The angiostatic 16K human prolactin overcomes endothelial cell anergy and promotes leukocyte infiltration via nuclear factor-kappaB activation.
The 16-kDa N-terminal fragment of human prolactin (16K hPRL) is a potent angiostatic factor that inhibits tumor growth in mouse models. Using microarray experiments, we have dissected how the endothelial-cell genome responds to 16K hPRL treatment. We found 216 genes that show regulation by 16K hPRL, of which a large proportion turned out to be associated with the process of immunity. 16K hPRL induces expression of various chemokines and endothelial adhesion molecules. These expressions, under the control of nuclear factor-kappaB, result in an enhanced leukocyte-endothelial cell interaction. Furthermore, analysis of B16-F10 tumor tissues reveals a higher expression of adhesion molecules (intercellular adhesion molecule 1, vascular cell adhesion molecule 1, or E-selectin) in endothelial cells and a significantly higher number of infiltrated leukocytes within the tumor treated with 16K hPRL compared with the untreated ones. In conclusion, this study describes a new antitumor mechanism of 16K hPRL. Because cellular immunity against tumor cells is a crucial step in therapy, the discovery that treatment with 16K hPRL overcomes tumor-induced anergy may become important for therapeutic perspectives.
Tabruyn
Sébastien P
SP
Unit of Molecular Biology and Genetic Engineering. GIGA Research, GIGA, B34, University of Liege, Sart Tilman 4000, Belgium.
Sabatel
Céline
C
Nguyen
Ngoc-Quynh-Nhu
NQ
Verhaeghe
Catherine
C
Castermans
Karolien
K
Malvaux
Ludovic
L
Griffioen
Arjan W
AW
Martial
Joseph A
JA
Struman
Ingrid
I
D043165:Angiostatic Proteins / Q000494:pharmacology*; D000818:Animals; D002448:Cell Adhesion; D017635:Clonal Anergy / Q000187:drug effects* / Q000235:genetics; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000276:immunology; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D010446:Peptide Fragments / Q000494:pharmacology*; D011388:Prolactin / Q000494:pharmacology*; D012878:Skin Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology
D043165:Angiostatic Proteins; D016328:NF-kappa B; D010446:Peptide Fragments; C503760:prolactin 16-kDa fragment, human; D011388:Prolactin