Leptin as a potential therapeutic target for breast cancer prevention and treatment

Background: Hepatocellular carcinoma (HCC) develops most often in a background of chronic inflammatory liver injury from viral infection or alcohol use. Most HCCs are diagnosed at a stage at which surgical resection is not feasible. Even in patients receiving surgery rates of recurrence and metastasis remain high. There are few effective HCC therapies and hence a need for novel, rational approaches to treatment. Platelet derived growth factor receptor-α (PDGFR-α) is involved in tumor angiogenesis and maintenance of the tumor microenvironment and has been implicated in development and metastasis of HCC. Objective: To examine PDGFR-α as a target for therapy of HCC and explore opportunities and strategies for PDGFR-α inhibition. Methods: A review of relevant literature. Results/conclusions: Targeted inhibition of PDGFR-α is a rational strategy for prevention and therapy of HCC.     

Targeting angiogenesis in ovarian cancer

Results of standard chemotherapy in ovarian cancer are hampered by the development of drug resistance leading to disease recurrence. This prompted interest in the development of therapies targeting critical pathways responsible for tumor progression. Angiogenesis is a key process that enables ovarian cancer growth and metastasis in the peritoneal space. Its regulation relies on signaling mechanisms initiated by the vascular endothelial growth factor, the platelet-derived growth factor, the fibroblast growth factor, angiopoietins, and others. These pathways are not only important to the modulation of the tumor microenvironment and vasculature, but also control cancer cell proliferation and survival. In this review, we discuss preclinical evidence supporting the rationale for inhibiting these pathways and provide an overview for the clinical development of agents targeting them. Clinical trials evaluating such agents alone and in combination with chemotherapy are ongoing. Early clinical results position antiangiogenic therapy at the forefront of change to the standard treatment of difficult to treat ovarian cancer.     

PDGF-A, PDGF-B, TGFbeta, and bFGF mRNA levels in patients with essential thrombocythemia treated with anagrelide

Plasmatic levels of PDGF-AB, TGFbeta1, and bFGF are increased in patients with essential thrombocythemia (ET) while intraplatelet levels are low for PDGF, normal for TGFbeta, and elevated for bFGF. To evaluate the contribution of gene expression to the dysregulated cytokine levels, we studied platelet PDGF-A, PDGF-B, TGFbeta1, and bFGF mRNA in ET patients before and during anagrelide treatment. We found decreased PDGF-A and PDGF-B, increased TGFbeta1, and normal bFGF mRNA levels. During treatment, mRNA levels remained decreased for PDGF-A, were increased for PDGF-B and normal for TGFbeta1. In untreated patients, protein expression of PDGF paralleled its mRNA levels while different patterns of RNA and protein were found for TGFbeta1 and bFGF.     

Glycosaminoglycans and PDGF Signaling in Mesenchymal Cells

Platelet derived growth factor (PDGF) is involved in the autocrine growth stimulation of normal and malignant cells, the stimulation of angiogenesis, and the recruitment and regulation of tumor fibroblasts. PDGF has been shown to physically interact with glycosaminoglycans which are abundant in the extracellular microenvironment. The present review discusses the effects of glycosaminoglycans on the functions mediated by the PDGF on cells of mesenchymal origin. Recent studies have demonstrated that both soluble and surface bound glycosaminoglycan chains can modulate PDGF-BB isoform signaling depending on the cell type. These data demonstrated that the microenvironment rich in GAGs/PGs is able to significantly modify the cellular response to PDGF-BB signaling in a critical way for cell growth and differentiation.     

Ephrin-B2 controls PDGFRβ internalization and signaling

B-class ephrins, ligands for EphB receptor tyrosine kinases, are critical regulators of growth and patterning processes in many organs and species. In the endothelium of the developing vasculature, ephrin-B2 controls endothelial sprouting and proliferation, which has been linked to vascular endothelial growth factor (VEGF) receptor endocytosis and signaling. Ephrin-B2 also has essential roles in supporting mural cells (namely, pericytes and vascular smooth muscle cells [VSMCs]), but the underlying mechanism is not understood. Here, we show that ephrin-B2 controls platelet-derived growth factor receptor β (PDGFRβ) distribution in the VSMC plasma membrane, endocytosis, and signaling in a fashion that is highly distinct from its role in the endothelium. Absence of ephrin-B2 in cultured VSMCs led to the redistribution of PDGFRβ from caveolin-positive to clathrin-associated membrane fractions, enhanced PDGF-B-induced PDGFRβ internalization, and augmented downstream mitogen-activated protein (MAP) kinase and c-Jun N-terminal kinase (JNK) activation but impaired Tiam1–Rac1 signaling and proliferation. Accordingly, mutant mice lacking ephrin-B2 expression in vascular smooth muscle developed vessel wall defects and aortic aneurysms, which were associated with impaired Tiam1 expression and excessive activation of MAP kinase and JNK. Our results establish that ephrin-B2 is an important regulator of PDGFRβ endocytosis and thereby acts as a molecular switch controlling the downstream signaling activity of this receptor in mural cells.     

Clinicopathological features of acute megakaryoblastic leukaemia: Relationship between fibrosis and platelet‐derived growth factor

Acute megakaryoblastic leukaemia (AMGL) is an uncommon disease with poor prognosis. Histopathologically, AMGL cases show variable degree of fibrosis and the presence of uniform blasts or mature dysplastic megakaryocytes. Here we examined 18 cases of AMGL, including idiopathic (n = 9) and secondary (n = 9) cases. Fourteen cases were males and four were females, ranging in age from 14 to 87 years (median, 58). All cases had anaemia, but leukocyte and platelet counts varied. Blast cells were detected in the peripheral blood of 14 cases. Fourteen of 16 cases showed chromosomal abnormalities. The median survival was 6 months (range, 1–48 months). Survival rates did not correlate with the severity of fibrosis, proportion of blast cells and cause of AMGL. Nine of the 11 cases examined immunohistochemically were positive for platelet‐derived growth factor (PDGF)(‐BB), especially megakaryoblasts and a few fibroblasts. The PDGF‐positive cases showed various degrees of fibrosis, while the negative cases showed no evidence of fibrosis. Our results confirmed the poor prognosis of patients with AMGL, irrespective of the degrees of fibrosis, and demonstrated that PDGF could play an important role in the pathogenesis of marrow fibrosis.     

Early Contribution of Pericytes to Angiogenic Sprouting and Tube Formation

Immunostaining with endothelial and pericyte markers was used to evaluate the cellular composition of angiogenic sprouts in several types of tumors and in the developing retina. Confocal microscopy revealed that, in addition to conventional endothelial tubes heavily invested by pericytes, all tissues contained small populations of endothelium-free pericyte tubes in which nerve/glial antigen 2 (NG2) positive, platelet-derived growth factor beta (PDGF beta ) receptor-positive perivascular cells formed the lumen of the microvessel. Perfusion of tumor-bearing mice with FITC-dextran, followed by immunohistochemical staining of tumor vasculature, demonstrated direct apposition of pericytes to FITC-dextran in the lumen, confirming functional connection of the pericyte tube to the circulation. Transplantation of prostate and mammary tumor fragments into NG2-null mice led to the formation of tumor microvasculature that was invariably NG2-negative, demonstrating that pericytes associated with tumor microvessels are derived from the host rather than from the conversion of tumor cells to a pericyte phenotype. The existence of pericyte tubes reflects the early participation of pericytes in the process of angiogenic sprouting. The ability to study these precocious contributions of pericytes to neovascularization depends heavily on the use of NG2 and PDGF beta -receptor as reliable early markers for activated pericytes.