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. Author manuscript; available in PMC: 2012 Feb 15.
Published in final edited form as: Cancer Cell. 2011 Feb 15;19(2):257–272. doi: 10.1016/j.ccr.2011.01.020

Figure 8. CXCR4/SDF1 inhibition reduced MF and MSC recruitment and tumor growth.

Figure 8

(A) Effects of TGF-β or CXCR4 inhibition in xenografts of co-injection with IL-1β BM-MF and MKN45 cells on one flank and MKN45 on the other flank. Tumor size (middle) after 6 weeks of tumor growth in mice given the TGF-βR2 inhibitor (upper panel) or CXCR4 inhibitor (lower panel). Representative IHC of each tumor (right, left) with staining for endogeneous GFP and αSMA (orange arrows indicate double staining and white arrows indicate expression of only GFP).

(B) Quantification and statistical analysis of xenograft experiment with mice co-injected with IL-1β BM-MF and MKN45 cells on one flank and MKN45 alone on the other flank. Tumor size in g after 6 weeks of tumor growth in mice given the TGF-βR2 inhibitor (SB-505124) or CXCR4 inhibitor (AMD3100) (*=p< 0.05 (Dunnett)) (C–F) Effect of CXCR4 inhibitor treatment on stomachs of 16 months old H. felis infected αSMA/RFP mice after 4 months of AMD3100 treatment:

(C) Representative IHC of (left) untreated control and (right) AMD3100 treated mice and

(D) histopathological scoring of the same experiment (*=p<0.05, (N=3)).

(E) Representative pictures of (left) untreated control BM and (right) BM of AMD3100 treated mice with αSMA staining and

(F) quantification of RFP+ cells in the BM by FACS (*=p<0.05, (N=3) . All data are represented as mean +/− SEM.

(G) Schematic drawing that depicts interactions between the bone marrow niche (left) and the gastric cancer stroma (right). A significant portion of CAFs (red) originate from the bone marrow and are derived from MSCs (green). The normal bone marrow niche consists of self-renewing MSCs that give rise to MF that resemble CAFs and likely contribute to the normal stem cell niche in the bone marrow. In their niche, MSC express both Gremlin-1 and SDF-1. TGF-β can induce the differentiation of MSC into MFs through an SDF1α-dependent pathway that involves DNA hypomethylation. MF express BMP4, which seems to induce Gremlin-1 in MSCs; BMP4 and Wnt5a likely induce DKK1 or Shh in the normal, heterogeneous population of MSC. With cancer progression, the number of CAFs increases markedly in the bone marrow niche and blood. These bone marrow niche cells are expanded in a TGF-β dependent matter and recruited through CXCR4/SDF1α signaling together with Gremlin-1-expressing MSC to incipient tumors where they now appear as CAFs.