Mini-reviewThe structure of the vascular network of tumors
Introduction
Tumor blood vessels are irregular in size, shape, and branching pattern, lack the normal hierarchy and do not display the recognizable features of arterioles, capillaries or venules. Their haphazard branching patterns and larger, less regular diameters contribute to the non-uniform perfusion of tumor cells.
Abnormalities are present in all components of the vessels wall. The organ and tissue-specific vascular architecture is not retained. Even large caliber vessels are mainly composed of just an endothelium and a basement membrane (BM).
Vessel density is very heterogeneous: the highest values are usually found in what is commonly known as the invading tumor edge, where the density is four to ten times greater than inside the tumor [1]. The arrangement of vessels in the centre of a tumor is much more chaotic than at its edges.
Section snippets
Tumor endothelial cell (EC) features
EC of mature, quiescent vessels are characteristically low proliferative and their estimated turnover times are measured in years, whereas those of tumor vessels are markedly dependent on growth factors for survival. Vascular endothelial growth factor (VEGF) has been convincing assigned a central role in the induction of host vessels into a growing tumor. When EC invade a newly formed tumor, they come into contact with tumor cells that produce VEGF, which may be responsible not only for
Tumor BM
The BM that envelops EC and pericytes (PC) of tumor vessels may have extra layers that have no apparent association with the cells [8]. It contains distinctive forms of fibronectin comprising the ED-B domain, and type IV collagen with exposed cryptic sites [9], and is a source of angiogenic and antiangiogenic molecules. Some of its structural proteins are broken down by enzymes to yield molecules with potent actions. Three examples are endostatin, which is a COOH-terminal fragment of collagen
Tumor PC
PC are perivascular cells that are thought to surround and stabilize new vessels. They extend thin processes around and along the microvascular tubes and have areas of direct contact with EC.
They are revealed by immunohistochemical staining of sections [12] and may cover 73–92% of endothelial sprouts in several murine tumor types. Breast and colon tumors recruit significantly more PC than gliomas or renal cell carcinoma [13].
Most tumor PC are loosely associated with EC, have abnormal shape,
Tumor lymphatic vessels
Convincing evidence for tumor lymphangiogenesis has begun to accumulate and show that it can be stimulated in a variety of experimental cancers by VEGF-C and VEGF-D that signal via VEGF receptor-3 (VEGFR-3) [22]. VEGF-C overexpression led to lymphangiogenesis and growth of the draining lymphatic vessels, intralymphatic tumor growth and lymph node metastasis in several tumor models [23] and clinicopathological studies have reported that expression of VEGF-C, VEGF-D or VEGFR-3 can correlate with
Vascular co-option
Holash et al. [29] reported that tumor cells migrate to host organ blood vessels in sites of metastases, or in vascularized organs such as the brain, and initiate blood-vessel-dependent tumor growth as opposed to classic angiogenesis. These vessels then regress owing to apoptosis of the constituent EC, apparently mediated by Ang-2. Lastly, at the periphery of the growing tumor mass angiogenesis occurs by cooperative interaction of VEGF and Ang-2.
Tumor cells often appear to have immediate access
Vasculogenic mimicry
Maniotis et al. [31] described a new model of formation of vascular channels by human melanoma cells and called it “vasculogenic mimicry” to emphasize the de novo generation of blood vessels without the participation of EC and independent of angiogenesis. Microarray gene chip analysis of a highly aggressive compared with poorly aggressive human cutaneous melanoma cell lines revealed a significant increase in the expression of laminin 5 and MMP-1, MMP-2, MMP-9 and MT1-MMP in the highly
The role of bone marrow-derived stem cells in tumor angiogenesis
Bone marrow-derived stem cells may be a source of endothelial precursor cells (EPC) recruited for tumor-induced neovascularization. High levels of VEGF produced by tumors may result in mobilization of these cells in the peripheral circulation and enhance their recruitment into the tumor vasculature [35]. Moreover, Hattori et al. [36] showed that combined elevation of VEGF and Ang-1 result in remodeling of the bone architecture, with depletion of the sinusoidal spaces of hematopoietic cells and
Vascular targeting to the tumor vasculature
EC lining tumor blood vessels express several cell surface markers that are absent in quiescent blood vessels. Ligand-directed vascular targeting can be accomplished by antibodies, specific peptides or growth factors complexed with immunomodulatory, procoagulant or cytotoxic molecules [40].
Antigenic determinants that are selectively and constitutively expressed on the tumor vasculature include endoglin, VEGF receptors, αν integrins, the fibronectin EDB domain, and prostate-specific membrane
Acknowledgements
Supported by Associazione Italiana per la Ricerca sul Cancro AIRC (National and Regional Funds) Milan, Fondazione Italiana per la Lotta al Neuroblastoma, Genoa, FIRB 2001 and PRIN 2005, Rome, Italy.
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