Imatinib tackles lymphoma via the PDGFRβ+ pericyte

JP Chute, HA Himburg - Blood, The Journal of the American …, 2013 - ashpublications.org
JP Chute, HA Himburg
Blood, The Journal of the American Society of Hematology, 2013ashpublications.org
Second, how does imatinib-mediated disruption of pericytes cause such profound vascular
disruption and lymphoma regression? In this study, imatinib-mediated inhibition of PDGFRb
signaling in vascular smooth muscle cells caused a significant reduction in activation of
PDGFRb, PDGFRa, and c-kit, as well as the downstream effectors Akt and mitogenactivated
protein kinase. Furthermore, imatinib treatment blunted vascular smooth muscle cell
expression and secretion of VEGF and transforming growth factor b, which are both …
Second, how does imatinib-mediated disruption of pericytes cause such profound vascular disruption and lymphoma regression? In this study, imatinib-mediated inhibition of PDGFRb signaling in vascular smooth muscle cells caused a significant reduction in activation of PDGFRb, PDGFRa, and c-kit, as well as the downstream effectors Akt and mitogenactivated protein kinase. Furthermore, imatinib treatment blunted vascular smooth muscle cell expression and secretion of VEGF and transforming growth factor b, which are both important in maintaining the survival, proliferation, and integrity of vascular ECs. 6, 7 The latter findings provide the basis for understanding mechanistically how imatinib-mediated disruption of PDGFRb 1 pericytes can cause such profound antiangiogenic effects in the absence of direct targeting of endothelium. It is worth noting in this study that treatment of mice with 2C5, an anti-PDGFRb–specific antibody, caused substantial depletion of NG2 1 pericytes in human lymphomas in vivo but more modest effects on tumor vascular density and tumor growth in vivo compared with imatinib. This may be explained by the persistence of perivascular CD68 1 myeloid cells in anti-PDGFRb–treated lymphomas, which were otherwise depleted in response to imatinib. The authors postulate that CD68 1 perivascular myeloid cells may serve as surrogates to maintain vascular integrity in tumors in the face of targeted depletion of pericytes. As pointed out by the authors, the stronger antilymphoma effects of imatinib compared with the anti-PDGFRb antibody may reflect the activity of imatinib against a wider range of stromal cell targets, including PDGFRa 1 fibroblasts and c-fms1 myelomonocytic cells, as well as via inhibition of c-kit signaling in pericytes. Taken together, this study provides proof of principle that administration of a TKI can mediate antiangiogenesis in a human lymphoma model via inhibition of PDGFRb 1 pericyte function. Importantly, this approach resulted in significant inhibition of human lymphoma growth in vivo. These interesting results provide the basis for more refined consideration of antiangiogenesis as a strategy to attack human lymphomas in the clinic. In that regard, it is also encouraging that the authors observed a differential toxicity of imatinib therapy against the lymphoma vasculature, whereas the vasculatures of organs not involved with lymphoma were not affected. It has been suggested that one reason anti-VEGF therapy has not succeeded in the treatment of patients with lymphoma is that other proangiogenic mechanisms were not disabled via this approach. 4 Targeting the PDGFRb 1 pericyte, which regulates multiple pathways involved in the maintenance and proliferation of vascular ECs, represents an attractive strategy to dismantle the lymphoma vasculature and, perhaps, the lymphoma itself.
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