Macrophage-derived SHP-2 inhibits the metastasis of colorectal cancer via Tie2-PI3K signals

Oncol Res. 2023 Apr 10;31(2):125-139. doi: 10.32604/or.2023.028657. eCollection 2023.

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)-expressing monocyte/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) signaling pathway 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 had significantly more metastatic cancer and inhibited nodules on the liver surface than wild-type mice, and the high-level expression of p-Tie2 was found in the liver tissue of the macrophages' specific SHP-2-deficient mice (SHP-2MAC-KO) + planted tumor mice. Compared with the SHP-2 wild type mice (SHP-2WT) + planted tumor group, the SHP-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), and MMP9 in the liver tissue. TEMs selected by in vitro experiments were co-cultured with remodeling endothelial cells and 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. The number of cells passing through the lower chamber and the basement membrane and the number of blood vessels formed by cells compared with the SHP-2WT + Angpt1/2 group, while these indexes were subjected to no changes under the simultaneous stimulation of Angpt1/2 + Neamine. To sum up, the conditional knockout of SHP-2 can activate the Ang/Tie2-PI3K/Akt/mTOR pathway in TEMs, thereby strengthening tumor micro angiogenesis in the microenvironment and facilitating CRC liver metastasis.

Keywords: Akt/mTOR signaling; Colorectal cancer; Liver metastasis; Macrophages; PI3K; SHP-2; Tie2.

MeSH terms

  • Animals
  • Colorectal Neoplasms* / genetics
  • Endothelial Cells
  • Humans
  • Liver Neoplasms* / genetics
  • Matrix Metalloproteinase 2
  • Mice
  • Phosphatidylinositol 3-Kinases
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11* / genetics
  • Proto-Oncogene Proteins c-akt
  • Receptor, TIE-2
  • TOR Serine-Threonine Kinases
  • Tumor Microenvironment
  • Vascular Endothelial Growth Factor A

Substances

  • Matrix Metalloproteinase 2
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • Vascular Endothelial Growth Factor A
  • Ptpn11 protein, mouse
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Tek protein, mouse
  • Receptor, TIE-2