Research On The Vascular Modulation In Tumorigenesis And Pre-metastasis

This study focuses on the vascular modulation in tumorigenesis and pre-metastasis. Tumors secrete various pro-angiogenic factors to induce angiogenesis at certain stages. Here we report that nucleolin only expressed on the surface of neo blood vessels, but not on the mature ones. Cell surface nucleolin contributes to the migration and tube formation of endothelial cells, and the surface nucleolin is derived from nucleus via cellular translocation. Upon endothelial cells adhering to extracellular matrix components, vascular endothelial growth factor (VEGF) mobilizes nucleolin from nucleus to cell surface. Interestingly, the translocation of nucleolin is accompanied with the formation actin filament and focal adhesion, which are hallmarkers of cell motility. Moreover, nonmuscle myosin heavy chain 9 (MyH9) is identified as a nucleolin-binding protein. Subsequent studies reveal that MyH9 serves as a physical linker between nucleolin and cytoskeleton, thus modulating the translocation and distribution of nucleolin. Besides inducing angiogenesis, primary tumor also modify the vasculatures in certain metastasis-preferential organs in the animal model. In the early stage of pre-metastasis, primary tumor destabilizes the pulmonary vasculature and enhances its permeability, which in turn facilitates the extravastion of metastatic tumor cells and infiltration of myeloid cells. Furthermore, we screen the gene expression in pre-metastatic lung, and indentify that angiopoietin-2 (Angpt2), matrix metalloproteinase 3 (MMP3), matrix metalloproteinase 10 (MMP10), placental growth factor, and stromal cell derived factor are all dramatically up-regulated in lung fibroblasts in the pre-metastatic stage. Angpt2, MMP3 and MMP10 have synergistic effect on disrupting vascular integrity and facilitate the extravasation of circulating tumor cells, while placental growth factor and stromal cell derived factor contribute to recruit myeloid cells in pre-metastatic niche. Lentivirus-based in vivo RNA interference of angpt2, MMP3 and MMP10, attenuates the pulmonary vascular permeability and suppresses the infiltration of myeloid cells, which results in significant inhibition of lung metastasis. Further investigations show that malignancy of tumor is correlated with vascular modulation in the pre-metastatic niche. Moreover, TGF-β1 and TNF-αsignaling get involved in the regulatory process.