Here we show that the fate of osteolytic bone
metastasis depends on the balance among autophagy, anoikis resistance and ossification, and that the
hepatocyte growth factor (HGF) signaling pathway seems to have an important role in orchestrating bone colonization. These findings are consistent with the pathophysiology of bone
metastasis that is influenced by the cross-talk of supportive and neoplastic cells through molecular signaling networks. We adopted the strategy to target
metastasis and stroma with the use of adenovirally expressed NK4 (AdNK4) and
Dasatinib to block HGF/Met axis and Src activity. In human bone metastatic 1833 cells, HGF conferred anoikis resistance via Akt and Src activities and HIF-1α induction, leading to Bim
isoforms degradation. When Src and Met activities were inhibited with
Dasatinib, the Bim
isoforms accumulated conferring anoikis sensitivity. The proviability effect of HGF, under low-nutrient stress condition, was related to a faster autophagy deactivation with respect to HGF plus
Dasatinib. In the 1833 xenograft model, AdNK4 switched
metastasis vasculature to blood lacunae, increasing HIF-1α in
metastasis. The combination of AdNK4 plus
Dasatinib gave the most relevant results for mice survival, and the following molecular and cellular changes were found to be responsible. In bone
metastasis, we observed a hypoxic condition - marked by HIF-1α - and an autophagy failure - marked by p62 without
Beclin-1. Then, osteolytic bone
metastases were largely prevented, because of autophagy failure in
metastasis and ossification in bone marrow, with
osteocalcin deposition. The abnormal repair process was triggered by the dysfunctional autophagy/anoikis interplay. In conclusion, the concomitant blockade of HGF/Met axis and Src activity seemed to induce HIF-1α in
metastasis, whereas the bone marrow hypoxic response was reduced. As a consequence, anoikis resistance might be hampered favoring, instead, autophagy failure and neoformation of woven bone trabeculae. Mice survival was, therefore, prolonged by overcoming an escape strategy adopted by metastatic cells by disruption of
tumor-stroma coevolution, showing the importance of autophagy inhibition for the
therapy of bone
metastasis.