Cancer-associated fibroblasts promote hepatocellular carcinoma metastasis through chemokine-activated hedgehog and TGF-β pathways

Cancer Lett. 2016 Aug 28;379(1):49-59. doi: 10.1016/j.canlet.2016.05.022. Epub 2016 May 20.


Fibroblasts are rich in the surrounding microenvironment of hepatocellular carcinoma (HCC) because most HCCs occur in fibrotic or cirrhotic livers. However, the role of cancer-associated fibroblasts (CAFs) in HCC metastasis remains obscure. Here, we reported that CAFs promote the migration and invasion of HCC cells in vitro and facilitate the HCC metastasis to the bone, brain and lung in NOD/SCID mice. The RayBio human chemokine antibody array revealed that CAFs secret higher levels of CCL2, CCL5, CCL7 and CXCL16 than peri-tumor fibroblasts. CCL2 and CCL5 increase the migration but not the invasion of HCC cells, while CCL7 and CXCL16 promote both migration and invasion of HCC cells. Moreover, CCL2 and CCL5 stimulate the activation of the hedgehog (Hh) pathway, while CCL7 and CXCL16 enhance the activity of the transforming growth factor-β (TGF-β) pathway in HCC cells. The neutralizing antibodies of chemokines notably attenuate the effect of CAFs on HCC metastasis and compromised the activation of Hh and TGF-β pathways in HCC cells. In summary, CAF-secreted CCL2, CCL5, CCL7 and CXCL16 promote HCC metastasis through the coordinate activation of Hh and TGF-β pathways in HCC cells.

Keywords: Cancer-associated fibroblasts; Chemokines; Hedgehog pathway; Metastasis; TGF-β pathway.

MeSH terms

  • Animals
  • Bone Neoplasms / metabolism
  • Bone Neoplasms / secondary
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / secondary
  • Cancer-Associated Fibroblasts / metabolism*
  • Cancer-Associated Fibroblasts / pathology
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / metabolism*
  • Carcinoma, Hepatocellular / secondary
  • Cell Line, Tumor
  • Cell Movement*
  • Chemokine CCL2 / metabolism
  • Chemokine CCL5 / metabolism
  • Chemokine CCL7 / metabolism
  • Chemokine CXCL16
  • Chemokines / metabolism*
  • Chemokines, CXC / metabolism
  • Hedgehog Proteins / genetics
  • Hedgehog Proteins / metabolism*
  • Humans
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / pathology
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / secondary
  • Male
  • Mice, Inbred NOD
  • Mice, Nude
  • Mice, SCID
  • Neoplasm Invasiveness
  • Paracrine Communication*
  • Receptors, Scavenger / metabolism
  • Signal Transduction*
  • Time Factors
  • Transfection
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism*
  • Tumor Cells, Cultured
  • Tumor Microenvironment


  • CCL2 protein, human
  • CCL5 protein, human
  • CCL7 protein, human
  • CXCL16 protein, human
  • Chemokine CCL2
  • Chemokine CCL5
  • Chemokine CCL7
  • Chemokine CXCL16
  • Chemokines
  • Chemokines, CXC
  • Hedgehog Proteins
  • Receptors, Scavenger
  • Transforming Growth Factor beta