| Abstract: | ![]()
This research aimed to explore the influence of Src homology-2 containing protein tyrosine phosphatase (SHP-2) on the functions of tyrosine kinase receptors with immunoglobulin and EGF homology domains 2 (Tie2)-expressingmonocyte/macrophages (TEMs) and the influence of the angiopoietin(Ang)/Tie2-phosphatidylinositol-3-kinase(PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) (Ang/Tie2-PI3K/Akt/mTOR) signalingpathway on the tumor microvascular remodeling in an immunosuppressive microenvironment. In vivo, SHP-2-deficient mice were used to construct colorectal cancer (CRC) liver metastasis models. SHP-2-deficient mice hadsignificantly more metastatic cancer and inhibited nodules on the liver surface than wild-type mice, and the high-levelexpression of p-Tie2 was found in the liver tissue of the macrophages’ specific SHP-2-deficient mice (SHP-2MACKO) + planted tumor mice. Compared with the SHP-2 wild type mice (SHP-2WT) + planted tumor group, theSHP-2MAC-KO + planted tumor group experienced increased expression of p-Tie2, p-PI3K, p-Akt, p-mTOR,vascular endothelial growth factor (VEGF), cyclooxygenase-2 (COX-2), matrix metalloproteinase 2 (MMP2), andMMP9 in the liver tissue. TEMs selected by in vitro experiments were co-cultured with remodeling endothelial cellsand tumor cells as carriers. It was found that when Angpt1/2 was used for stimulation, the SHP-2MAC-KO +Angpt1/2 group displayed evident increases in the expression of the Ang/Tie2-PI3K/Akt/mTOR pathway. Thenumber of cells passing through the lower chamber and the basement membrane and the number of blood vesselsformed by cells compared with the SHP-2WT + Angpt1/2 group, while these indexes were subjected to no changesunder the simultaneous stimulation of Angpt1/2 + Neamine. To sum up, the conditional knockout of SHP-2 canactivate the Ang/Tie2-PI3K/Akt/mTOR pathway in TEMs, thereby strengthening tumor micro angiogenesis in themicroenvironment and facilitating CRC liver metastasis. |
