Abstract
Anti-angiogenic therapy of solid tumors has until now failed to produce the long lasting clinical benefits desired, possibly due to the complexity of the neoangiogenic process. Indeed, a prominent role is played by "vasculogenic" or "vascular" mimicry (VM), a phenomenon in which aggressive cancer cells form an alternative microvascular circulation, independently of endothelial cell angiogenesis. In this study we observed, in melanoma patient cell lines having vasculogenic/stem-cell like phenotype and in melanoma tumors, the syndecan-1 co-expression with VM markers, such as CD144 and VEGFR-2. We show that melanoma cells lose their ability to form tubule-like structures in vitro after blocking syndecan-1 activity by the specific human recombinant antibody, OC-46F2. Moreover, in a human melanoma xenograft model, the combined therapy using OC-46F2 and L19-IL2, an immunocytokine specific for the tumor angiogenic-associated B-fibronectin isoform(B-FN), led to a complete inhibition of tumor growth until day 90 from tumor implantation in 71% of treated mice, with statistically significant differences compared to groups treated with OC-46F2 or L19-IL2 as monotherapy. Furthermore, in the tumors recovered from mice treated with OC-46F2 either as monotherapy or in combination with L19-IL2, we observed a dramatic decrease of vascular density and loss of VM structures. These findings indicate for the first time a role of syndecan-1 in melanoma VM and that targeting syndecan-1, together with B-FN, could be promising in improving the treatment of metastatic melanoma.
Highlights
Building on the premise that blood vessels are essential for tumor growth and metastasis in all solid tumors, including melanoma, anti-angiogenic therapy was originally developed to “starve” primary and metastatic tumors by blocking blood vessel recruitment [1,2,3,4,5,6]
Characterization of human metastatic melanoma cells showing vasculogenic phenotype We tested melanoma cell lines SKMEL28, MV3 and melanoma cells isolated from ten patients, all positive for Syndecan-1, to form tubule-like structures on Matrigel
A higher rate of vascular” mimicry (VM) has been reported in melanoma patients with metastasis compared to patients with primary melanoma, indicating that VM is able to promote tumor metastasis [20, 36]
Summary
Building on the premise that blood vessels are essential for tumor growth and metastasis in all solid tumors, including melanoma, anti-angiogenic therapy was originally developed to “starve” primary and metastatic tumors by blocking blood vessel recruitment [1,2,3,4,5,6]. While anti-angiogenic drugs are effective at reducing angiogenesis, these therapies have not produced widespread or long lasting clinical benefits and have shown their limitations, due to many other mechanisms involved in tumor progression and regulated by the tumor microenvironment [3, 7,8,9]. It is known that in many malignant tumors, including metastatic melanoma, other forms of blood supply in tumor tissues exist in addition to angiogenesis. One of these mechanisms is “vasculogenic” or “vascular” mimicry (VM), in which cells of a highly aggressive malignant tumor can form vascular-like channels without implicating endothelial cells, thereby providing nutrients for tumor growth [19, 20]. Markers of VM may be important targets for this purpose [7,8,9, 20]
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