PMC:3730145 / 17892-21178 JSONTXT

{"project":"2_test","denotations":[{"id":"23970998-15746043-82904846","span":{"begin":313,"end":315},"obj":"15746043"},{"id":"23970998-23106467-82904847","span":{"begin":625,"end":627},"obj":"23106467"},{"id":"23970998-18289304-82904848","span":{"begin":854,"end":856},"obj":"18289304"},{"id":"23970998-12196922-82904849","span":{"begin":1218,"end":1220},"obj":"12196922"},{"id":"23970998-15461861-82904850","span":{"begin":1222,"end":1224},"obj":"15461861"},{"id":"23970998-12949405-82904851","span":{"begin":1321,"end":1323},"obj":"12949405"},{"id":"23970998-15872381-82904852","span":{"begin":1625,"end":1627},"obj":"15872381"},{"id":"23970998-21962280-82904853","span":{"begin":1866,"end":1868},"obj":"21962280"},{"id":"23970998-10735894-82904854","span":{"begin":2271,"end":2273},"obj":"10735894"},{"id":"23970998-22782219-82904855","span":{"begin":2459,"end":2461},"obj":"22782219"},{"id":"23970998-18715602-82904856","span":{"begin":2670,"end":2672},"obj":"18715602"},{"id":"23970998-20609206-82904857","span":{"begin":2674,"end":2676},"obj":"20609206"},{"id":"23970998-15133168-82904858","span":{"begin":2779,"end":2781},"obj":"15133168"},{"id":"23970998-8920221-82904859","span":{"begin":2783,"end":2785},"obj":"8920221"},{"id":"23970998-15172638-82904860","span":{"begin":3063,"end":3065},"obj":"15172638"},{"id":"23970998-21569196-82904861","span":{"begin":3149,"end":3151},"obj":"21569196"},{"id":"23970998-23106467-82904862","span":{"begin":3282,"end":3284},"obj":"23106467"},{"id":"T57376","span":{"begin":313,"end":315},"obj":"15746043"},{"id":"T90070","span":{"begin":625,"end":627},"obj":"23106467"},{"id":"T18300","span":{"begin":854,"end":856},"obj":"18289304"},{"id":"T87965","span":{"begin":1218,"end":1220},"obj":"12196922"},{"id":"T49611","span":{"begin":1222,"end":1224},"obj":"15461861"},{"id":"T4400","span":{"begin":1321,"end":1323},"obj":"12949405"},{"id":"T71429","span":{"begin":1625,"end":1627},"obj":"15872381"},{"id":"T10360","span":{"begin":1866,"end":1868},"obj":"21962280"},{"id":"T4686","span":{"begin":2271,"end":2273},"obj":"10735894"},{"id":"T94158","span":{"begin":2459,"end":2461},"obj":"22782219"},{"id":"T85274","span":{"begin":2670,"end":2672},"obj":"18715602"},{"id":"T69021","span":{"begin":2674,"end":2676},"obj":"20609206"},{"id":"T55161","span":{"begin":2779,"end":2781},"obj":"15133168"},{"id":"T58919","span":{"begin":2783,"end":2785},"obj":"8920221"},{"id":"T58387","span":{"begin":3063,"end":3065},"obj":"15172638"},{"id":"T85994","span":{"begin":3149,"end":3151},"obj":"21569196"},{"id":"T91734","span":{"begin":3282,"end":3284},"obj":"23106467"}],"text":"2.4.2. Molecular Markers of Proliferation and Angiogenesis\nHNSCC is characterized by tumor-associated angiogenesis, with elevations in the proangiogenic cytokine vascular endothelial growth factor (VEGF) and increased microvessel density (MVD) scores correlated with clinical stage and an overall poor prognosis [51]. In FOSCC, MVD is significantly higher in tumor samples (50.3 ± 23.6), compared with normal feline gingiva (7.6 ± 4.06) with tumor-associated vessels exhibiting morphologic atypia and a thin endothelial lining [52]. There may also be anatomic variability with tongue tumors reported to have the highest MVD [47]. In cats clinically affected with FOSCC, treatment with zoledronate, an aminobisphosphonate used for skeletal malignancies that has putative antiangiogenic properties, rapidly decreases circulating serum VEGF concentrations [16].\nProstaglandins and cyclooxygenase-2 (COX-2) play a critical role in tumor development and growth by regulating numerous biologic processes including tumor angiogenesis. More than 77% of HNSCC express high levels of COX-2 and COX-2 overexpression and higher prostaglandin E2 (PGE2) levels are associated with poor survival and correlated with VEGF expression [53, 54]. In FOSCC, COX-2 expression is variable, with up to 67% of tumors exhibiting COX-2 expression [55–57]. However, COX-2 expression is not reported to be correlated with survival [57]. Although the significance of this is unclear, functional COX-2 enzymatic activity is reported to be dissociated from relative IHC-based COX-2 protein expression in some cell lines including the FOSCC cell line SCCF1 [58]. In HNSCC, lipoxygenase is also overexpressed, and similarly in FOSCC tissue samples there is high-intensity staining of lipoxygenase. Additionally, in vitro, the 5-lipoxygenase inhibitor tepoxalin induces apoptosis in feline SCC cells [59]. \nThe tumor suppressor gene p53 is often dysregulated in cancer, with loss of functional p53 protein contributing to disease progression via aberrant cell cycle checkpoint control and regulation of apoptosis. p53 gene mutation associated with allelic loss at 17p is one of the most common genetic abnormalities in HNSCC, and p53 status is an independent predictive factor of response to chemotherapy [60]. In HNSCC HPV-negative tumors, which have a worse overall survival, often have mutated p53, while the HPV-positive HNSCCs have both a better overall survival as well as wild-type p53 [38]. In addition, HPV-positive tumors tend to occur in younger people compared with HPV-negative HNSCC which commonly affects older patients. Similarly, most FOSCCs occur in geriatric cats and are HPV-negative [39, 40]. Aberrant p53 expression has been documented in FOSCC and is associated with tobacco smoke exposure [44, 61]. \nKi67 and mitotic index (MI) are markers of proliferation commonly assessed in tumor biopsy samples. Ki67 is a nuclear protein not expressed in senescent cells (G0). In HNSCC, Ki67 expression is related to aberrant p53 expression and is associated with a poor prognosis [62, 63]. In FOSCC, high expression of Ki67 is associated with decreased overall survival [48]. In another study, both Ki 67 and mitotic index exhibited wide variation among tumors, with no correlation between MI and Ki 67 [47]."}