title: Hypoxia-induced nitric oxide release by luminal cells stimulates proliferation and uPA secretion of myoepithelial cells in a bicellular murine mammary tumor.
abstract: BACKGROUND
  LM38 murine mammary adenocarcinoma model is formed by LM38-LP (myoepithelial 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.
  
  
  OBJECTIVE
  To study the role of nitric oxide (NO) as one of the mediators of functional interactions between malignant luminal and myoepithelial cells.
  
  
  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 1400 W. On the other side, NO was not detectable in LM38-D2 cells either in basal or in 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 (500 μM) was able to increase uPA secretion and in vitro growth of LM38-D2. In agreement, 1400 W 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.
authors: Área Investigación, Instituto de Oncología "Ángel H Roffo", Av. San Martín 5481, C1417DTB, Buenos Aires, Argentina, mkrasnapolski@gmail.com.
authors: Martin Alejandro
authors: MA
authors: Krasnapolski
authors: Catalina
authors: C
authors: Lodillinsky
authors: Elisa
authors: E
authors: Bal De Kier Joffé
authors: Ana María
authors: AM
authors: Eiján
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology*; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D000860:Hypoxia / Q000473:pathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D014568:Urokinase-Type Plasminogen Activator