Correlation of Expression of Cyclooxygenase-2, Vascular Endothelial Growth Factor, and Peroxisome Proliferator–Activated Receptor δ With Head and Neck Squamous Cell Carcinoma

Jaeckel, Elise C.; Raja, Subramani; Tan, Jian; Das, Sanjoy K.; Dey, Sudhansu K.; Girod, Douglas A.; Tsue, Terrance T.; Sanford, Thomas

doi:10.1001/archotol.127.10.1253

Cited by 74 publications

(57 citation statements)

References 31 publications

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“…It is unknown whether the same pathway acts in squamous cell carcinoma and what are the possible crossacts (if any) with the COX-2 mediated angiogenesis procedure, for the significance of which in head and neck squamous cell carcinoma, enough evidence exists. 10,11,27 In this study the most impressive finding was the strong association of the spontaneous overexpression of COX-2 and VEGF-C with the presence of lymph node metastases at the time of diagnosis. These results confirm the previous observations for each protein independently, and also suggest that a lymphangiogenic pathway, in which COX-2 overexpression stimulates VEGF-C upregulation and thus the formation of new lymphatic vessels, which is the first step for spreading and establishment of tumor cells to the regional lymph nodes, probably exists in head and neck squamous cell carcinoma.…”

Section: Discussionmentioning

confidence: 57%

COX-2 expression correlates with VEGF-C and lymph node metastases in patients with head and neck squamous cell carcinoma

2005

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Recent observations suggest an implication of the cyclooxygenase-2 (COX-2) in tumor lymphangiogenesis through an upregulation of vascular endothelial growth factor-C expression. It is unknown whether this mechanism also acts in squamous cell carcinoma of the head and neck region. We performed a retrospective study of 70 patients with head and neck squamous cell carcinoma in order to investigate whether COX-2 immunohistochemical expression correlates with vascular endothelial growth factor-C expression. We also examined the association of the expression of these molecules with clinicopathologic parameters (especially lymph node status) and outcome for these patients. We performed immunostaining on formalin-fixed, paraffinembedded tissue sections by the routine streptavidin-biotin peroxidase labeled procedure. Increased cyclooxygenase-2 expression was observed in 30 of the 68 tumor samples (44%), while high vascular endothelial growth factor-C expression occurred in 26 of the 68 tumor samples (38%). High expression of the two proteins was correlated with the presence of lymph node metastasis at the time of diagnosis, and the observed association was even stronger when there was overexpression for both the antibodies (Po0.001). High expression of vascular endothelial growth factor-C, but not of COX-2 was correlated with increased mortality in patients with oral-larynx squamous cell carcinoma. When multivariate Cox regression model was applied, the presence of lymph node metastasis at the time of diagnosis, combined with overexpression of both the antibodies, was the only independent prognostic factor for mortality of these patients. Our results suggest that a lymphangiogenic pathway, in which COX-2 overexpression stimulates vascular endothelial growth factor-C upregulation, probably exists in head and neck squamous cell carcinoma. Also, the predictive ability for mortality of regional lymph node metastasis can be improved with the combined evaluation of the immunohistochemical expression of these two proteins. Keywords: cyclooxygenase-2; head and neck cancer; lymphangiogenesis; metastasis; survival; vascular endothelial growth factor-C Clinical and pathological observations have shown that lymph node metastases at the time of diagnosis, is the most reliable prognostic factor for mortality or recurrence in patients with head and neck squamous cell carcinoma.

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Section: Discussionmentioning

confidence: 57%

COX-2 expression correlates with VEGF-C and lymph node metastases in patients with head and neck squamous cell carcinoma

2005

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“…PPAR␣ is now known to be expressed in colon tumors and overexpressed in human breast and prostate cancer (Collett et al 2000;Roberts-Thomson and Snyderwine 2000). The levels of PPAR␦ are also elevated in colon and head and neck carcinomas (Gupta et al 2000;Jaeckel et al 2001). Absence of PPAR␦ reduces tumor growth, and this PPAR may itself be a target of Wnt signaling (He et al 1999;Park et al 2001).…”

Section: Discussionmentioning

confidence: 99%

PPARγ signaling exacerbates mammary gland tumor development

Sáez¹,

Rosenfeld²,

Livolsi³

et al. 2004

Genes Dev.

173

148

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Breast cancer cell lines that express the nuclear peroxisome proliferator-activated receptor ␥ (PPAR␥) can be prompted to undergo growth arrest and differentiation when treated with synthetic PPAR␥ ligands. To evaluate the therapeutic potential of increased PPAR␥ signaling in vivo, we generated transgenic mice that express a constitutively active form of PPAR␥ in mammary gland. These mice are indistinguishable from their wild-type littermates. However, when bred to a transgenic strain prone to mammary gland cancer, bigenic animals develop tumors with greatly accelerated kinetics. Surprisingly, in spite of their more malignant nature, bigenic tumors are more secretory and differentiated. The molecular basis of this tumor-promoting effect may be an increase in Wnt signaling, as ligand activation of PPAR␥ potentiates Wnt function in an in vivo model of this pathway. These results suggest that once an initiating event has taken place, increased PPAR␥ signaling serves as a tumor promoter in the mammary gland. Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily, ligand-responsive transcription factors that participate in many important physiological processes . Mammals have three different PPARs (PPAR␣, PPAR␦, PPAR␥) that form functional heterodimers with the retinoid receptor RXR. These complexes are chief regulators of lipid storage and catabolism. Native and oxidized polyunsaturated fatty acids bind the PPARs and stimulate their transcriptional activity. The function of the PPARs is also modulated by arachidonic acid derivatives, such as prostaglandins and eicosanoids.PPAR␥ is the best-characterized member of the family. Its most prominent role is to regulate differentiation of cell types with active lipid metabolism, such as adipocytes and macrophage foam cells Walczak and Tontonoz 2002). The importance of this receptor in lipid homeostasis and energy balance is accentuated by the widespread use of thiazolidinediones (TZDs), synthetic PPAR␥ ligands, as antidiabetic drugs. The existence of FDA-approved PPAR␥ agonists and the ability of this receptor to induce cellular differentiation encouraged us to explore whether stimulation of PPAR␥ activity could curtail malignant cell growth, in analogy with what is observed with retinoic acid in acute promyelocytic leukemia.A survey of tumors revealed that PPAR␥ is generally overexpressed in liposarcoma, colon, breast, and prostate carcinoma (Tontonoz et al. 1997;DuBois et al. 1998). When treated with PPAR␥ and RXR ligands, cell lines derived from these neoplasms undergo morphological transformation and growth arrest in vitro (Tontonoz et al. 1997;Elstner et al. 1998;Kubota et al. 1998;Mueller et al. 1998;Sarraf et al. 1998). Additional cell culture studies have suggested that lung, pancreatic, and hematopoietic tumor cells also respond to thiazolidinedione treatment (Sporn et al. 2001). These observations prompted trials to evaluate PPAR␥ agonists as therapeutics in human liposarcoma, colon, breast, and prostate cancer...

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“…VEGF can stimulate endothelial cell proliferation and prevents apoptosis in the endothelial cells of newly formed vessels [22] . VEGF has been identified as one of the potential targets of PPARδ in colorectal cancer (CRC) cells [13] . We hypothesized that curcumin can decrease the expression of VEGF.…”

Section: C B Amentioning

confidence: 99%

“…PPARδ can directly bind to PPAR response elements located between -1426 and -1477 of the 14-3-3ε promoter region, thereby activating 14-3-3ε promoter activity and protein expression [10] . PPARδ can also regulate the expression of vascular endothelial growth factor (VEGF), which can promote colon tumor epithelial cell survival [12,13] .…”

Section: Introductionmentioning

confidence: 99%

Curcumin suppresses PPARδ expression and related genes in HT-29 cells

Wang¹,

Li²,

Zheng³

et al. 2009

WJG

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AIM:To investigate the effects of curcumin on the expression of peroxisome proliferator-activated receptorδ (PPARδ) and related genes in HT-29 cells. METHODS:HT-29 cells were treated with curcumin (0-80 μmol/L) for 24 h. The effects of curcumin on the morphology of HT-29 cells were studied by Hoechst 33342 staining. The activity of caspase-3 was determined using DEVD-p NA as substrate. The levels of peroxisome PPARδ, 14-3-3ε and vascular endothelial growth factor (VEGF) in HT-29 cells were determined by Western blotting analysis and their mRNA expression was determined by real-time quantitative RT-PCR. RESULTS:Treatment with 10-80 μmol/L curcumin induced typical features of apoptosis and activated the caspase-3 in HT-29 cells. The expression of PPARδ, 14-3-3ε and VEGF was reduced and the activity of β-catenin/Tcf-4 signaling was inhibited by curcumin treatment. CONCLUSION:Curcumin can induce apoptosis of HT-29 cells and down-regulate the expression of PPARδ, 14-3-3ε and VEGF in HT-29.

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Correlation of Expression of Cyclooxygenase-2, Vascular Endothelial Growth Factor, and Peroxisome Proliferator–Activated Receptor δ With Head and Neck Squamous Cell Carcinoma

Cited by 74 publications

References 31 publications

COX-2 expression correlates with VEGF-C and lymph node metastases in patients with head and neck squamous cell carcinoma

COX-2 expression correlates with VEGF-C and lymph node metastases in patients with head and neck squamous cell carcinoma

PPARγ signaling exacerbates mammary gland tumor development

Curcumin suppresses PPARδ expression and related genes in HT-29 cells

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