition on metastases non-invasively and efficiently in the future.