Increased angiogenesis in primary myelofibrosis: latent transforming growth factor-β as a possible angiogenic factor

Abstract

ObjectiveThe aim of this work was to demonstrate a possible relationship between anti-latency-associated peptide human latent transforming growth factor beta 1 (latent TGF-β1) expression in megakaryocytes and microvascular density in bone marrow biopsies from patients with essential thrombocythemia and primary myelofibrosis.MethodsMicrovascular density was evaluated by immunohistochemical analysis and the expression of latent TGF-β1 in samples (100 megakaryocytes per bone marrow sample) from 18 essential thrombocythemia and 38 primary myelofibrosis (19 prefibrotic and 19 fibrotic) patients. Six bone marrow donor biopsies were used as controls. Fibrosis in the bone marrow biopsies was evaluated according to the European Consensus.ResultsThe average fibrosis grade differed between essential thrombocythemia and primary myelofibrosis groups when compared to the control group. Latent TGF-β1 expression differed significantly between the fibrotic primary myelofibrosis (PMF) group and the control group (p-value < 0.01). A high degree of neo-angiogenesis (demonstrated by analysis of CD34 expression) was detected in patients with myelofibrosis. There were correlations between latent TGF-β1 expression and microvascular density (r = 0.45; p-value < 0.0009) and between degree of microvascular density and fibrosis grade (r = 0.80; p-value < 0.0001). Remarkable differences for neo-angiogenesis were not observed between patients with essential thrombocythemia and controls.ConclusionAngiogenesis participates in the pathogenesis of primary myelofibrosis, in both the prefibrotic and fibrotic stages, while latent TGF-β is differentially expressed only in the prefibrotic stage.

Efficacy of ALK5 inhibition in myelofibrosis

“…TGF-β is a well-established fibrotic cytokine that plays a vital role in the pathophysiology of MF as well as other fibrotic diseases (15,17,(19)(20)(21)(37)(38)(39)(40)(41)(42). Elevated levels of the TGF-β1 isoform were detected in plasma and bone marrow serum in MF mouse models.…”

“…Among the abnormally expressed cytokines in MF, TGF-β1 has received attention due to its critical role in inducing fibrosis not only in bone marrow (15)(16)(17)(18), but other organs (19)(20)(21). TGF-β1 may be produced by abnormal megakaryocytes or monocytes, and this in turn may remodel the MSCs that promote the changes illustrated by MF (22)(23)(24)(25).…”

Genes Involved in Maintaining the Bone Marrow Stroma Are Dysregulated in Patients with Myelofibrosis: Lenalidomide Treatment Upregulates SOCS3

“…Finally, the up-regulation of COX2, an enzyme involved in the formation of prostaglandins, which are key mediators of inflammation and angiogenesis (among other functions), is consistent with the increased inflammation and angiogenesis seen in BM in primary MF. 5,10,12 In T-cells from BM in multiple myeloma, lenalidomide has been shown to decrease SOCS1 expression. 4 How lenalidomide increases SOCS3 expression in primary MF is therefore not…”

Efeito de SMADs e de microRNAs na expressão gênica de TGF-β1 e seu papel na angiogênese em pacientes com mielofibrose e trombocitemia essencial

“…A análise das imunoexpressões de TGF-b1 ativo e TGF-β1 latente foram realizadas conforme método previamente descrito (Ponce et al, 2012;Ponce et al, 2014). Foram empregadas IgG policlonal de coelho anti-TGF-b1 ativo humano (Santa Cruz Biotech; SC-146) e IgG policlonal de cabra anti-peptídeo associado à latência (LAP) humana para TGF-β1 latente (R&D Systems; AF-246-NA).…”

“…Não foi possível observar diferenças nas imunoexpressões de TGF-b1 ativo e TGF-β1 latente, c-MPL e CD34 entre os grupos de pacientes desse estudo, embora Panteli et al (2004) tenha demonstrado que a angiogênese é mais intensa em pacientes com MF do que na TE. Além disso, foi demonstrada correlação entre TGF-β1 latente e a expressão de CD34 na medula óssea de pacientes com MFP e TE, enquanto o TGF-β1 latente apresenta tendência a ser mais expresso em ambos os grupos, embora seja diferencialmente expresso em relação aos controles somente no estágio pré-fibrótico da MFP (Ponce et al, 2014). Essas diferenças podem não ter sido encontradas devido ao número limitado de medulas incluídas em cada grupo desse estudo, portanto, não se pode descartar o papel dessas proteínas nas NMPs.…”