Stromal cell-derived factor-1 (SDF-1) as a target in liver diseases

Abstract

The chemokine stromal cell-derived factor-1 (SDF-1) or CXCL12 is constitutively expressed in healthy liver. However, its expression increases following acute or chronic liver injury. Liver sinusoidal endothelial cells (LSEC), hepatic stellate cells (HSC), and malignant hepatocytes are important sources of SDF-1/CXCL12 in liver diseases. CXCL12 is able to activate two chemokine receptors with different downstream signaling pathways, CXCR4 and CXCR7. CXCR7 expression is relevant on LSEC, while HSC, mesenchymal stem cells, and tumor cells mainly respond via CXCR4. Here, we summarize recent developments in the field of liver diseases involving this chemokine and its receptors. SDF-1-dependent signaling contributes to modulating acute liver injury and subsequent tissue regeneration. By activating HSC and recruiting mesenchymal cells from bone marrow, CXCL12 can promote liver fibrosis progression, while CXCL12-CXCR7 interactions endorse proregenerative responses in chronic injury. Moreover, the SDF-1 pathway is linked to development of hepatocellular carcinoma (HCC) by promoting tumor growth, angiogenesis, and HCC metastasis. High hepatic CXCR4 expression has been suggested as a biomarker indicating poor prognosis of HCC patients. Tumor-infiltrating myeloid-derived suppressor cells (MDSC) also express CXCR4 and migrate toward CXCL12. Thus CXCL12 inhibition might not only directly block HCC growth but also modulate the tumor microenvironment (angiogenesis, MDSC), thereby sensitizing HCC patients to conventional or emerging novel cancer therapies (e.g., sorafenib, regorafenib, nivolumab, pembrolizumab). We herein summarize the current knowledge on the complex interplay between CXCL12 and CXCR4/CXCR7 in liver diseases and discuss approaches on the therapeutic targeting of these axes in hepatitis, fibrosis, and liver cancer.

Mesenchymal Stem Cells and Induced Bone Marrow-Derived Macrophages Synergistically Improve Liver Fibrosis in Mice

“…Thus, we next investigated the contribution of host cells. The damaged liver expresses the chemoattractant SDF‐1 . Moreover, our macrophages cultured with or without serum from mice with CCl 4 ‐induced liver damage expressed high levels of chemoattractants such as CXCL1, CXCL2, CCL2, and CXCR4.…”

Bioinformatics Analysis Reveals Biomarkers With Prognostic Benefits in Diffuse Type Gastric Cancer

“…CXCL12 overexpression will enhance the proliferation and invasion of colon cancer cells through the MAPK/PI3K/AP-1 signaling pathway (35). Serve as a hub gene, high CXCR4 expression could be a biomarker indicating poor prognosis for hepatocellular carcinoma patients (36). CXCL12/CXCR4 antagonists, such as plerixafor or BKT140, have already produced and display encouraging results in anti-cancer activity (37).…”

Longitudinal studies can identify distinct inflammatory cytokines associated with the inhibition or progression of liver cancer

“…A longitudinal analysis of circulating cytokines/chemokines in males identified different inflammatory cytokines such as CCL12, CCL17, CXCL9 and LIX/CXCL5 during WD while these chemokines remained low in females. CCL12 is constitutively expressed in healthy liver, which is the case during CD. It is also induced during acute liver injury to support hepatic cell regeneration .…”

“…CCL12 is constitutively expressed in healthy liver, which is the case during CD. It is also induced during acute liver injury to support hepatic cell regeneration . In males, it was induced late during WD during tumour progression, which could be hijacked by malignant cells for cell proliferation.…”