Hypoxia-induced Nitric Oxide release by luminal cells stimulates proliferation and uPA secretion of myoepithelial cells in a bicellular murine mammary tumor

KRASNAPOLSKI MARTIN ALEJANDRO, ; LODILLINSKY CATALINA, ; BAL DE KIER JOFFE ELISA ; EIJAN ANA MARIA

JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY

SPRINGER

Lugar: New York; Año: 2015 vol. 141 p. 1727 - 1738

0171-5216

LM38 murine mammary adenocarcinoma model, is formed by LM38-LP (myoephitelial and luminal), LM38-HP (luminal) and LM38-D2 (myoepithelial) cell lines. In a previous work we had shown that LM38-HP and LM38-D2 cell lines are less malignant than the bicellular LM38-LP cell line. Purpose: to study the role of nitric oxide (NO) as one of the mediators of functional interactions between malignant luminal and myoepithelial cells. Methods and results: using immunohistochemistry, in vivo iNOS expression was only detected in the luminal cells of bicellular LM38-LP and most cells of LM38-HP tumors. In cobalt-induced pseudohypoxia, LM38-LP and LM38-HP cell lines significantly increased HIF-1α and iNOS expression (western blotting) and therefore, NO production (Griess method). This increase was inhibited by the iNOS inhibitor 1400W. On the other side, NO was not detectable in LM38-D2 cells either in basal or pseudohypoxia. In addition, pseudohypoxia increased urokinase-type Plasminogen Activator (uPA) secretion by LM38-LP and LM38-HP cells and migration in the LM38-LP cell line, without modulating these properties in LM38-D2 cells (radial caseinolysis). The NO donor DETA/NONOate (500μM) was able to increase uPA secretion and in vitro growth of LM38-D2. In agreement, 1400W prevented in vivo growth of the myoepithelial LM38-D2 cells. Conclusions: hypoxia leads to an enhanced NO production by the luminal component, through HIF-1α and iNOS, which can stimulate myoepithelial cell proliferation and uPA secretion. In these new conditions, myoepithelial cells might act as an invasive forefront generating gaps that could help luminal cells to escape from the primary tumor.