Details

Autor(en) / Beteiligte

• Aghi, Manish K
• Jahangiri, Arman
• Mascharak, Smita
• De Lay, Michael

Titel

A C-MET-s1 INTEGRIN COMPLEX DRIVES INVASIVE RESISTANCE TO ANTI-ANGIOGENIC THERAPY

Ist Teil von

• Neuro-oncology (Charlottesville, Va.), 2014-07, Vol.16 (suppl 3), p.iii31-iii32

Erscheinungsjahr

2014

Quelle

Oxford Journals 2020 Medicine

Beschreibungen/Notizen

• BACKGROUND: Anti-angiogenic therapies like bevacizumab are promising for cancer, but acquired resistance, which often includes increased invasiveness, can limit their utility. We investigated mediators of this invasive resistance using a large archive of bevacizumab-resistant glioblastoma (BRG) tissue and by developing novel xenograft models of anti-angiogenic therapy resistance. METHODS: Microarray analysis, immunostaining, immunoprecipitation, and proximity ligation assays (PLAs) were used to define mediators of invasive anti-angiogenic therapy resistance. RESULTS: Microarray analysis and immunostaining revealed increased hypoxia and reactive-oxygen species (ROS), along with upregulated s1 integrin and receptor tyrosine kinase c-Met, in BRGs compared to pre-treatment (P < 0.005). An siRNA screen and western blot revealed upregulation of AP-1 (P < 0.01), an ROS-activated transcription factor, in BRGs and BRG-derived xenografts with siRNA targeting AP-1 components reducing s1 integrin and c-Met expression in BRG-derived cells. Immunoprecipitation and PLA revealed formation of a c-Met-s1 integrin complex involving s1 heterodimer partners alpha5 and alphaV integrins, with the formation of this complex increased in culture by hypoxia, a feature of anti-angiogenic therapy resistance, and prolonged bevacizumab treatment in vivo. Cross-activation occurred in this complex, with c-Met activation by HGF increasing cell adhesion to fibronectin and fibronectin leading to c-Met phosphorylation. We also found that increasing VEGF concentration suppressed formation of the c-Met-s1 integrin complex (P < 0.05). We developed U87-BevR, a novel xenograft model of acquired bevacizumab resistance through serial multi-generational treatment of U87MG xenografts. U87-BevR exhibited upregulated c-Met and s1 integrin upon development of resistance. Treating U87-BevR with s1 or c-Met inhibitors transiently suppressed invasive growth and reduced c-Met-s1 complex formation. Use of 3- and 10-fold less bevacizumab to treat xenografts led to less initial efficacy but in a more durable fashion associated with less c-Met-s1 integrin complex formation (P < 0.05). CONCLUSIONS: Invasive resistance limits the efficacy of anti-angiogenic therapy. We demonstrated increased activity of s1 integrin and c-Met in BRGs and the formation of a c-Met-s1 complex. The combination of chemotactic c-Met and haptotactic s1 integrin endows BRG cells with their tremendous invasive capacity. The formation of this complex is promoted by two parallel mechanisms-increased transcription of each individual factor driven by hypoxia-induced ROS leading to AP-1 activation and relief of VEGF suppression of the formation of the complex. One option to prevent the formation of a c-Met-s1 complex and thereby counteract the evolution of therapeutic resistance is dose reduction, which may be associated with lesser, but more durable responses, suggesting that, with anti-angiogenic therapy, "less is more." SECONDARY CATEGORY: Preclinical Experimental Therapeutics.