Have you seen? Sox2, a marker for stem-like tumor cells in skin squamous cell carcinoma and hedgehog subgroup medulloblastoma

T here are several sources of tumor heterogeneity which include clonal evolution, heterogeneity in the microenvironment, and the hierarchical organization of certain cancers whereby highly tumorigenic cancer stem cells differentiate into less tumorigenic progeny (Meacham & Morrison, 2013). Employing genetic fatemapping and limited dilution transplantation analyses, two studies independently discovered Sox2 as a cancer stem-cell marker in medulloblastoma and squamous-cell carcinoma, respectively (Vanner et al, 2014; Boumahdi et al, 2014). In the first study, Peter Dirks and colleagues perform elegant lineage tracing experiments to demonstrate the role of rare, relatively quiescent, Sox2 tumor cells in propagating a murine model of sonic hedgehog subgroup medulloblastoma (MB) in primary tumors and allografts. In the second study, Cedric Blanpain and colleagues unravel the role of Sox2 in both tumor initiation and tumor maintenance in murine models of skin squamous-cell carcinoma (SCC) and also provide evidence that Sox2 is a driver of stemness. While both cancer models display a hierarchical organization reminiscent of the normal tissue from which they arise, there are some notable differences between the two hierarchies (Fig 1). The hierarchy presented by Dirks and colleagues is steep with a rare population of slow-cycling Sox2 cancer stem cells (comprising 5% of tumor population) giving rise to rapidly proliferating doublecortin progenitor cells (comprising 60% of tumor population), which subsequently differentiate to shortlived postmitotic NeuN cells (comprising 30% of the tumor population). By contrast, the Sox2 cancer stem cell population of skin SCC is larger accounting for approximately 25% of tumor epithelial cells. Furthermore, this population in skin SCC is not slow cycling as evident by the increasing percentage of Sox2 cells with each round of transplantation (80% after the second transplantation). These results suggest that the hierarchical organization of each cancer resembles the normal tissue homeostasis from which it arises. Importantly, both hierarchies are preserved in limiting dilution transplantation assays. A related concept to the hierarchical growth of some cancers is the reversible plasticity of cancer cells. The cancer stem cell hypothesis predicts that the conversion of highly tumorigenic cancer stem cell to non-stem cell progeny is irreversible. However, there is mounting evidence in several cancers such as colon cancer, glioblastoma, and melanoma that the conversion of cancer stem cells to differentiated progeny is reversible (Charles et al, 2010; Roesch et al, 2010; Schwitalla et al, 2013; Suva et al, 2014). This has been demonstrated in melanoma with JARID1B as a cancer stem cell marker, in the perivascular niche of gliomas with nitric oxide promoting stem cell character, and in colon cancer where inflammation triggers dedifferentiation of non-stem cells to stem cells. Blanpain and colleagues provide further evidence in support of reversible plasticity between cancer stem cells and their differentiated progeny by demonstrating that SOX2 GFP tumor epithelial cells can give rise to tumors that contain both SOX2 GFP and SOX2 GFP tumor epithelial cells. Thus, the conversion between cancer stem cells and their non-stem cell progeny appears reversible in skin SCC. Dirks and colleagues also observe that Sox2 GFP tumor cells can form tumors in transplantation assays. It would be interesting to know whether such tumors also contain Sox2 GFP cells. Nonetheless, lineage tracing from differentiated cell types will be required to definitively evaluate the plasticity between Sox2 and Sox2 tumor populations in the two tumor types and determine whether these tumor subtypes follow the cancer stem cell model. While there are numerous cancer stem cell markers, very few of them have been demonstrated to promote stemness. Examples of cancer stem cell markers that primarily mark stemness include cell surface