Cancer-associated fibroblasts promote the stemness of CD24+ liver cells via paracrine signaling
- 148 Downloads
Cancer stem cells (CSCs), which support tumor progress in hepatocellular carcinoma (HCC) developed in fibrotic or cirrhotic livers, are regulated by the tumor microenvironment. Cancer-associated fibroblasts (CAFs) are the major component of the tumor stroma in HCC; however, the mechanisms by which CAFs contribute to stemness maintenance remain largely unknown. Here, we found that the expression of CD24 was high in HCC tissues compared with adjacent normal liver tissues, and positively correlated with the poor prognosis and α-SMA expression in CAFs. CD24+ cells isolated from HCC cell lines exhibited stemness properties of self-renewal, chemotherapy resistance, metastasis, and tumorigenicity in NOD/SCID mice. Moreover, CAF-derived HGF and IL6 enhanced the stemness properties of CD24+ cells via activating STAT3 Tyr705 phosphorylation. Blockade of HGF/c-Met or IL6/IL6R signaling significantly abolished the effect of CAFs on stemness properties, which compromised the activation of STAT3 pathway in CD24+ cells. Meanwhile, knockdown of STAT3 in CD24+ cells notably attenuated CAF-induced stemness characteristics of CD24+ cells. Furthermore, in HCC patients, higher expression of phospho-STAT3 was also demonstrated to be positively correlated with poor clinical outcomes. In summary, HGF and IL6 secreted by CAFs promoted the stemness properties of CD24+ cells through the phosphorylation of STAT3 signaling, and targeting the paracrine pathways may provide a new therapeutic strategy for HCC.
CD24, identified as a marker for HCC CSCs, was positively correlated with the poor prognosis and α-SMA expression in CAFs.
CAFs promoted self-renewal, chemotherapy resistance, metastasis, and tumorigenicity of CD24+ HCC cells.
HGF and IL6 secreted by CAFs promoted the stemness properties of CD24+ HCC cells through the phosphorylation of STAT3.
KeywordsCancer stem cell Cancer-associated fibroblasts Hepatocellular carcinoma Interleukin-6 Hepatocyte growth factor STAT3
This work was supported by grants from the National Natural Science Foundation of China (81172063 and 81372352).
Compliance with ethical standards
All human studies were approved by the Ethical Committee of Tongji Hospital, Huazhong University of Science and Technology (HUST, Wuhan, China) (IRB ID: TJ-C20160117) and informed consent was obtained from each patient. The animal studies were conducted according to Tongji Hospital Institutional Review Board Approval of Experimental Animals (IRB ID: TJ-A20161205).
Conflict of interest
The authors declare that they have no conflict of interest.
- 4.Ooki A, VandenBussche CJ, Kates M, Hahn NM, Matoso A, McConkey DJ, Bivalacqua TJ, Hoque MO (2018) CD24 regulates cancer stem cell (CSC)-like traits and a panel of CSC-related molecules serves as a non-invasive urinary biomarker for the detection of bladder cancer. Br J Cancer 119:961–970CrossRefGoogle Scholar
- 13.Tsuyada A, Chow A, Wu J, Somlo G, Chu PG, Loera S, Luu TH, Li AXJ, Wu XW, Ye W, Chen SA, Zhou WY, Yu Y, Wang YZ, Ren XB, Li H, Scherle P, Kuroki Y, Wang SE (2012) CCL2 mediates cross-talk between cancer cells and stromal fibroblasts that regulates breast cancer stem cells. Cancer Res 72:2768–2779CrossRefGoogle Scholar
- 15.Wu X, Tao P, Zhou Q, Li J, Yu Z, Wang X, Li J, Li C, Yan M, Zhu Z, Liu B, Su L (2017) IL-6 secreted by cancer-associated fibroblasts promotes epithelial-mesenchymal transition and metastasis of gastric cancer via JAK2/STAT3 signaling pathway. Oncotarget 8:20741–20750Google Scholar
- 16.Luo J, Wang P, Wang R, Wang J, Liu M, Xiong S, Li Y, Cheng B (2016) The notch pathway promotes the cancer stem cell characteristics of CD90+ cells in hepatocellular carcinoma. Oncotarget 7:9525–9537Google Scholar
- 18.Xiong SWR, Chen Q, Luo J, Wang J, Zhao Z, Li Y, Wang Y, Wang X, Cheng B (2018) Cancer-associated fibroblasts promote stem cell-like properties of hepatocellular carcinoma cells through IL-6/STAT3/notch signaling. Am J Cancer Res 8:302–316Google Scholar
- 21.Maini RN, Taylor PC, Szechinski J, Pavelka K, Broll J, Balint G, Emery P, Raemen F, Petersen J, Smolen J, Thomson D, Kishimoto T, Group CS (2006) Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate. Arthritis Rheum 54:2817–2829CrossRefGoogle Scholar
- 25.Su S, Chen J, Yao H, Liu J, Yu S, Lao L, Wang M, Luo M, Xing Y, Chen F, Huang D, Zhao J, Yang L, Liao D, Su F, Li M, Liu Q, Song E (2018) CD10(+)GPR77(+) cancer-associated fibroblasts promote cancer formation and chemoresistance by sustaining cancer stemness. Cell 172(841–856):e816Google Scholar
- 29.Hasegawa T, Yashiro M, Nishii T, Matsuoka J, Fuyuhiro Y, Morisaki T, Fukuoka T, Shimizu K, Shimizu T, Miwa A, Hirakawa K (2014) Cancer-associated fibroblasts might sustain the stemness of scirrhous gastric cancer cells via transforming growth factor-beta signaling. Int J Cancer 134:1785–1795CrossRefGoogle Scholar
- 31.Owusu BY, Galemmo R, Janetka J, Klampfer L (2017) Hepatocyte growth factor, a key tumor-promoting factor in the tumor microenvironment. Cancers (Basel) 9:Google Scholar
- 32.Vermeulen L, De Sousa EMF, van der Heijden M, Cameron K, de Jong JH, Borovski T, Tuynman JB, Todaro M, Merz C, Rodermond H, Sprick MR, Kemper K, Richel DJ, Stassi G, Medema JP (2010) Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat Cell Biol 12:468–476CrossRefGoogle Scholar
- 38.Wang CQ, Sun HT, Gao XM, Ren N, Sheng YY, Wang Z, Zheng Y, Wei JW, Zhang KL, Yu XX, Zhu Y, Luo Q, Yang LY, Dong QZ, Qin LX (2016) Interleukin-6 enhances cancer stemness and promotes metastasis of hepatocellular carcinoma via up-regulating osteopontin expression. Am J Cancer Res 6:1873–1889Google Scholar
- 46.Ma Z, He H, Sun F, Xu Y, Huang X, Ma Y, Zhao H, Wang Y, Wang M, Zhang J (2017) Selective targeted delivery of doxorubicin via conjugating to anti-CD24 antibody results in enhanced antitumor potency for hepatocellular carcinoma both in vitro and in vivo. J Cancer Res Clin Oncol 143:1929–1940CrossRefGoogle Scholar