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Divergent Impact of Osteopontin Isoforms on Lung Cancer Angiogenesis
Justin D. Blasberg, Jessica S. Donington, Chandra M. Goparaju, Harvey I. Pass; New York University Medical Center, New York, NY
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Objective: Osteopontin (OPN) is a multifunctional phosphoprotein with a significant role in the pathogenesis of many solid tumors including non-small cell lung cancer (NSCLC). NSCLC cell lines which express OPN have greater metastatic potential, but the molecular pathways for OPN tumorigenicity and the role of the three human isoforms (OPNa, OPNb, and OPNc) are incompletely understood. Increased angiogenesis is essential for tumor growth and metastasis. We hypothesize that the individual OPN isoforms play a divergent role in determining the angiogenic potential of NSCLC.
Methods: Using RT-PCR primers for the three OPN isoforms, we examined OPN expression in nine lung cancer cell lines and correlated expression with OPN secretion detected by ELISA of culture media. The angiogenic impact of the individual OPN isoforms were evaluated by transfecting cDNA plasmids specific to each isoform and empty vector controls into NSCLC cell lines. Conditioned media was compared on a bovine capillary endothelial cell (BCE) platform measuring tubule length, and by ELISA of VEGF concentrations.
Results: OPNa mRNA expression correlated with OPN secretion in the experimental cell lines (r=0.912, p=0.0006). OPNa transfection into NCI-H153, a NSCLC cell line with no native OPN expression, resulted in a significant increase in BCE tubule length (1597u) compared to empty vector controls (719u, p<0.0001). OPNb had a similar effect (861u, p<0.00001). OPNc however resulted in a significant decrease in tubule length compared to controls (582u, p<0.0001).(Fig) The inhibitory effect of OPNc was validated in NCI-H460 and A549, NSCLC cell lines with high endogenous OPNa expression. OPNc overexpression decreased tubule length 55% in NCI-H460 (1558u vs 704u, p<0.0001), and 37% in A549 (1707 vs 1070u, p<0.0003) compared to controls. OPNc overexpression also resulted in a significant decrease in VEGF secretion (ug/ml) in all cell lines compared to controls. In A549, VEGF concentration decreased from 2341 to 347 (p<0.016), in NCI-H460 from 4506 to 2847 (p<0.008), and in NCI-H153 from 17923 to 13885 (p<0.007). OPNa and OPNb overexpression had no significant impact on VEGF secretion. (Fig)
Conclusion: In an in vitro angiogenesis assay we have demonstrated divergent impact of individual OPN isoforms. OPNa and OPNb increase BCE tubule formation, while OPNc reduces tubule length and VEGF secretion. This data may lead to therapeutic strategies which selectively inhibit OPN isoforms to potentially alter the metastatic potential of NSCLC.


Figure: Impact of individual osteopontin isoforms on BCE tubule length and VEGF concentration.
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