Cancer stem/progenitor cells are highly enriched in CD133⁺CD44⁺ population in hepatocellular carcinoma

Abstract

Both our previous study and other reports have suggested that CD133, originally classified as a hematopoietic stem cell marker, could be used for enrichment of cancer stem cells (CSCs) in human hepatocellular carcinoma (HCC). It was also noted that not all of CD133 1 cells were representative of CSCs. Further identification and characterization of CSCs or tumor-initiating cells in HCC are necessary to better understand hepatocarcinogenesis. In present study, we demonstrated that CSC phenotype could be precisely defined by co-expression of CD133 and CD44 cell surface markers. CD133 1 CD44 1 HCC cells showed stem cell properties, including extensive proliferation, self-renewal, and differentiation into the bulk of cancer cells. In vivo xenograft experiments revealed that, actually, the highly tumorigenic capacity of CD133 1 cells as previously described was primarily attributed to CD133 1 CD44 1 cell subpopulation, instead of their CD133 1 CD44 2 counterparts. Moreover, cells double-positive for CD133 and CD44 exhibited preferential expression of some stem cell-associated genes and were more resistant to chemotherapeutic agents due to the upregulation of ATP-binding cassette (ABC) superfamily transporters, including ABCB1, ABCC1, and ABCG2, further supporting these cells as HCC cell origin. Our findings suggest that CD133 1 CD44 1 cells might represent true cancer stem/progenitor cells in HCC, which could allow a better understanding of HCC initiation and progression, as well as establish a precise target for the development of more effective therapies.

Tunicamycin Potentiates Cisplatin Anticancer Efficacy through the DPAGT1/Akt/ABCG2 Pathway in Mouse Xenograft Models of Human Hepatocellular Carcinoma

“…This cell population is further characterized by the co-expression of CD133 and CD44 (7). Importantly, a significant difference in ABCG2 expression was observed between CD133 þ /CD44 þ cells and a corresponding double negative subpopulation.…”

Wnt/?-Catenin Signalling during Liver Metabolism, Chronic Liver Disease and Hepatocarcinogenesis

“…Within the CD133 + population, cells with the expression profile CD133 + CD44 + have been described as more tumorigenic and metastatic than CD133 + CD44 − cells (29,30). Other studies have suggested the mucin-like cell surface glycoprotein CD24 (31) and the glycosylphosphatidylinositol-anchored glycoprotein CD90 or Thy-1 (32) as liver CSC markers.…”

The Roles of MicroRNAs in the Cancer Invasion-Metastasis Cascade

“…Several miRNAs such as miR-328, miR-373 and miR-520c have been reported to regulate CD44 and promote cancer cell motility or invasion [64][65][66]. In addition, CD44 has recently been recognized as a cell surface marker of CSC and mesenchymal stem cells (MSC) [67][68][69][70][71][72]. Therefore, these CD44-regulating miRNAs may function in CSC and MSC.…”

“…The oncogenic miR-17-92 cluster is not only induced by transcriptional factors c-Myc, E2F [36][37][38], but also by Hedgehog signaling [115,116], which suggests that this cluster may play a role in promoting self renewal of cancer stem cells. miR-328, miR-373, and miR520c have been reported to regulate CSC surface marker CD44 and may promote CSC proliferation and motility [67][68][69][70][71][72].…”