Abstract
Osteopontin (OPN) is a multi-functional phospho-glycoprotein that can stimulate angiogenesis through acting on endothelial cells. As angiogenic sprouting involves endothelial-to-mesenchymal transition (EndoMT), we are intrigued to know whether OPN exerts an effect on EndoMT. Clinically, we indeed detected EndoMT-derived cells next to OPN-expressing cells in colorectal cancer tissues. Furthermore, we treated OPN to primary cultures of endothelial cells to investigate the EndoMT-inducing activity and the underlying mechanisms. Integrin αVβ3 rather than CD44 is involved in OPN-induced EndoMT. OPN-integrin αVβ3 engagement induces HIF-1α expression through a PI3K/Akt/TSC2-mediated and mTORC1-dependent protein synthesis pathway, which in turn trans-activates TCF12 gene expression. TCF12 further interacts with EZH2 and histone deacetylases to transcriptionally repress VE-cadherin gene and thus facilitates EndoMT. Like cancer-associated fibroblasts, EndoMT-derived cells promote tumor growth and metastasis by secreting certain proteins. Secreted HSP90α is a candidate suggested by microwestern array assay, and is herein verified to induce stemness properties in colorectal cancer cells. As OPN is overexpressed in human cancers, OPN-induced EndoMT and EndoMT-derived cells can be potentially taken as cancer therapeutic targets.
Highlights
Cell plasticity is essential for many mature functional cells to retain the potential to de-differentiate back to stem/progenitor cells or to trans-differentiate into other distant cell lineages [1]
By down-regulating VE-cadherin expression, OPN showed a repressive effect on cell-cell junctions of Human umbilical vein endothelial cells (HUVECs), which was demonstrated by reduction of cellular gap-junction activity measured by Calcein transfer assay (Figure 1F)
We found that Hypoxia-inducible factor-1α (HIF-1α) was induced at protein level but not at mRNA level via an integrin αVβ3- and PI3K/Akt-mediated signaling pathway in HUVECs after a 12-h stimulation with OPN (Figure 5A)
Summary
Cell plasticity is essential for many mature functional cells to retain the potential to de-differentiate back to stem/progenitor cells or to trans-differentiate into other distant cell lineages [1]. As a result, it provides various cell types needed for tissue microenvironmental reprogramming upon physiological or pathological demands. Endothelial-to-mesenchymal transition (EndoMT) is a remarkable example of cell plasticity widely observed in embryonic heart formation [2,3,4] and diseases like cardiac fibrosis [5], atherosclerosis [6], pulmonary hypertension [7], and cancer development [8]. It is thought to participate in vascular sprouting, allowing the tip cells to migrate/invade into adjacent tissue [10]
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