Abstract
TGF-β1 has the potential to activate multiple signaling pathways required for inducing metastatic potential of tumor cells. However, TGF-β1 was inefficient in inducing metastatic potential of many non-invasive human tumor cells. Here we report that the enhancement of TGF-β1 signaling is required for inducing metastatic potential of non-invasive breast cancer cells. TGF-β1 alone could not efficiently induce the sustained activation of Smad and non-Smad pathways in non-invasive breast cancer cells. TLR4 ligand (LPS) and H2O2 cooperated with TGF-β1 to enhance the sustained activation of non-Smad pathways, including p38MAPK, ERK, JNK, PI3K, and NF-κB. The activation of MAPK and PI3K pathways resulted in a positive feed-back effect on TGF-β1 signaling by down-regulating Nm23-H1 expression and up-regulating the expression of TβRI and TβRII, favoring further activation of multiple signaling pathways. Moreover, the enhanced TGF-β1 signaling induced higher expression of SNAI2, which also promoted TβRII expression. Therefore, the sustained activation levels of both Smad and non-Smad pathways were gradually increased after prolonged stimulation with TGF-β1/H2O2/LPS. Consistent with the activation pattern of signaling pathways, the invasive capacity and anoikis-resistance of non-invasive breast cancer cells were gradually increased after prolonged stimulation with TGF-β1/H2O2/LPS. The metastatic potential induced by TGF-β1/H2O2/LPS was sufficient for tumor cells to extravasate and form metastatic foci in an experimental metastasis model in nude mice. The findings in this study suggested that the enhanced signaling is required for inducing higher metastatic capacity of tumor cells, and that targeting one of stimuli or signaling pathways might be potential approach in comprehensive strategy for tumor therapy.
Highlights
The efficient activation of multiple signaling pathways is the important driving force for tumor cell metastasis [1,2,3]
Our results showed that TLR4 ligand and H2O2 could cooperate with Transforming growth factor b1 (TGF-b1) to induce sustained activation of multiple signaling pathways in non-invasive human breast cancer cells, promoting the metastatic potential sufficient for invasion and extravasation of tumor cells
These results indicated that TGF-b1, H2O2, and LPS could cooperate to promote the invasive migration of noninvasive breast cancer cells
Summary
The efficient activation of multiple signaling pathways is the important driving force for tumor cell metastasis [1,2,3]. The carcinomas with excess TGF-b1 production are more motile and invasive, and exhibit increased tumor cell metastasis in athymic mice [7]. All of these findings implicate the important roles of TGF-b1 in tumor metastasis. Many non-invasive tumor cells could not undergo TGF-b1-induced EMT in vitro [7], suggesting that TGF-b1 might not be able to efficiently activate multiple signaling pathways in non-invasive tumor cells. The effect of TGF-b1 in tumor milieu might be enhanced by other factor(s) which could cooperate with TGF-b1 to induce sufficient activation of multiple signaling pathways, and promote the metastatic capacity, including invasion and extravasation, of tumor cells
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