PMC:3730145 / 15860-22894
Annnotations
{"target":"http://pubannotation.org/docs/sourcedb/PMC/sourceid/3730145","sourcedb":"PMC","sourceid":"3730145","source_url":"https://www.ncbi.nlm.nih.gov/pmc/3730145","text":"2.4. Comparative Molecular Aspects: HNSCC and FOSCC\n\n2.4.1. Epidermal Growth Factor Receptor\nThe epidermal growth factor receptor (EGFR) signaling pathway has been implicated in the oncogenesis of HNSCC. Epidermal growth factor receptor is a transmembrane receptor tyrosine kinase that controls cellular pathways crucial in cancer development, growth, invasion, metastasis, and angiogenesis. Up to 90% of HNSCC exhibit overexpression of EGFR, which is prognostic for overall survival and disease-free interval [37, 45]. EGFR-targeted therapies have been explored, with blocking of EGFR resulting in inhibition of cell proliferation, enhancement of apoptosis, and reduction in the metastatic and angiogenic potential of HNSCC. In addition, monoclonal antibodies (e.g., cetuximab) have been investigated in clinical HNSCC patients with modest results [37]. \nIn cats with FOSCC, EGFR is similarly highly expressed (69%–100%) [46–48]. The significance of EGFR tumor expression is unclear, with two studies demonstrating either high or low EGFR scores associated with better survival [47, 48]. Limitations in comparison of these studies as well as comparison to human studies include the retrospective nature, small sample size, variability in patient treatment, and variability in method of EGFR scoring and cellular localization. In vitro in feline cells, EGFR has been associated with proliferation and migration [49]. A population of putative cancer stem cells with enhanced sphere-forming ability, reduced sensitivity to radiation and conventional chemotherapy, and demonstrated resistance to gefitinib (EGFR-targeting drug) has also been demonstrated in FOSCC [50]. Gefitinib results in reduced cell proliferation and migration as well as a change in cell morphology and gene expression suggestive of epithelial to mesenchymal transition [49, 50]. EGFR-targeting with RNAi resulted in reduction in EGFR activity, reversal of acquired gefitinib resistance, and an additive effect on cell killing when combined with radiation [49].\n\n2.4.2. 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].\n\n2.4.3. Malignant Osteolysis\nBoth HNSCC and FOSCC are highly invasive into surrounding soft tissue structures and frequently characterized by malignant osteolysis of underlying bone. Bone-invasion contributes to clinical morbidity and poorer prognosis for HNSCC patients. In both species, in vitro and in vivo bone resorption and osteoclastogenesis are associated with high levels of parathyroid hormone-related protein (PTHrP) [15, 24]. PTHrP is known to stimulate osteoclastic bone resorption by increasing the expression of RANKL in osteoblasts. RANKL expression results in differentiation and activation of osteoclasts, ultimately resulting in bone resorption. SCC cells (murine, human, and feline) also express increased receptor activator of nuclear factor kappa-B ligand (RANKL) or an altered RANKL:OPG (osteoprotegerin) ratio [15, 52]. Osteoprotegerin is a decoy receptor for the receptor activator of nuclear factor kappa B ligand (RANKL); binding of RANKL by OPG inhibits nuclear kappa B (NF-κB) downstream signaling. In feline SCC cells, the aminobisphosphonate zoledronate, clinically used in people to inhibit malignant osteolysis, induces a dose-dependent reduction in RANKL expression [16, 52]. In a murine xenograft (feline SCC cells), zoledronate treatment reduced tumor growth and prevented osteolysis [64]. Serum carboxy-terminal collagen crosslink (CTx) is a useful marker of bone resorption and turnover in clinical patients with skeletal malignancies. Cats with naturally occurring bone-invasive SCC have greater serum CTx concentrations in comparison with geriatric, healthy controls and in FOSCC-affected cats treatment with zoledronate rapidly decreased circulating serum CTx levels 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