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

Ponce, Cesar Cilento; Chauffaille, Maria de Lourdes Lopes Ferrari; Ihara, Silvia Saiuli Miki; Silva, Maria Regina Regis

doi:10.1016/j.bjhh.2014.07.010

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Revista Brasileira de Hematologia e Hemoterapia

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Original Articles • Rev. Bras. Hematol. Hemoter. 36 (5) • Sep-Oct 2014 • https://doi.org/10.1016/j.bjhh.2014.07.010 copy

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

Authorship SCIMAGO INSTITUTIONS RANKINGS

Objective:

The 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.

Methods:

Microvascular 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.

Results:

The 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.

Conclusion:

Angiogenesis 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.

Angiogenesis inducing agents; Primary myelofibrosis; Transforming growth factor beta; Antigens, CD34; Fibrosis

A Positivity (%)	B Intensity
0 Negative (0–10)	0 – negative
1 Slight (11–25)	1 – weak
2 Intermediate (26–50)	2 – moderate
3 Extensive (over 50)	3 – strong

		Control n = 6	ET n = 18	Prefibrotic PMF n = 19	Fibrotic PMF n = 19
Latent TGF-β1 positivity – n (%)
	Negative	–	–	–	–
	Discrete	1 (16.67)	–	–	–
	Intermediate	1 (16.67)	2 (11.11)	2 (10.52)	1 (5.27)
	Extensive	4 (66.67)	16 (88.89)	17 (89.48)	18 (94.73)
Latent TGF-β1 intensity – n (%)
	Negative	–	–	–	–
	Weak	6 (100.00)	8 (44.44)	4 (21.05)	6 (31.58)
	Moderate	–	5 (27.78)	3 (15.79)	8 (42.11)
	Strong	–	5 (27.78)	12 (63.16)	5 (26.31)
Latent TGF-β1 score – n (%)
	Zero	–	–	–	–
	One	1 (16.67)	–	–	–
	Two	1 (16.67)	2 (11.11)	2 (10.52)	1 (5.27)
	Three	4 (66.67)	6 (33.33)	2 (10.52)	5 (26.31)
	Six	–	5 (27.78)	3 (15.79)	8 (42.11)
	Nine	–	5 (27.78)	12 (63.16)	5 (26.31)
Latent TGF-β1 score mean (±SD)		2.50 (±0.83)^a a p-value < 0.01.	5.39 (±2.70)	7.15 (±2.71)^a a p-value < 0.01.	5.79 (±2.41)
Fibrosis grade – n (%)
	Zero	5 (83.33)	–	–	–
	One	1 (16.67)	12 (66.67)	1 (5.27)	–
	Two	–	5 (27.78)	16 (84.21)	–
	Three	–	1 (5.55)	2 (10.52)	19 (100.00)
Fibrosis grade mean (±SD)		0.17 (±0.40)^a a p-value < 0.01.	1.39 (±0.60)^a a p-value < 0.01.	2.05 (±0.40)^a a p-value < 0.01.	3.00 (±0.00)^a a p-value < 0.01.

		Control n = 5	ET n = 14	Prefibrotic PMF n = 18	Fibrotic PMF n = 14
Microvessel grade – n (%)
	One	5 (100.00)	1 (7.14)	–	–
	Two	–	12 (85.72)	6 (33.33)	–
	Three	–	1 (7.14)	7 (38.89)	5 (35.71)
	Four	–	–	5 (27.78)	9 (64.29)
Microvessel grade Mean (±SD)		1.00 (±0.00)^a a p-value < 0.05.	2.00 (±0.39)^a a p-value < 0.05.	2.94 (±0.80)^a a p-value < 0.05.	3.64 (±0.49)^a a p-value < 0.05.
Microvessel density Mean (±SD)		0.72 (±0.17)^a a p-value < 0.05.	2.42 (±0.69)^a a p-value < 0.05.	6.46 (±3.53)^a a p-value < 0.05.	8.78 (±1.94)^a a p-value < 0.05.

Associação Brasileira de Hematologia e Hemoterapia e Terapia Celular R. Dr. Diogo de Faria, 775 cj 114, 04037-002 São Paulo/SP/Brasil, Tel. (55 11) 2369-7767/2338-6764 - São Paulo - SP - Brazil
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[1] *Corresponding author at: Universidade Federal de São Paulo, Campus São Paulo, Av. Vicente de Carvalho, 65, apto 72, Gonzaga, 11045-501 Santos, SP, Brazil. E-mail address: cesarcponce@gmail.com (C.C. Ponce).