Norepinephrine Up-regulates the Expression of Vascular Endothelial Growth Factor, Matrix Metalloproteinase (MMP)-2, and MMP-9 in Nasopharyngeal Carcinoma Tumor Cells

Abstract

Recent studies using ovarian cancer cells have shown that the catecholamine hormones norepinephrine (norepi) and epinephrine (epi) may influence cancer progression by modulating the expression of matrix metalloproteinases (MMP) and vascular endothelial growth factor (VEGF). The purpose of this study is to determine if the stress hormone norepi can influence the expression of MMP-2, MMP-9, and VEGF in nasopharyngeal carcinoma (NPC) tumors by using three NPC tumor cell lines. The NPC cell lines HONE-1, HNE-1, and CNE-1 were treated with norepi. The effects of norepi on MMP-2, MMP-9, and VEGF synthesis were measured by ELISA; functional MMP activity was measured by the invasive potential of the cells using a membrane invasion culture system whereas functional activity of VEGF was analyzed using a human umbilical vein endothelial cell tube formation assay. Norepi treatment increased MMP-2, MMP-9, and VEGF levels in culture supernatants of HONE-1 cells, which could be inhibited by the B-blocker propranolol. Norepi induced the invasiveness of all NPC cell lines in a dose-dependent manner, which was blocked by CMT-3, an MMP inhibitor, and propranolol. Norepi stimulated the release of functional angiogenic VEGF by HONE-1 cells as well. Finally, HONE-1 cells were shown to express B-adrenergic receptors as did seven of seven NPC biopsies examined. The data suggest that catecholamine hormones produced by the sympatheticadrenal medullary axis may affect NPC tumor progression, in part, through modulation of key angiogenic cytokines.

Is norepinephrine an etiological factor in some types of cancer?

“…1), rather than ionotropic receptors that directly gate ion channels in cellular membranes. 9 G proteins can affect various processes inside the cell, such as the level of cyclic AMP, and in doing so might influence carcinogenesis in complicated ways [60][61][62][63] that could have various time courses. A simple time course is that while a high level of NE is excessively stimulating its receptors on a cell, this increases the probability of immediately developing cancer within that cell; however, epidemiological drug studies suggest that there may be a significant delay, perhaps of many years.…”

“…These drugs may also help treat existing cancers since some cancerous cells have functional adrenoceptors. [60][61][62][63]74,80 As described earlier, reducing the activation of some adrenoceptor subtypes by lowering the level of NE or via a or b blocking drugs may actually increase carcinogenesis rather than decrease it, 79 and this may vary for different organs. And when examining whether NE drugs affect cancer rates, it is not only important to compare people who are taking these drugs for a condition such as hypertension with healthy control subjects (some of whom may be taking these drugs), but also with hypertensive people taking classes of drugs that do not affect the NE system.…”

Depression, social support, and beta-adrenergic transcription control in human ovarian cancer

“…Many solid epithelial tumors express receptors for neuroendocrine mediators from the sympathetic nervous system (SNS) (the catecholamines, epinephrine and norepinephrine) (Mitra and Carraway 1999;Lutgendorf, Cole et al 2003;Nagmani, Pasco et al 2003;Palm, Lang et al 2006;Thaker, Han et al 2006;Ramos-Jimenez, Soria-Jasso et al 2007;Sastry, Karpova et al 2007) or the hypothalamus-pituitary-adrenal (HPA) axis (the glucocorticoid, cortisol) (Wu, Chaudhuri et al 2004). Analyses carried out in vitro and in mouse xenograft models have shown that neuroendocrine receptors regulate several biological processes involved in cancer metastasis and disease progression, including angiogenesis (Lutgendorf, Cole et al 2003;Thaker, Han et al 2006), tissue invasion (Sood, Bhatty et al 2006;Yang, Sood et al 2006), cell motility (Palm, Lang et al 2006), and programmed cell death (Wu, Chaudhuri et al 2004;Sastry, Karpova et al 2007). Analyses of mouse xenograft models also show that experimentally imposed behavioral stress can increase the growth and metastatic activity of implanted human carcinoma cells via direct neuroendocrine regulation of tumor cell biology (Thaker, Han et al 2006).…”

“…For example, catecholamines can enhance the expression of several genes involved in angiogenesis (e.g., VEGF, IL6) and tissue invasion (MMP2, MMP9) in ovarian and asopharyngeal carcinoma cells (Lutgendorf, Cole et al 2003;Sood, Bhatty et al 2006;Yang, Sood et al 2006;Nilsson, Armaiz-Pena et al 2007). These effects are mediated by betaadrenergic receptors, and subsequent activation of the cyclic 3′,5′-adenosine monophosphate / protein kinase A (cAMP/ PKA) signaling pathway.…”

β-adrenoceptors are upregulated in human melanoma and their activation releases pro-tumorigenic cytokines and metalloproteases in melanoma cell lines

“…[3][4][5][6][7][8] Moreover, some stress neurotransmitters, such as norepinephrine (NE) and epinephrine (E), have been demonstrated to contribute to the regulation of tumour cell invasion, at least in part through b-AR activation. 6,7,9 Interactions between tumour cells and soluble factors originated from the nervous system has recently been proposed to favour metastasis formation. 10 Improved survival rates have been demonstrated in mice with metastatic tumour by combined administration of b-AR antagonists.…”