Architectural Differences between Normal and Tumor Microvasculature

All tissues and organs develop a very specific vascular architecture reflecting the specific demands. The large intestine microvasculature, for example, is characterized by a flatly extended mucosal capillary plexus with a hexagonal, honeycomb pattern around the tissue of the mucosal glands (Figure 2a). This subepithelial plexus is supplied by arteries that divide within the submucosa and is drained by venules originating immediately under the mucosal surface. Elongated capillaries in the renal medulla are densely packed in vascular bundles permitting the essential countercurrent exchange mechanism, whereas the capillaries derived from the afferent arterioles branch within the renal corpuscle with its unique architecture (Figure 2b). Microvessel plexuses within loose connective tissue such as the subcutis are flatly organized with undulating capillary courses that enable compliance with shear stress exerted by the skin (Figure 2c). Capillaries coursing into dermal papillae show typical hairpin loops that are involved in temperature regulation (Figure 2d).

In tumors, the organ- and tissue specific vascular architecture is not retained but is replaced by newly formed vessels without significant hierarchy (Figure 2e-h). Vessel densities may vary considerably; the highest vessel densities are usually found in the periphery within the invasion front. Vessel density within "hot spots," that is, densely vascular-ized areas, may be even higher than in the autochthonous tissue. In desmoplasias next to the neoplastic tissue, sprouting, dilatation, and structural adaptation may change the original architecture of the preexisting vessels as result of the release of proangiogenic factors.

Common features of human primary and of experimental tumor vascularities—irrespective of origin, size, and growth behavior—are missing hierarchy, the formation of large-caliber sinusoidal vessels (Figure 2e, f), and markedly expressed vessel density heterogeneity (Figure 2e, g). The diameters within individual tumor vessels vary significantly. Sinusoids originating from and draining into venous vessels increase vessel densities, but do not contribute to nutritive blood flow. Capillary elongations by more than tenfold explain the low intratumoral pO2. Vessel compressions and blind ends are found close together.

Tortuous courses and elongated sinusoidal vessels may occur also in other forms of secondary angiogenesis; however, in wound healing and chronic inflammation a real remodeling of the newly formed vasculature takes place with differentiation into arteries and veins and elimination of ineffective vessel segments.

Renal Microvasculature

Figure 1 Transmission electron microscopy of tumor vascularity. (a) Established sinusoidal vessel (late form) of a renal cell carcinoma transplanted under murine renal capsule with flattened endothelium (arrows) without medial layer. Note the edema (e) within some endothelial cell protrusions. (b) Intercellular bud formation through endothelial cell migration in a human melanoma xenografted onto nude mice. The eccentrically located perikaryon of cell 2 and a pseudopodium of cell 1 veer out from the endothelial structure, forming a new lumen, which is not fully connected to the primary lumen. (c) Early form in a melanoma. Note the height of the endothelium and the unusual overlapping of the three lumen-confining cells. (d) Partial compression of an early form by extravascular tumor cells (tc) next to a lumen-confining cell (1), which results in a thinning of the endothelium. (Inset) Fenestrated endothelium is superimposed by continuous endothelium. (e) Structural defects in sinusoidal vessel of a xenografted squamous cell carcinoma with evasions. The endothelial cells (left) show some bleb formation indicative of cytoskeleton damage, whereas the pericytes appear normal. (f) Interstitial channel (ic) lined completely by hypoxic tumor cells in a xenografted spindle cell sarcoma. All bars = 5 mm.

Figure 1 Transmission electron microscopy of tumor vascularity. (a) Established sinusoidal vessel (late form) of a renal cell carcinoma transplanted under murine renal capsule with flattened endothelium (arrows) without medial layer. Note the edema (e) within some endothelial cell protrusions. (b) Intercellular bud formation through endothelial cell migration in a human melanoma xenografted onto nude mice. The eccentrically located perikaryon of cell 2 and a pseudopodium of cell 1 veer out from the endothelial structure, forming a new lumen, which is not fully connected to the primary lumen. (c) Early form in a melanoma. Note the height of the endothelium and the unusual overlapping of the three lumen-confining cells. (d) Partial compression of an early form by extravascular tumor cells (tc) next to a lumen-confining cell (1), which results in a thinning of the endothelium. (Inset) Fenestrated endothelium is superimposed by continuous endothelium. (e) Structural defects in sinusoidal vessel of a xenografted squamous cell carcinoma with evasions. The endothelial cells (left) show some bleb formation indicative of cytoskeleton damage, whereas the pericytes appear normal. (f) Interstitial channel (ic) lined completely by hypoxic tumor cells in a xenografted spindle cell sarcoma. All bars = 5 mm.

Endothelial Cells

Figure 2 Scanning electron microscopy of normal (a-d) and tumor microvascular corrosion casts (e-h). (a) The human colonic mucosal capillary plexus (c) is arranged in a honeycomb pattern and shows numerous intercapillary connections. The supplying arterioles (a) and draining veins (v) take a straight course from the underlying submucosal vessels. (b) Mouse kidney vessels with cortical vessels and glomeruli (lower left and inset) and parallel-oriented medullary vessels (upper part). (c) Subcutaneous vessel plexus on the fascia with undulating vessel courses. (d) Hairpin loops of skin capillaries oriented along the dermal papillae (sheep ear skin). (e) Loss of original vessel architecture in human colonic carcinoma (pT3, pNo, pMx; G2). Note the heterogeneous distribution of the sinusoids and the loss of hierarchy. (f) Murine RenCa-tumor sinusoids with varying diameters and numerous blind ends. (g) Xenografted sarcoma with compressed main veins (v) and avascular areas (+) next to hot spots. (h) Tumor vascular envelope in a xenografted squamous cell carcinoma.

Last, it should be pointed that the features seen in primary tumor vascularity can be seen qualitatively as well in precancerous lesions—although to a lesser extent—long before the transformation to the malignant phenotype.

Glossary

Microvascular corrosion casting: Replication of vessel systems by injection of low-viscosity casting media and digestion of all surrounding tissues, allowing for scanning electron microscopic examination.

Microvascular unit: Capillary bed segment fed by an individual metarteriole.

Tumor sinusoids: Relatively undifferentiated vessels with capillary wall building and increased diameter.

Vascular mimicry: Nonendothelial cells lining vessels or perfused channels.

Frequently xenografted tumors induce the formation of a vascular envelope of sprouting and preexistent host vessels embedded in connective tissue, in which a certain hierarchy is retained (Figure 2h). This is not true for human primary tumors since the invasive growth prevents the formation of such a vascular and/or fibrous tissue capsule.

Despite the common features, which are expressed to different extents, the architecture of tumor vasculature is tumor-type specific. This is in contrast to the structure of the tumor vascular cells. Morphometry of parameters determining the architecture of the microvascular unit such as inter-vessel and interbranch distances as well as diameter and variability of diameter prove that individual tumor entities express characteristic vascular patterns. The inherent architecture of the tumor seems to be primarily determined by the tumor cells themselves; experiments involving transfected tumor cells with different capacity to produce and release FGFII showed significant differences in tumor growth, but not in microvascular architecture.

Further Reading

Burri, P. H., and Tarek, M. R. (1990). A novel mechanism of capillary growth in the rat pulmonary microcirculation. Anat. Rec. 228, 35-45. The first paper describing intussusceptive angiogenesis. Cliff, W. J. (1981). Endothelial structure and ultrastructure during growth, development and aging. In Structure and Function of the Circulation, C. J. Schwartz and N. T. Werthessen, eds., Vol. 2, pp. 695-718. New York: Plenum Press. Hammersen, F., Endrich, B., and Messmer, K. (1985). The fine structure of tumor blood vessels. I. Participation of nonendothelial cells in tumor angiogenesis. Int. J. Microcirc. Clin. Exp. 4, 31-43. The first article proving the involvement of tumor cells in angiogenesis. Konerding, M. A., Fait, E., and Gaumann, A. (2001). 3D microvascular architecture of pre-cancerous lesions and invasive carcinomas of the colon. Br. J. Cancer 84, 1354-1362. McDonald, D. M., and Choyke, P. L. (2003). Imaging of angiogenesis: From microscope to clinic. Nat. Med. 9, 713-725. Comprehensive review.

Capsule Biography

Dr. Konerding has been Professor of Anatomy at the Institute of Anatomy in Mainz, Germany, since 1993. His group focuses on secondary angiogenesis and antiangiogenesis as well as on clinical anatomy. His work is mainly supported by grants of the DFG and EC.

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