Osteopontin-integrin engagement induces HIF-1α–TCF12-mediated endothelial-mesenchymal transition to exacerbate colorectal cancer

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.

Myeloid-derived macrophages and secreted HSP90α induce pancreatic ductal adenocarcinoma development

“… 31 Recently, eHSP90α is also found to induce stemness in prostate cancer and CRC cells. 32 , 33 Elevation of serum/plasma HSP90α levels has been detected in several malignancies including PDAC, non-small cell lung cancer, breast carcinoma, hepatocellular carcinoma, CRC, and glioblastoma. 27-31…”

Mechanistic Insight on the Interaction between OPN and Integrin ανβ3 in Osteoarthritis

“…Many subtypes of integrin receptors bind with OPN. This interaction regulates the expression of tumor-related proteins during carcinogenesis in patients with rectal and/or lung cancer [ 29 , 30 ]. Moreover, integrin interacts with HA to modulate differentiation and metastasis of tumor cells [ 31 , 32 ], suggesting a mechanism involving the stimulation of downstream effects upon OPN and integrin receptor interaction.…”

Octyl Gallate Induces Pancreatic Ductal Adenocarcinoma Cell Apoptosis and Suppresses Endothelial-Mesenchymal Transition-Promoted M2-Macrophages, HSP90α Secretion, and Tumor Growth

“…For oral administration in mice, OG was dissolved in 40% PEG400 (Sigma-Aldrich) aqueous solution. Osteopontin (OPN; R&D Systems, Minneapolis, MN, USA) was dissolved in PBS to induce Cells 2020, 9, 91 3 of 16 the EndoMT of 3B-11 cells (Supplementary Figure S1) [4,5]. Recombinant HSP90α (rHSP90α) was purchased from Enzo Life Sciences Inc. (Farmingdale, NY, USA) and filtrated with 0.2-µm filters before use.…”

“…The endothelial-to-mesenchymal transition (EndoMT) of endothelial cells is also an important resource contributing to 30-40% of CAFs [3]. EndoMT-derived CAFs can exhibit a potent tumor-promoting effect by secreting proteins like HSP90α, TGF-β, and soluble Jagged-1 [4,5]. Besides CAFs, myeloid-derived macrophages are abundantly present in the tumor stroma.…”