Vascularization of cutaneous melanoma involves vessel co‐option and has clinical significance

Abstract

This study was undertaken to determine the role and the fate of the peritumoural vascular plexus during the vascularization of human malignant melanoma (hMM) and in an appropriate murine melanoma model system. The prognostic significance of the vascularity of different tumour areas was also evaluated. Despite morphometry revealing several-fold higher microvessel densities (MVDs) in the peritumoural tissue than at the centre of the tumour, the development of visceral metastases of hMM was exclusively correlated with the MVD of the tumour centre. Furthermore, the 5-year survival of the patient group with low tumour centre MVD (<30/mm(2), n=29) was 100%, compared to 1/16 patients alive with high tumour centre MVD (>30/mm(2), n=16). Morphometric analysis and three-dimensional reconstruction of vessel networks of both human and murine melanomas showed clearly that the peritumoural vascular plexus present at the melanoma base is continuously being incorporated into the growing tumour mass. Once vessels become incorporated, sprouting ceases and the proliferating endothelial cells (EC) take part only in vessel dilatation. Moreover, the immunohistochemical and ultrastructural characterization of microvessels demonstrated that the pericyte coverage of endothelial tubes was complete in all of the investigated areas, in both human and murine melanomas.

Vascular remodelling of an arterio-venous blood vessel network during solid tumour growth

“…Hemodynamic properties are averaged over occupied bonds only. MVD and vessel-radius show the typical compartmentalization that has been observed in melanoma (Döme et al, 2002) and glioma (Va-…”

“…(a) The experimentally observed compartmentalization of the tumour vasculature (Holash et al, 1999a;Döme et al 2002) is independent of the initial vasculature and a consequence of the basic mechanisms that we identified: 1) The existence of an original vasculature, 2) Angiogenic sprouting in the tumour perimeter, 3) Blood flow correlated vessel regression and 4) a switch from angiogenic sprouting to circumferential growth within the tumour. If the latter is absent, thick vessels will be rare, leading to increased shear flow and concomitantly to increased stability of the tumour vesselsthus altering the compartmentalization.…”

“…In the model defintion we restrict ourselves to the mathematical formulation and refer to the introductory subsections 1.2.1-1.2.4 for the supporting biological observations and experimental literature. Section 3 presents the results for global properties for a choice of parameters that is guided by experimental data for melanoma (Döme et al, 2002). These results include a discussion of the emerging morphologies; radial distributions of vessel density, vessel radius, tumour density, flow rates, shear forces etc., vessel statistics, parameter dependencies, spatial inhomogeneities, and drug flow.…”

“…We set the TC proliferation time t (prol) T C to 10 h, the viability time under hypoxia t (uo) T C to 100 h, and the apoptosis time to 2 h, the O 2 -threshold for proliferation c EC to 100 h (estimated from figures in (Nehls et al, 1998)), sprouting site separation 11 distance l (spr) to 20 μm, the initial sprout radius r (sprout) to 4 μm, the delay until the switch to circumferential growth happens t (switch) EC to 24 h, the circumferential growth rate k r to 0.4 μm/h, the maximum radius r (max) to 25 μm and the growth factor diffusion range R g to 200 μm (estimated from morphological data by Döme et al, 2002).…”

“…Vessel cooption has now been observed in different tumour types like human melanoma (Döme et al, 2002), neuroblastoma (Kim et al, 2002), and ovarian cancer (Zhang et al, 2003), it can persist during the entire period of tumour growth and it can even represent the only source for nutrients in angiogenesis-independent tumour growth (Sakariassen et al, 2006). From these experimental observations the anatomy of solid, vascularized tumour grown within in a vascularized tissue displays a characteristic compartmentalization into essentially three regions (Holash et al, 1999a, Döme et al, 2002: I) The highly vascularized tumour perimeter with a microvascular density (MVD) that is substantially higher than the MVD of the surrounding normal tissue. II) The well vascularized tumor periphery with dilated blood vessels and a tortuous vessel network topology.…”