Platelet-derived growth factor (PDGF)–PDGF receptor interaction activates bone marrow–derived mesenchymal stromal cells derived from chronic lymphocytic leukemia: implications for an angiogenic switch

Abstract

IntroductionThe cancer microenvironment has been implicated as playing a critical role(s) in cancer initiation and progression. There are multiple cellular components present in cancer microenvironments, which in general include immune/inflammatory cells such as lymphocytes, monocytes/macrophages and neutrophils/mast cells, fibroblast-like cells such as cancer-associated fibroblasts, mesenchymal stromal cells (MSCs), and vascular cells such as endothelial cells, pericytes, and smooth muscle cells. 1 Chronic lymphocytic leukemia (CLL) has long been recognized as a cumulative disease resulting from a failure of apoptosis; however, recent evidence also points out that CLL is a dynamic disease of leukemic cell proliferation and circulation. 2,3 Indeed, proliferation centers in CLL have been identified in lymph nodes, bone marrow, and spleen. 4 In vitro experiments have demonstrated the importance of stromal cellular components including bone marrow stromal cells, 5,6 nurselike cells, 7 and T cells 8,9 in maintaining CLL cell survival and, to a lesser degree, leukemic cell proliferation. 9,10 However, the exact mechanism and nature of the interactions between diverse stromal cellular components and CLL leukemic cells remains to be clearly determined.MSCs comprise one cellular component in the cancer microenvironment, and these cells have recently been studied in terms of the immune regulatory function, cancer promoting function, and wound repair function in a variety of disease models. 11 We have established an in vitro culture system to generate bone marrow stromal cells and demonstrated that they are mesenchymal stem cell in nature. 10,12 When we examined the MSC-CLL B-cell interaction, we found active bidirectional crosstalk was present between the 2 cell types, and this crosstalk was able to activate both cell types. 10 This interaction was associated with both an increase in vascular endothelial growth factor (VEGF) and a decrease in thrombospondin-1 (TSP-1) expression, which taken together is representative of an angiogenic switch, 13 a phenomenon known to be associated with disease progression in malignancy. 13 Therefore, in our study, we were interested in defining the signals sent from leukemic cells to MSC and how these interactions modify MSC function. Our studies demonstrate that platelet-derived growth factor (PDGF), secreted by CLL cells, activated MSCs via its interaction with the PDGF receptor (PDGFR) present on the MSC membrane. This activation by PDGF was able to enhance MSC proliferation and induce AKT phosphorylation, which was necessary for MSC VEGF production. Methods Patient populationBlood and bone marrow biopsies were obtained from CLL patients who had provided written informed consent under a Mayo Clinic Institutional Review Board approved protocol in accordance with the Declaration of Helsinki. All CLL patients had a confirmed diagnosis using the National Cancer Institute Working Group definition. 14 Patients in this study cohort were from all Rai stages and had not been treated for at leas...

Sorafenib induces cell death in chronic lymphocytic leukemia by translational downregulation of Mcl-1

“…Recently, PDGF-induced production of VEGF production by stromal cells suggested a more indirect role of PDGF for the pathogenesis of CLL. 37 In contrast to stromal cells, by analyzing Erk1/2-mitogen-activated protein kinase activity in CLL cells we excluded that inhibition of a constitutive signal though the PDGFR by sorafenib contributed to its cytotoxicity ex vivo. Again, this does not exclude the possibility that in vivo inhibition of PDGF signalling by sorafenib could have some additional therapeutic effects.…”

Treatment of older patients with chronic lymphocytic leukemia: key questions and current answers

“…Inclusion of an alkylating agent appears to be important for patients with deletion 11q23. 68 Although associated with PFS, this cytogenetic defect does not appear to effect OS when these patients are treated with FCR-like platforms. 69 As outlined in the accompanying chapter in this publication by Gribben and Riches, 70 suitable young patients with del(17p13) in need of treatment should be debulked and proceed to reduced intensity allogeneic stem cell transplantation.…”

Targeting Angiogenesis in Cancer Therapy: Moving Beyond Vascular Endothelial Growth Factor

“…Furthermore, direct activation of PDGF signaling has been observed in multiple tumor types, and coexpression of PDGF and its receptor suggests a role for autocrine and paracrine activation [41]. Roles for aberrant PDGF signaling in tumor angiogenesis include pericyte recruitment to vessels; secretion of proangiogenic factors; stimulation of endothelial cell proliferation, migration, sprouting, and tube formation in tumors; and promotion of lymphangiogenesis and subsequent lymphatic metastasis [42][43][44][45]. The importance of PDGF signaling in tumor angiogenesis is further supported by several studies demonstrating that PDGFR inhibitors improve the antitumor efficacy of VEGFR blocking agents [46].…”