Abstract
Metastasis, the greatest clinical challenge associated with cancer, is closely connected to multiple biological processes, including invasion and adhesion. The hypoxic environment in tumors is an important factor that causes tumor metastasis by activating HIF-1α. Fucoidan, extracted from brown algae, is a sulfated polysaccharide and, as a novel marine biological material, has been used to treat various disorders in China, Korea, Japan and other countries. In the present study, we demonstrated that fucoidan derived from Undaria pinnatifida sporophylls significantly inhibits the hypoxia-induced expression, nuclear translocation and activity of HIF-1α, the synthesis and secretion of VEGF-C and HGF, cell invasion and lymphatic metastasis in a mouse hepatocarcinoma Hca-F cell line. Fucoidan also suppressed lymphangiogenesis in vitro and in vivo. In addition, accompanied by a reduction in the HIF-1α nuclear translocation and activity, fucoidan significantly reduced the levels of p-PI3K, p-Akt, p-mTOR, p-ERK, NF-κB, MMP-2 and MMP-9, but increased TIMP-1 levels. These results indicate strongly that the anti-metastasis and anti-lymphangiogenesis activities of fucoidan are mediated by suppressing HIF-1α/VEGF-C, which attenuates the PI3K/Akt/mTOR signaling pathways.
Highlights
Tumor metastasis is the dissemination of cancer cells from the initial site of primary tumor growth to distant organs, where they survive, proliferate and form secondary tumors
(A) Cell viability was measured by the Cell Counting Assay Kit-8 solution (CCK-8) assay; (B) the cell death rate (D%) was counted and calculated; (C) the morphological change of fucoidan-treated cells was slightly dilated
The results showed that the levels of vascular endothelial growth factors (VEGFs)-C and HGF proteins in the culture medium of the cells treated with fucoidan in hypoxia were lower compared with those of the control
Summary
Tumor metastasis is the dissemination of cancer cells from the initial site of primary tumor growth to distant organs, where they survive, proliferate and form secondary tumors. Metastasis is a complex process involving tumor cell invasion, adhesion, angiogenesis and lymphangiogenesis. Less attention has been focused on research into tumor lymphangiogenesis as opposed to angiogenesis. Oxygen concentration changes and altered levels of oxygen-dependent or oxygen-independent growth factor lead to upregulation of hypoxia-inducible factor-1 alpha (HIF-1α) expression. Increasing evidence supports the hypothesis that the PI3K/Akt/mTOR pathway acts as a master switch controlling. HIF-1α synthesis, thereby determining whether cells, especially tumor cells, grow and proliferate [1]. PI3K/Akt/mTOR represents an attractive target for therapeutic intervention [2]. Matrix metalloproteinase-2, -9 (MMP-2, -9) and its endogenous inhibitor, tissue inhibitor of metalloproteinase-1
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