alpha(2)-Adrenoceptors Enhance Cell Proliferation and Mammary Tumor Growth Acting Through both the Stroma and the Tumor Cells

作者：Bruzzone A; Perez Pinero C; Rojas P; Romanato M; Gass H; Lanari C; Luethy I A

来源：Current Cancer Drug Targets, 2011, 11(6): 763-774.

• Clonidine
• rauwolscine
• adrenoceptors
• mammary tumor
• carcinoma-associated fibroblasts
• breast cancer

We have previously described enhanced human breast cancer cell proliferation and mouse mammary tumor growth induced by alpha(2)-adrenergic agonists, associated with alpha(2)-adrenoceptor (alpha(2)-AR) expression in epithelial cells. The aim of the present work was to assess if stromal fibroblasts can contribute to this effect.
alpha(2)-AR expression was assessed by immunocytochemistry and immunohistochemistry, cell proliferation by [H-3]-Thymidine incorporation and tumor growth by measuring with caliper.
All tested mouse and human fibroblasts expressed at least two alpha(2)-AR subtypes and alpha(2)-adrenergic agonists enhanced fibroblast proliferation. In vivo, the alpha(2)-adrenergic agonist clonidine significantly enhanced tumor growth. The alpha(2)-adrenergic antagonist rauwolscine reversed this effect, but when administered alone, significantly inhibited tumor growth. Clonidine significantly stimulated cell proliferation in the epithelial-enriched fraction, the cancer associated fibroblast-enriched fraction and the co-culture of both fractions in primary cultures from both tumors (IBH-4 and IBH-6). Rauwolscine reversed clonidine stimulation in every fraction. However, when incubated alone, the inhibitory effect was observed in fractions from IBH-4 tumors but not from IBH-6 tumors.
These experiments show that fibroblasts from tumor stroma are also influenced by alpha(2)-adrenergic compounds through the alpha(2)-ARs expressed in these cells. Moreover, the alpha(2)-adrenergic antagonist rauwolscine could eventually block in both epithelial and stromal cells, the mitogenic effect of catecholamines released during stress, providing a potential additional treatment for breast cancer patients. Chemists synthesizing adrenergic compounds should consider their action in breast cancer patients.

• 出版日期2011-7