012) lower compared with UT-SCC-34 xenografts. CA IX is considered as a promising endogenous hypoxia-related marker, and a significant but weak correlation has been reported between CA IX staining and the distribution of the exogenous hypoxic cell marker pimonidazole [22]. However, also, other microenvironmental factors, such as pH homeostasis, affect the expression of CA IX [23]. In a number of studies, CA IX has been shown to be associated with a poorer locoregional control, overall survival, and aggressive phenotype [24] and [25]
Our selleck products finding that [18F]EF5 uptake, in addition to hypoxia, also reflects an adverse phenotype is further supported by previous studies depicting a relationship between unlabeled EF5 binding and tumor aggressiveness [19] and [20]. We also found a higher, with a trend toward significance (P = .082), expression pattern of Hif-1α in UT-SCC-34 xenografts ( Figure 2 and Table 2) compared to UT-SCC-8, whereas the Hif-1α expression was significantly lower this website in UT-SCC-74A xenografts (P = .012). In other words, we did not observe any relationship between Hif-1α expression and the uptake of [18F]EF5
( Figure 1). Our results are in line with earlier studies reporting a limited, or nonexisting, colocalization of Hif-1α with pimonidazole [26] and [18F]FMISO ([18F]fluoromisonidazole) [27]. Vucovic et al. [28] described a significant correlation between Hif-1α expression and EF5 staining in cervical cancer xenografts. However, the percentages of Hif-1α–positive cells staining for EF5 and vice versa ranged between 10% to 20%, pointing to a rather low association between these two markers. Moreover, declines in Hif-1α levels and Hif-1 activity in the later phase of tumorigenesis have been reported by Lehmann et al. [27]. In comparison Nintedanib (BIBF 1120) to UT-SCC-8 xenografts, the uptake of [18F]FDG was also higher, although not statistically significantly, in UT-SCC-34 and UT-SCC-74A xenografts (Figure 1). This finding further supports our conclusion that the phenotype of UT-SCC-34 and UT-SCC-74A xenografts
is more aggressive. Membranous Glut-1 expression was detected in all three UT-SCC xenografts. The expression of Glut-1 did not relate to the uptake of [18F]FDG or [18F]EF5. The highest expression was seen in UT-SCC-8 and UT-SCC-34 xenografts, whereas the lowest expression was detected in UT-SCC-74A xenografts (Figure 2 and Table 2). Although tumors frequently overexpress Glut-1, the cellular uptake of [18F]FDG is not exclusively attributable to Glut-1 [16], which probably explains the previous contradictory studies on the relationship between Glut-1 and [18F]FDG. To further evaluate phenotype differences detected in the xenografts in vivo, we determined the uptake of [18F]EF5 and [18F]FDG in the cell lines in vitro. Cells were grown under normoxia and for 1, 3, 6, 12, and 24 hours of 1% of oxygen ( Figure 3 and Figure 4).