IL-3 affects endothelial cell-mediated smooth muscle cell recruitment by increasing TGF beta activity: potential role in tumor vessel stabilization.

Abstract

Interleukin-3 (IL-3) expression by tumor-infiltrating lymphocytes (TILs) and its effects on vessel assembly were evaluated. TILs from 'in situ' human breast cancers expressed CD4/CD25 antigens and IL-3. An injection of Matrigel containing SMC and IL-3 or basic-fibroblast growth factor (bFGF) into SCID mice confirmed the neoangiogenetic effect of both factors. However, in response to IL-3, but not to bFGF, only few SMC became incorporated into the nascent vessels. To evaluate the possibility that signals emanated by the nascent vasculature in the presence of IL-3 may negatively regulate SMC recruitment, conditioned media (CM) from IL-3-treated endothelial cells (EC) or SMC were tested for their biological effects on SMC and EC. CM from IL-3-treated SMC stimulated the migration of EC. In contrast, the migration of SMC was not affected by CM from IL-3-stimulated EC; however, it was greatly enhanced by blocking transforming growth factor beta (TGF beta) activity. TGF beta immunoenzymatic assay demonstrated the following: (i) the absence of TGF beta activity in CM from IL-3-stimulated EC; (ii) a barely detectable TGF beta activity in CM from IL-3-stimulated SMC; and (iii) the presence of TGF beta activity in the supernatants of SMC stimulated with CM from IL-3-, but not from bFGF-stimulated EC. Increased TGF beta mRNA expression was only detected in SMC stimulated with CM from IL-3-treated EC. Finally, the inhibitory signals induced by IL-3 in vivo were abrogated by the addition of the neutralizing TGF beta antibody. Thus, the positive immunostaining for IL-3 by TILs in 'in situ' breast cancers sustains the possibility that early in tumor development, IL-3 can contribute to the chronic immaturity of these vessels.

• Authors: Patrizia Dentelli, Arturo Rosso, Cristina Calvi, Bruno Ghiringhello, Giovanni Garbarino, Giovanni Camussi, Luigi Pegoraro, Maria Felice Brizzi
• Journal: Oncogene (Oncogene) Vol. 23 Issue 9 Pg. 1681-92 (Mar 04 2004) ISSN: 0950-9232 [Print] England
• PMID: 14755254 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Culture Media, Conditioned
• Drug Combinations
• Interleukin-3
• Laminin
• Mitogens
• Proteoglycans
• RNA, Messenger
• Transforming Growth Factor beta
• Vascular Endothelial Growth Factor A
• Fibroblast Growth Factor 2
• matrigel
• Collagen
• Matrix Metalloproteinase 2

Topics

• Animals
• Breast Neoplasms (blood supply, immunology)
• Cell Movement (drug effects)
• Cells, Cultured
• Collagen
• Culture Media, Conditioned (pharmacology)
• Drug Combinations
• Endothelial Cells (cytology, drug effects, physiology)
• Enzyme Activation (drug effects)
• Female
• Fibroblast Growth Factor 2 (pharmacology)
• Humans
• Interleukin-3 (metabolism, pharmacology)
• Laminin
• Lymphocytes (metabolism)
• Matrix Metalloproteinase 2 (metabolism)
• Mice
• Mice, SCID
• Mitogens (pharmacology)
• Models, Biological
• Muscle, Smooth, Vascular (cytology, drug effects, metabolism)
• Neovascularization, Pathologic
• Proteoglycans
• RNA, Messenger (genetics, metabolism)
• Transforming Growth Factor beta (antagonists & inhibitors, genetics, metabolism, pharmacology)
• Vascular Endothelial Growth Factor A (antagonists & inhibitors, biosynthesis, metabolism)