Skip to main content
. Author manuscript; available in PMC: 2016 Apr 15.
Published in final edited form as: Cancer Res. 2015 Mar 5;75(8):1592–1602. doi: 10.1158/0008-5472.CAN-14-1493

Figure 7. DLL Blockade promotes SEC sprouting while JAGGED blockade promotes HSC migration.

Figure 7

(A) Fibrin bead assay with mSEC transfected with Fc, N11–24-decoy, N11–13-decoy, and N110–24-decoy. Arrows indicate sprouts. Bar, 200 μm. (B) Sprouts per bead, (C) Sprout length, Mean±stddev. *P<0.05; **P<0.01; ***P<0.001. (D) In the top-chamber of a Boyden chamber, HSC-GFP cells were co-cultured with NGP cells expressing Notch1 decoys. (E) migration of HSC-GFP measured at 48h. Mean±stddev. *P<0.05; **P<0.01. (F) Immunoblot of Hes1, Hey1, αSMA, and β-actin of FACS sorted HSCs. (G) Migration of HSC-GFP, at 48h, co-cultured with NGP or NGP-siJag1. Mean±stddev. ***P<0.001. (H) Model of Notch blockade effects on hepatic microenvironment. Quiescent: SECs are maintained in quiescence by Notch1 signaling. HSCs in the space of Disse are maintained in quiescence by Notch2/3 signaling from JAG1 expressing hepatocytes (28). SEC Proliferation and Sprouting: Soluble N1D inhibits DLL4 activation of Notch1 in SECs, leading to expression of ICAM-1 and proliferation of SECs, and subsequent sprouting into tumor micrometastases (<300μm). HSC Recruitment: N1D blocks tumor JAG1, promoting HSC activation, (indicated by αSMA(+) expression), migration, and recruitment to the vasculature of macrometastases (>300 μm).