Active detachment involves inhibition of cell-matrix contacts of malignant melanoma cells by secretion of melanoma inhibitory activity.
Melanoma inhibitory activity (MIA) has been identified as a small protein secreted from malignant melanoma cells. Recent results revealed a direct interaction of MIA and epitopes within extracellular matrix proteins including fibronectin. The aim of this study was to analyze functional consequences mediated by this interaction. Here we show that MIA interferes specifically with attachment of melanoma cells to fibronectin, a phenomenon we refer to as active detachment. Antibodies inhibiting binding of alpha4beta1 and alpha5beta1 integrins to fibronectin cross-react specifically with MIA, suggesting that MIA shares significant structural homology with the binding pockets of these integrins and thereby masks the respective epitopes on extracellular matrix molecules. Several peptides derived from fibronectin and from a phage display screening were tested with respect to a potential MIA-inhibitory effect. In vitro tests identified two peptides affecting MIA function; both inhibited growth of melanoma metastases in vivo. In summary, we conclude that MIA may play a role in tumor progression and spread of malignant melanomas via mediating active detachment of cells from extracellular matrix molecules within their local milieu. Further, our results suggest that inhibiting MIA functions in vivo may provide a novel therapeutic strategy for metastatic melanoma disease.
Bosserhoff
Anja-Katrin
AK
Institute of Pathology, University of Regensburg, Regensburg, Germany. anja.bosserhoff@klinik.uni-regensburg.de
Stoll
Raphael
R
Sleeman
Jonathan P
JP
Bataille
Frauke
F
Buettner
Reinhard
R
Holak
Tad A
TA
D000595:Amino Acid Sequence; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor / Q000187:drug effects; D003429:Cross Reactions; D016326:Extracellular Matrix Proteins; D005353:Fibronectins / Q000378:metabolism*; D006801:Humans; D039041:Integrin alpha4beta1 / Q000378:metabolism; D039081:Integrin alpha5beta1 / Q000378:metabolism; D008544:Melanocytes / Q000187:drug effects / Q000378:metabolism*; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000556:secondary; D010446:Peptide Fragments / Q000627:therapeutic use
D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D039041:Integrin alpha4beta1; D039081:Integrin alpha5beta1; C090059:MIA protein, human; C513263:Mia protein, mouse; D009363:Neoplasm Proteins; D010446:Peptide Fragments