title: Hypoxia Enhances Tumor-Stroma Crosstalk that Drives the Progression of Hepatocellular Carcinoma.
abstract: Crosstalk between tumor cells and their microenvironment plays a crucial role in the progression of hepatocellular carcinoma (HCC). Hypoxia, a common feature of advanced HCC, has been shown to modulate the evolution of the tumor microenvironment. In this study, we investigated the effect of hypoxia on tumor-stroma crosstalk in HCC.
  
  
  
  Human HCC cell lines (Huh-BAT, SNU-475) were cocultured with an activated human hepatic stellate cell line (HSCs; LX-2) under either normoxic or hypoxic conditions. Cell growth was evaluated with the MTS assay. Apoptotic signaling cascades were assessed by immunoblot analysis. Expression of CD31 and phosphorylated (p-) Akt in HCC tissues was detected by immunohistochemistry.
  
  
  
  Coculturing HCC cells with HSCs under hypoxic conditions enhanced their proliferation, migration, and resistance to bile acid (BA)-induced apoptosis compared to coculturing under normoxic conditions. Under hypoxia, of various HSC-derived growth factors, PDGF-BB was the most up-regulated, leading to the activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in HCC cells. Immunohistochemical study also revealed that p-Akt was highly expressed in hypoxic, hypovascular HCC as compared to hypervascular HCC. Neutralizing antisera to PDGF-BB or a PI3K inhibitor attenuated the proliferation of HCC cells cocultured with HSCs, and sensitized HCC cells to BA-induced apoptosis, especially under hypoxic conditions.
  
  
  
  In conclusion, hypoxic HSC-derived PDGF-BB stimulates the proliferation of HCC cells through activation of the PI3K/Akt pathway, while the inhibition of PDGF-BB or PI3K/Akt pathways enhances apoptotic cell death. Targeting tumor-stroma crosstalk might be a novel therapy in the management of human HCCs.
authors.affiliation: Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.|Department of Internal Medicine, CHA Gangnam Medical Center, CHA University, Seoul, Republic of Korea.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Cho
authors.affiliation: Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.
authors.forename: Eun Ju
authors.initials: EJ
authors.lastname: Cho
authors.affiliation: Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.
authors.forename: Jeong-Hoon
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.
authors.forename: Su Jong
authors.initials: SJ
authors.lastname: Yu
authors.affiliation: Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.
authors.forename: Yoon Jun
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.
authors.forename: Chung Yong
authors.initials: CY
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea. yoonjh@snu.ac.kr.
authors.forename: Jung-Hwan
authors.initials: JH
authors.lastname: Yoon
mesh_terms: D057134:Antibodies, Neutralizing / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D000077214:Becaplermin; D001647:Bile Acids and Salts / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D055166:Hepatic Stellate Cells; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D015151:Immunoblotting; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D000072258:Tumor Hypoxia; D059016:Tumor Microenvironment
chemical_list: D057134:Antibodies, Neutralizing; D001647:Bile Acids and Salts; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D047428:Protein Kinase Inhibitors; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt
keywords: Crosstalk; Hepatic stellate cell; Hepatocellular carcinoma; Hypoxia; PI3K/Akt pathway