Our study is the first

report on TRP-2 expression in over 200 melanomas and melanoma cell cultures. According to our data TRP-2 negative cells are considered an aggressive subpopulation, which has a survival benefit and which is highly proliferative. Interestingly, this TRP-2 negative/Mib-1 positive subpopulation is significantly associated with Breslow tumor thickness. Furthermore, patients with more than 15 percent of TRP-2 negative/Mib-1 positive cells in their primary melanoma, approached significance for Seliciclib in vitro a less favourable tumor specific survival. The course of their disease was more aggressive with earlier development of metastases and death (Figure 1E). Remarkably, the presence of the TRP-2 negative/Mib-1 positive subpopulation is significantly hypoxia related. TRP-2 and other genes involved in the pigment production pathway, including selleck inhibitor Melan A, are transcriptional targets of the transcription factor microphthalmia-associated transcription factor (MITF). Hoek et al. and others have developed a model of tumor progression, in which melanoma cells are switching between two cell phenotypes of proliferation and invasion. MITF and many of its target genes, including TRP-2, were shown to be downregulated in the dedifferentiated invasive phenotype cells compared to the more melanocytic proliferative

phenotype cells. Our experiments show below a clear downregulation by TRP-2 by hypoxia, supporting recent studies which show that hypoxia, through Hif-1α is leading to a downregulation of melanocytic markers like MITF and its targets and therefore causing a dedifferentiation of the melanoma cells with increased invasive potential [24] and [25]. Hypoxia plays an important role in the differentiation process of cells [26] and [27] as well as in tumor progression [28].

Therefore, our finding in melanoma that the TRP-2 negative/Mib-1 positive cells are hypoxia related is of relevance as this indicates that this subpopulation of cells would not be targeted by vaccination. Several chemotherapies target hypoxic cells and moreover hypoxic specific therapies have been developed (ie TH302) [29]. In the field of tumor immunology, a successful strategy implies polyvalent immunization and synergistic combination of chemotherapies and vaccination. Taken together our results demonstrate TRP-2 as a good differentiation marker highlighting the importance to combine TRP-2 vaccination with other strategies targeting the aggressive undifferentiated hypoxia related subpopulation. We are grateful to N. Wey for photographic reproductions. “
“Oral cancer, which includes cancers of the lips, tongue, cheeks, floor of the mouth, hard and soft palate, sinuses, and pharynx (throat), is the sixth most common cancer nationally and the third most prevalent cancer in developing countries [1], [2] and [3].