Technological advances and greater understanding of stem cell biology have contributed to the identification and characterization of the tissues and organs involved with these cells. Recently, cancer stem cells (CSCs) also have been recognized as playing a pivotal role in tumorigenesis, therapeutic resistance, and metastasis. As with normal stem cells, CSCs have markers and signaling pathways that regulate various aspects of self-renewal and differentiation.

Two major theories have been proposed to describe the stem cells in cancer: In the stochastic model, every tumor cell has the capacity for tumor initiation and growth, and depends on some random and varying intrinsic factor. In the hierarchical model, CSCs make up only a very small subpopulation of cells within the whole tumor. Uniquely, these cells have a greater capacity for self-renewal, differentiation, and tumorigenicity, and may be more resistant to chemotherapy and radiotherapy.^1,2

The CSC hypothesis has received support, since it can explain, in part, the heterogenous nature of hepatocellular carcinoma (HCC), and is one potential mechanistic explanation for its high degree of relapse, metastasis, and resistance to therapies.

Identification of Liver CSCs and Their Role in HCC

Attempts at identifying liver CSC (LCSC) markers in established cell lines have shown a high degree of heterogeneity in expression patterns. Given the variability, it is unlikely that a single, universal LCSC marker for HCC exists. Many cell surface antigens have been identified in LCSCs including CD24, CD44, CD90, CD133, and the epithelial cell adhesion molecule (EpCAM; CD326).^1,2 

While HCC screening and diagnosis is dependent on imaging and serum alpha-fetoprotein (AFP) levels, their use is limited in some contexts, such as with disease recurrence and postoperative detection. Expression of progenitor stem cell markers may serve as alternative indicators of disease assessment and prognosis.

CD24 is associated with early-onset HCC and one mutation, P170T/T, is more common in patients with hepatitis B virus (HBV) than in those without infection. CD44 expression is associated with recurrence after local ablation therapy and metastasis. Tumors that co-express CD44 with CD90 and CD133 are more aggressive than tumors that express CD90 or CD133 alone. Similar to CD24, CD90 expression correlates with HBV-associated HCC and is linked to poor prognosis. In comparison with patients with CD133-negative tumors, patients with CD133-positive tumors have a shorter overall survival (OS) and higher recurrence rate. EpCam-positive, AFP-positive HCCs are associated with poor prognosis and a high metastatic rate.¹ 

The search for novel CSC markers in HCC is ongoing. The identification of a novel marker that can be easily detected by blood is especially of interest. In a recent study, transcription factor sex-determining region Y-box 9 (SOX9) was identified as a novel CSC marker in HCC, according to results published in Scientific Reports by Takayuki Kawai and colleagues3 from Kyoto University, Japan.

SOX9 plays a vital role in the development of many different tissues and organs, including the heart, lungs, testes, pancreas, and central nervous system. During development, SOX9 helps to keep cells in an undifferentiated state, and is regulated by various cell signaling pathways such as Wnt/beta-catenin, Notch, and transforming growth factor beta (TGFb)/Smad. As with many of the other LCSC markers, SOX9 expression is activated during organogenesis, but then normally switched off in adult hepatocytes. Kawai et al3 sought to determine whether aberrant SOX9 expression was an indicator of CSC in human HCC.

Using flow cytometry, investigators identified greater proportions of SOX9+ cells than SOX9- cells from multiple human HCC cell lines, including Huh7, HLF, PLC/PRF/5, and Hep3B. In Huh7 cells, those that expressed SOX9 demonstrated higher proliferative activity, colony formation, and sphere formation, which are all indicative of a tumorigenic phenotype. Additionally, these cells were more resistant to chemotherapy using 5-fluorouracil (5-FU), with resistance being a hallmark property of CSCs.

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Stemness is a term that was initially used to describe stem cell gene expression, but is now used to express characteristics shared by both embryonic and adult stem cells. Stemness is measured by a cell’s ability to form spheres in culture. Hypermalignant CSCs, or stemness-high CSCs, are highly tumorigenic and metastatic, and are resistant to conventional chemotherapy and radiation. These traditional treatment modalities have been shown to induce stemness genes in cancers, having the negative effective of converting stemness-low CSCs to stemness-high CSCs. Some hypothesize that this is a significant driving factor of relapse in HCC.9 Stemness-high CSCs have traditionally been difficult to target effectively due to increased DNA repair ability, overexpression of drug efflux pumps, and the activation of prosurvival and antiapoptotic signaling pathways.