Tumor blood vessels play an important role in tumor progression and metastasis.,It has been reported that tumor endothelial cells (TECs) exhibit highly angiogenic phenotypes compared with those of normal endothelial cells (NECs).,TECs show higher proliferative and migratory abilities than those NECs, together with upregulation of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2).,Furthermore, compared with NECs, stem cell markers such as Sca-1, CD90, and multidrug resistance 1 are upregulated in TECs, suggesting that stem-like cells exist in tumor blood vessels.,In this study, to reveal the biological role of stem-like TECs, we analyzed expression of the stem cell marker aldehyde dehydrogenase (ALDH) in TECs and characterized ALDHhigh TECs.,TECs and NECs were isolated from melanoma-xenografted nude mice and normal dermis, respectively.,ALDH mRNA expression and activity were higher in TECs than those in NECs.,Next, ALDHhigh/low TECs were isolated by fluorescence-activated cell sorting to compare their characteristics.,Compared with ALDHlow TECs, ALDHhigh TECs formed more tubes on Matrigel-coated plates and sustained the tubular networks longer.,Furthermore, VEGFR2 expression was higher in ALDHhigh TECs than that in ALDHlow TECs.,In addition, ALDH was expressed in the tumor blood vessels of in vivo mouse models of melanoma and oral carcinoma, but not in normal blood vessels.,These findings indicate that ALDHhigh TECs exhibit an angiogenic phenotype.,Stem-like TECs may have an essential role in tumor angiogenesis.
A fundamental problem in cancer research is identifying the cell type that is capable of sustaining neoplastic growth and its origin from normal tissue cells.,Recent investigations of a variety of tumor types have shown that phenotypically identifiable and isolable subfractions of cells possess the tumor-forming ability.,In the present paper, using two lineage-related human melanoma cell lines, primary melanoma line IGR39 and its metastatic derivative line IGR37, two main observations are reported.,The first one is the first phenotypic evidence to support the origin of melanoma cancer stem cells (CSCs) from mutated tissue-specific stem cells; and the second one is the identification of a more aggressive subpopulation of CSCs in melanoma that are CXCR6+.,We defined CXCR6 as a new biomarker for tissue-specific stem cell asymmetric self-renewal.,Thus, the relationship between melanoma formation and ABCG2 and CXCR6 expression was investigated.,Consistent with their non-metastatic character, unsorted IGR39 cells formed significantly smaller tumors than unsorted IGR37 cells.,In addition, ABCG2+ cells produced tumors that had a 2-fold greater mass than tumors produced by unsorted cells or ABCG2- cells.,CXCR6+ cells produced more aggressive tumors.,CXCR6 identifies a more discrete subpopulation of cultured human melanoma cells with a more aggressive MCSC phenotype than cells selected on the basis of the ABCG2+ phenotype alone.,The association of a more aggressive tumor phenotype with asymmetric self-renewal phenotype reveals a previously unrecognized aspect of tumor cell physiology.,Namely, the retention of some tissue-specific stem cell attributes, like the ability to asymmetrically self-renew, impacts the natural history of human tumor development.,Knowledge of this new aspect of tumor development and progression may provide new targets for cancer prevention and treatment.