Abstract
Primary hepatocellular carcinoma (HCC) often invades into vessels and has a distal metastasis at an early stage, resulting in poor prognosis and therapeutic outcome. The metastasis has been attributable to the dissemination of tumor cells into circulation as circulating tumor cells (CTCs). Moreover, cancer stem cells (CSCs) within CTCs, which are termed as circulating tumor stem cells (CTSCs), are critical for formation of distal metastatic tumors. Although CD133 and CD90 have been used to characterize and isolate CTCs or CSCs in HCC, no good marker (cocktail) has been identified so far for CTSCs in HCC. Here, we show evidence that CD90+CXCR4+ HCC cells may be CTSCs in HCC. CD90+CXCR4+ HCC cells formed tumor spheres in culture and developed tumors after serial adoptive transplantations into NOD/SCID mice, while the CD90−CXCR4−, CD90-CXCR4+ or CD90+CXCR4− cells did not. Moreover, tumor cells were significantly more frequently detected in the circulation when CD90+CXCR4+ HCC cells were subcutaneously transplanted. Further, subcutaneous transplantation of CD90+CXCR4+ HCC cells, but not transplantation of CD90−CXCR4−, CD90−CXCR4+, or CD90+CXCR4− cells significantly developed distal metastatic tumors. Together, these data suggest that CD90+CXCR4+ HCC cells may be CTSCs and selective elimination of these cells may substantially improve the current HCC therapy by reducing cancer metastasis.
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Chiba T, Kanai F, Iwama A, Yokosuka O. Circulating cancer stem cells: a novel prognostic predictor of hepatocellular carcinoma. Hepatobiliary Surg Nutr. 2013;2:4–6.
Sainz Jr B, Heeschen C. Standing out from the crowd: cancer stem cells in hepatocellular carcinoma. Cancer Cell. 2013;23:431–3.
Nagano H, Ishii H, Marubashi S, Haraguchi N, Eguchi H, Doki Y, et al. Novel therapeutic target for cancer stem cells in hepatocellular carcinoma. J Hepatobiliary Pancreat Sci. 2012;19:600–5.
Chiba T, Kamiya A, Yokosuka O, Iwama A. Cancer stem cells in hepatocellular carcinoma: recent progress and perspective. Cancer Lett. 2009;286:145–53.
Ge Z, Zhang B, Bu X, Wang Y, Xiang L, Tan J. Molecular mechanism of activating protein-4 regulated growth of hepatocellular carcinoma. Tumour Biol. 2014;35:12441–7.
Wang J, Su H, Han X, Xu K. Inhibition of fibroblast growth factor receptor signaling impairs metastasis of hepatocellular carcinoma. Tumour Biol. 2014;35:11005–11.
Powell AA, Talasaz AH, Zhang H, Coram MA, Reddy A, Deng G, et al. Single cell profiling of circulating tumor cells: transcriptional heterogeneity and diversity from breast cancer cell lines. PLoS One. 2012;7:e33788.
Fusi A, Liu Z, Kummerlen V, Nonnemacher A, Jeske J, Keilholz U. Expression of chemokine receptors on circulating tumor cells in patients with solid tumors. J Transl Med. 2012;10:52.
Li CX, Shao Y, Ng KT, Liu XB, Ling CC, Ma YY, et al. Fty720 suppresses liver tumor metastasis by reducing the population of circulating endothelial progenitor cells. PLoS One. 2012;7:e32380.
Charles J, Di Domizio J, Salameire D, Bendriss-Vermare N, Aspord C, Muhammad R, et al. Characterization of circulating dendritic cells in melanoma: role of ccr6 in plasmacytoid dendritic cell recruitment to the tumor. J Invest Dermatol. 2010;130:1646–56.
Lee K, Qian DZ, Rey S, Wei H, Liu JO, Semenza GL. Anthracycline chemotherapy inhibits hif-1 transcriptional activity and tumor-induced mobilization of circulating angiogenic cells. Proc Natl Acad Sci U S A. 2009;106:2353–8.
Petersson M, Niemann C. Stem cell dynamics and heterogeneity: implications for epidermal regeneration and skin cancer. Curr Med Chem. 2012;19:5984–92.
Perez-Losada J, Balmain A. Stem-cell hierarchy in skin cancer. Nat Rev Cancer. 2003;3:434–43.
Singh SR. Stem cell niche in tissue homeostasis, aging and cancer. Curr Med Chem. 2012;19:5965–74.
Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, et al. Identification of a cancer stem cell in human brain tumors. Cancer Res. 2003;63:5821–8.
Nagata T, Sakakura C, Komiyama S, Miyashita A, Nishio M, Murayama Y, et al. Expression of cancer stem cell markers cd133 and cd44 in locoregional recurrence of rectal cancer. Anticancer Res. 2011;31:495–500.
Fang DD, Kim YJ, Lee CN, Aggarwal S, McKinnon K, Mesmer D, et al. Expansion of cd133(+) colon cancer cultures retaining stem cell properties to enable cancer stem cell target discovery. Br J Cancer. 2010;102:1265–75.
Shi C, Tian R, Wang M, Wang X, Jiang J, Zhang Z, et al. Cd44+ cd133+ population exhibits cancer stem cell-like characteristics in human gallbladder carcinoma. Cancer Biol Ther. 2010;10:1182–90.
Ottaiano A. Finding markers for cancer stem cells in renal cell carcinoma: looking beyond cd133. Cell Cycle. 2010;9:4431.
Ma S, Chan KW, Lee TK, Tang KH, Wo JY, Zheng BJ, et al. Aldehyde dehydrogenase discriminates the cd133 liver cancer stem cell populations. Mol Cancer Res. 2008;6:1146–53.
Wang J, Sakariassen PO, Tsinkalovsky O, Immervoll H, Boe SO, Svendsen A, et al. Cd133 negative glioma cells form tumors in nude rats and give rise to cd133 positive cells. Int J Cancer. 2008;122:761–8.
Duester G. Families of retinoid dehydrogenases regulating vitamin a function: production of visual pigment and retinoic acid. Eur J Biochem. 2000;267:4315–24.
Magni M, Shammah S, Schiro R, Mellado W, Dalla-Favera R, Gianni AM. Induction of cyclophosphamide-resistance by aldehyde-dehydrogenase gene transfer. Blood. 1996;87:1097–103.
Armstrong L, Stojkovic M, Dimmick I, Ahmad S, Stojkovic P, Hole N, et al. Phenotypic characterization of murine primitive hematopoietic progenitor cells isolated on basis of aldehyde dehydrogenase activity. Stem Cells. 2004;22:1142–51.
Hess DA, Craft TP, Wirthlin L, Hohm S, Zhou P, Eades WC, et al. Widespread nonhematopoietic tissue distribution by transplanted human progenitor cells with high aldehyde dehydrogenase activity. Stem Cells. 2008;26:611–20.
Hess DA, Meyerrose TE, Wirthlin L, Craft TP, Herrbrich PE, Creer MH, et al. Functional characterization of highly purified human hematopoietic repopulating cells isolated according to aldehyde dehydrogenase activity. Blood. 2004;104:1648–55.
Hess DA, Wirthlin L, Craft TP, Herrbrich PE, Hohm SA, Lahey R, et al. Selection based on cd133 and high aldehyde dehydrogenase activity isolates long-term reconstituting human hematopoietic stem cells. Blood. 2006;107:2162–9.
Silva IA, Bai S, McLean K, Yang K, Griffith K, Thomas D, et al. Aldehyde dehydrogenase in combination with cd133 defines angiogenic ovarian cancer stem cells that portend poor patient survival. Cancer Res. 2011;71:3991–4001.
Ma I, Allan AL. The role of human aldehyde dehydrogenase in normal and cancer stem cells. Stem Cell Rev. 2011;7:292–306.
Liu Y, Jiang X, Zeng Y, Zhou H, Yang J, Cao R. Proliferating pancreatic beta-cells upregulate aldh. Histochem Cell Biol. 2014;142:685–91.
Zhang L, Wang L, Liu X, Zheng D, Liu S, Liu C. Aldh expression characterizes g1-phase proliferating beta cells during pregnancy. PLoS One. 2014;9:e96204.
Yang ZF, Ngai P, Ho DW, Yu WC, Ng MN, Lau CK, et al. Identification of local and circulating cancer stem cells in human liver cancer. Hepatology. 2008;47:919–28.
Chen X, Lingala S, Khoobyari S, Nolta J, Zern MA, Wu J. Epithelial mesenchymal transition and hedgehog signaling activation are associated with chemoresistance and invasion of hepatoma subpopulations. J Hepatol. 2011;55:838–45.
Lingala S, Cui YY, Chen X, Ruebner BH, Qian XF, Zern MA, et al. Immunohistochemical staining of cancer stem cell markers in hepatocellular carcinoma. Exp Mol Pathol. 2010;89:27–35.
Piao LS, Hur W, Kim TK, Hong SW, Kim SW, Choi JE, et al. Cd133+ liver cancer stem cells modulate radioresistance in human hepatocellular carcinoma. Cancer Lett. 2012;315:129–37.
Zhang J, Luo N, Luo Y, Peng Z, Zhang T, Li S. Microrna-150 inhibits human cd133-positive liver cancer stem cells through negative regulation of the transcription factor c-myb. Int J Oncol. 2012;40:747–56.
Haraguchi N, Ishii H, Mimori K, Tanaka F, Ohkuma M, Kim HM, et al. Cd13 is a therapeutic target in human liver cancer stem cells. J Clin Invest. 2010;120:3326–39.
Yang ZF, Ho DW, Ng MN, Lau CK, Yu WC, Ngai P, et al. Significance of cd90+ cancer stem cells in human liver cancer. Cancer Cell. 2008;13:153–66.
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This work was supported by a grant from National Natural Sciences Foundation of China, number: 81171432.
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Zhu, L., Zhang, W., Wang, J. et al. Evidence of CD90+CXCR4+ cells as circulating tumor stem cells in hepatocellular carcinoma. Tumor Biol. 36, 5353–5360 (2015). https://doi.org/10.1007/s13277-015-3196-6
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DOI: https://doi.org/10.1007/s13277-015-3196-6