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Thymus and Angiogenesis Recent Advances in Angiogenesis and Antiangiogenesis, 2009 41 direct by vascular endothelium-derived factors or indirect, in the form of factors carried through the circulation [1]. Fig. (1). Architecture of the human postnatal thymus (H&E, x4). A rich network of epithelial cells is found throughout the cortex and medulla (Fig. 2) and based on their structure and functions there six different subtypes were described. These cells express mainly basal cytokeratin and were used to propose a histogenetic classification of thymoma [7]. Therefore, the thymus is unique not only in terms of its functions and dramatic changes during physiological involution but also in structure, because it is the only organ in the human body that has an epithelial stroma. Fig. (2). The network of epithelial cells (cytokeratin, high molecular weight, x400). Besides lymphocytes and epithelial cells, the medulla consists of a mixture of macrophages, antigenpresenting cells, mast cells, eosinophils (mainly in the interlobular septa in children), scattered myoid and neuroendocrine cells. The functions and behavior of all these cells that form the thymus parenchyma were largely investigated but for some of them, there are still uncertain aspects in human. The particular development and structure of the thymus is the base for some specific diseases, as developmental abnormalities with associated immunodeficiency, myasthenia gravis and tumors. A broad spectrum of tumors was described in the thymus. Among them, thymoma is the only specific neoplastic proliferation of the organ and consists of proliferating epithelial cells of the stroma. Thymomas are relatively rare tumors with the most elusive histological classification presently and unpredictable behavior. In all the normal and pathologic conditions of the thymus, angiogenesis was significantly less investigated than in other organs. Angiogenesis, the formation of new blood vessels from preexisting, seems to be directly involved in the development and involution of the normal thymus, and in different pathologic conditions. Moreover, the thymus can be considered as a source for proangiogenic molecules. Of particular interest, mainly in pathology, is the perivascular space (PVS), defined as the tissue found within the capsule but outside the thymic epithelial network [8]. PVS is a virtual space containing only blood vessels in the infant thymus. It becomes more prominent with aging and does not contain developing thymocytes [9]. High endothelial venules can be frequently identified in lymphocyte-rich PVS in both normal thymus and in patients with myasthenia gravis. The recirculation of peripheral lymphocytes was hypothesized through a MECA-79 and L-selectin dependent mechanism [9]. The formation of the blood and efferent lymphatic vessels of the thymus is largely unknown and few data are available about vasculogenesis and angiogenesis in the normal human thymus and its pathologic conditions. 2. BLOOD VESSELS Arteries of the thymus derive from the internal mammary, superior and inferior thyroid arteries and to a lesser degree the pericardiophrenic arteries [10]. Arterial branches enter the interlobular connective tissue and then in the parenchyma, near the corticomedullary junction. This is why on histological sections, the vessels with the largest lumen of the parenchyma are found at the corticomedullary junction (Fig. 3). On occasion, in the interlobular area can be found pillow arterioles that regulate the blood flow. Blood vessels of the parenchyma are surrounded by a sheath of connective tissue that gradually becomes thinner in small vessels [11]. Capillaries are found in both cortex and medulla. Capillaries of the cortex descend into the medulla and give rise to postcapillary venules and then interlobular veins. Finally, the venous system drains into the left brachiocephalic, internal thoracic and inferior thyroid veins [10]. Vascular endothelial growth factor (VEGF) secretion by thymic epithelial cells is required for normal vascular architecture of the thymus [12].
42 Recent Advances in Angiogenesis and Antiangiogenesis, 2009 Raica and Cimpean Fig. (3). Normal human thymus. Blood vessels with large lumen near the corticomedullary junction, x200. Immunoreaction for factor VIII. Endothelial cell (EC) markers: It is difficult to identify blood vessels in the thymus parenchyma on slides stained with haematoxylin-eosin because of the closely packed lymphocytes. In order to evaluate the microvasculature it is necessary to perform immunohistochemistry, using a specific EC marker. Factor VIII seems to be the most specific marker of the ECs in the normal and pathologic thymus (Fig. 4). Fig. (4). Involution of the normal human thymus, anti-factor VIII, x400. CD34 is highly sensitive but less specific. CD31, because of unknown reasons, shows only a weak expression in the interlobular vessels and almost does not stain intralobular blood vessels of the normal thymus (fetal and postnatal, including physiological involution). On the other hand, CD31 strongly stains blood vessels in thymoma, and therefore, it can be used to count vessels (Fig. 5). CD105 (endoglin) does not stain blood vessels of the fetal and postnatal thymus but becomes positive in scattered vessels in thymoma B3 and thymic carcinoma. Initially, CD105 Fig. (5). Thymoma, CD31 expression in ECs, x400. was thought to identify some tumor blood vessels with activated ECs. This is not completely true, because CD105-positive ECs may be found also in most mature vessels containing a relatively thick sheath of perivascular cells (Fig. 6). Therefore, CD105 should be used to identify activated ECs but not to perform microvessel density. Fig. (6). Mature blood vessels with ECs stained for CD105 (brown) and smooth muscle cell actin (red), x400. Microvessel density (MVD): MVD was introduced many years ago by Weidner et al [13] to evaluate tumor angiogenesis. There were accumulated many data that showed a correlation between MVD, invasion and lymph node and systemic metastasis in many human tumors [14]. On the other hand, MVD reflects the intercapillary distance and present data do not support the use of this parameter as predictor of the response to antiangiogenic therapy. Despite the large interest in this evaluation, few data are available about MVD in the normal counterpart of malignant tumors. In the normal fetal and postnatal thymus till puberty, on slides stained for factor VIII, we found an average of 21.4 blood vessels / x200. MVD significantly increases during thymus involution, and numerous large vessels can be seen at the interface between the remaining thymic tissue and surrounding fat. MVD
Page 2 and 3: Recent Advances in Angiogenesis and
Page 4 and 5: FOREWORD It has been known for a ve
Page 6 and 7: single proangiogenic protein. Howev
Page 8 and 9: v Vito Pistoia Head, Laboratory of
Page 10 and 11: 2 Recent Advances in Angiogenesis a
Page 12 and 13: 10 Recent Advances in Angiogenesis
Page 16 and 17: The Role of Mesenchymal Stem Cells
Page 32 and 33: Role of Thymidine Recent Advances i
Page 34 and 35: Role of Stromal Cells Recent Advanc
Page 40 and 41: Tumor Targeting with Transgenic End
Page 44 and 45: Tumor Vascular Disrupting Agents Re
Page 50 and 51: Tumour Vascular Disrupting Agents R
Page 52: Index Recent Advances in Angiogenes

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