Recent Advances in Angiogenesis and ... - Bentham Science

40 Recent Advances in Angiogenesis and Antiangiogenesis, 2009, 40-53
Thymus and Angiogenesis
Marius Raica and Anca Maria Cimpean
Domenico Ribatti (Ed.)
All rights reserved - © 2009 Bentham Science Publishers Ltd.
CHAPTER 5
Department of Histology and Molecular Pathology, “Victor Babes” University of Medicine and Pharmacy, 2
Eftimie Murgu Square, Tmisoara, 300041, Romania
Address correspondence to: Dr. Marius Raica, Department of Histology and Molecular Pathology, “Victor
Babes” University of Medicine and Pharmacy, 2 Eftimie Murgu Square, Tmisoara, 300041, Romania; Tel: 004-
0256204476; E-mail: raica@umft.ro
1. INTRODUCTION
Abstract: Thymus plays a key role in the development of the immune system of the organism
and vasculature seems to be involved in some steps of its development. Few data are available
about vasculogenesis/angiogenesis in the thymus in normal and pathological conditions, despite
the architecture of the vascular tree being relatively well known. There are some particular
models of expression of endothelial cell (EC) markers in the thymus. In normal conditions,
CD31 and CD105 are less expressed, opposite to CD34 and factor VIII that stain almost all
vessels. The aspect is different in thymoma, where both CD31 and CD105 stain intratumoral
blood vessels. Microvessel density significantly increases from normal thymus to thymic
involution, myasthenia gravis and thymoma. In the tumor area, most of the vessels are
immature or intermediate, and their number and type correlate with progression of thymoma.
Proliferative ECs, defined by the co-expression of CD34 and Ki67, were found in high number
mainly in high-grade advanced-stage thymoma. Progenitor ECs were not found in the prenatal
and normal postnatal thymus, but isolated ECs that co-express AC133 and Tie2 were found in
high grade thymoma. Besides ECs and perivascular cells, mast cells seem to be involved in
thymus angiogenesis. A strong correlation was found between mast cell number and MVD.
Few data are available about the expression of angiogenic factors and their receptors in the
thymus. Vascular endothelial growth factor (VEGF) is expressed by epithelial cells of the
normal thymus and overexpressed by tumor cells in thymoma B3 and thymic carcinoma. The
expression of VEGF correlates with the presence of immature blood vessels and Masaoka
clinical stage. VEGF receptors 1 and 2 are also expressed in normal and tumoral thymus. A
divergent expression of VEGFR1 and 2 is found during thymoma progression. Other growth
factors, like fibroblast growth factor and platelet derived growth factor and their receptors may
contribute to angiogenesis in the thymus as they are expressed with different patterns in normal
and pathological conditions. Lymphatic vessels seem to be better developed than previously
thought, and they were also found in the thymic medulla. On the other hand, D2-40/podoplanin
stains a subset of stromal epithelial cells and the corresponding thymoma. Thymus is not only a
site for angiogenesis, but also a source for angiogenic factors. From these, it was shown that
thymosins are involved not only in thymus but also in systemic angiogenesis.
The thymus is a unique organ in the human body that
initiates and maintains the normal functioning immune
system. Since its development from the endoderm of
the third pharyngeal pouch [1] till the late postnatal
life, the thymus suffers some significant changes that
are globally referred to as physiological involution or
atrophy. These changes are more evident after puberty,
and after 20-25 years, the general microscopic aspect
maybe described as atrophy. An initial depletion in
lymphocytes and changes in the arrangement of
epithelial cells characterize this process [2].
The general microscopic appearance of the postnatal
thymus is characterized by the parenchyma with
cortex, containing densely packed lymphocytes, and
medulla with less lymphocytes and more
heterogeneous cell population (Fig. 1). In the medulla
reside the typical structures of the thymus known as
Hassall’s bodies that consist of epithelial cells and
scattered S100 positive cells. Hassall’s corpuscles are
not residual structures because it was demonstrated
that epithelial cells secrete thymic stromal
lymphopoietin that is crucial for B and T lymphocytes
development in the medulla [3, 4]. Interestingly, the
thymus medulla seems to arise as a series of clonal
islets that aggregate as the thymus matures [5]. The
close association of the adult medullary compartment
with the vasculature could indicate that blood vessels
may have a role in the initial organization of the
mature medulla. Medullary epithelium was associated
with intermediate size blood vessels, but not with
capillaries or large vessels [6]. This effect might be