Yuri Cho1,2, Eun Ju Cho1, Jeong-Hoon Lee1, Su Jong Yu1, Yoon Jun Kim1, Chung Yong Kim1, Jung-Hwan Yoon3. 1. Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea. 2. Department of Internal Medicine, CHA Gangnam Medical Center, CHA University, Seoul, Republic of Korea. 3. 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.
Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND: 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. METHODS: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. RESULTS: 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. CONCLUSIONS: 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: N Théret; O Musso; B Turlin; D Lotrian; P Bioulac-Sage; J P Campion; K Boudjéma; B Clément Journal: Hepatology Date: 2001-07 Impact factor: 17.425
Authors: Jean S Campbell; Steven D Hughes; Debra G Gilbertson; Thomas E Palmer; Matthew S Holdren; Aaron C Haran; Melissa M Odell; Renay L Bauer; Hong-Ping Ren; Harald S Haugen; Matthew M Yeh; Nelson Fausto Journal: Proc Natl Acad Sci U S A Date: 2005-02-22 Impact factor: 11.205
Authors: A Lal; H Peters; B St Croix; Z A Haroon; M W Dewhirst; R L Strausberg; J H Kaanders; A J van der Kogel; G J Riggins Journal: J Natl Cancer Inst Date: 2001-09-05 Impact factor: 13.506
Authors: M S Kim; H J Kwon; Y M Lee; J H Baek; J E Jang; S W Lee; E J Moon; H S Kim; S K Lee; H Y Chung; C W Kim; K W Kim Journal: Nat Med Date: 2001-04 Impact factor: 53.440
Authors: J G Park; J H Lee; M S Kang; K J Park; Y M Jeon; H J Lee; H S Kwon; H S Park; K S Yeo; K U Lee Journal: Int J Cancer Date: 1995-07-28 Impact factor: 7.396
Authors: Oliver Stoeltzing; Syed A Ahmad; Wenbiao Liu; Marya F McCarty; Jane S Wey; Alexander A Parikh; Fan Fan; Niels Reinmuth; Michiya Kawaguchi; Corazon D Bucana; Lee M Ellis Journal: Cancer Res Date: 2003-06-15 Impact factor: 12.701
Authors: Hyo Jeong Lee; Hyo Jeong Kang; Kang Mo Kim; Eun Sil Yu; Ki Hun Kim; Seung-Mi Kim; Tae Won Kim; Ju Hyun Shim; Young-Suk Lim; Han Chu Lee; Young-Hwa Chung; Yung Sang Lee Journal: Clin Mol Hepatol Date: 2015-03-25
Authors: Yuri Cho; Yun Bin Lee; Jeong-Hoon Lee; Dong Hyeon Lee; Eun Ju Cho; Su Jong Yu; Yoon Jun Kim; Jong In Kim; Jong Hun Im; Jung Hwan Lee; Eun Ju Oh; Jung-Hwan Yoon Journal: PLoS One Date: 2016-08-05 Impact factor: 3.240
Authors: Quirino Lai; Alessandro Vitale; Tommaso M Manzia; Francesco G Foschi; Giovanni B Levi Sandri; Martina Gambato; Fabio Melandro; Francesco P Russo; Luca Miele; Luca Viganò; Patrizia Burra; Edoardo G Giannini Journal: Cancers (Basel) Date: 2019-10-15 Impact factor: 6.639