Notch Suppresses Angiogenesis and Progression of Hepatic Metastases

Abstract

The Notch pathway plays multiple key roles in tumorigenesis, and its signaling components have therefore aroused great interest as targets for emerging therapies. Here we show that inhibition of Notch, using a soluble receptor Notch1 decoy, unexpectedly caused a remarkable increase in liver metastases from neuroblastoma and breast cancer cells. Increased liver metastases were also seen after treatment with the γ-secretase inhibitor PF-03084014. Transgenic mice with heterozygous loss of Notch1 demonstrated a marked increase in hepatic metastases, indicating that Notch1 signaling acts as metastatic suppressor in the liver microenvironment. Inhibition of DLL1/4 with ligand-specific Notch1 decoys increased sprouting of sinusoidal endothelial cells into micrometastases, thereby supporting early metastatic angiogenic growth. Inhibition of tumor-derived JAG1 signaling activated hepatic stellate cells, increasing their recruitment to vasculature of micrometastases, thereby supporting progression to macrometastases. These results demonstrate that inhibition of Notch causes pathological activation of liver stromal cells, promoting angiogenesis and growth of hepatic metastases. Our findings have potentially serious implications for Notch inhibition therapy.

GATA4-dependent organ-specific endothelial differentiation controls liver development and embryonic hematopoiesis

“…Endothelial Notch signaling also contributes to LSEC differentiation and seems to be essential for the development and maintenance of a proper hepatic vascular architecture and its function (37). Functionally, sinusoidal dilatation and enhanced angiogenesis as seen in endothelial Notch signaling-deficient LSECs may promote hepatic metastasis (38). Notably, sinusoidal dilatation is a common end point of several signaling defects in LSECs; for example, plexin B2-transgenic mice defective in Rho guanine nucleotide exchange factor binding show sinusoidal dilatation and further abnormalities in the architecture of the liver vasculature (39).…”

Comparative analysis of CD4 and CD8 lymphocytes — evidences for different distribution in primary and secondary liver tumors

“…Quantitative arguments which attest CD8+ prevalence in LM suggest a stronger antitumor defense reaction in comparison to HCC. A possible explanation of enhanced CD8+ cells number in LM than in HCC may be related to the increased tumor angiogenesis in metastases [42][43][44] and to the intrinsic relationship between proangiogenic factors and TILs [45,46].…”

Notch Inhibitor PF-03084014 Inhibits Hepatocellular Carcinoma Growth and Metastasis via Suppression of Cancer Stemness due to Reduced Activation of Notch1–Stat3

“…PF-03084014 (PF-4014) is a GSI developed by Pfizer, which shows antitumor efficacy in hematologic, breast, colorectal, and pancreatic cancer models (13)(14)(15)(16)(17)(18), and suppresses hepatic metastases of neuroblastoma and breast cancer cells (19). Currently PF-03084014 is in phase I or phase II trials for the treatment of T-ALL, lymphoma, desmoid tumors, and fibromatosis (4,20,21).…”