Effects of tumour cells on angiogenesis and vasoconstrictor responses in sponge implants in mice

Abstract

SummaryThe effects of tumour cells (Colon 26) on the development and response of new blood vessels to different vasoconstrictors (platelet activating factor; PAF, endothelin-1, angiotensin II, adrenalin and 5-hydroxytryptamine) have been investigated. Sponge implants in mice were used to host tumour cells while washout of '33Xe was employed to assess local blood flow in the implanted sponges.By 14 days after implantation the response of vessels in tumour-bearing implants to the various vasoconstrictors generally was decreased compared to that obtained in control sponge implants or adjacent normal skin. Thus at this time point the tl/2 for '33Xe washout from control sponges treated with adrenalin (0.5 pg) was 30 ± 4 min whereas in tumour-bearing sponges it was 5 ± 1 min.This decreased sensitivity in tumour vessels was probably not due to a complete lack of contractile elements since actin was demonstrated by immunohistochemistry around blood vessels in both types of implant.The results of the present study have shown that the pharmacological responses of blood vessels in a growing tumour, Colon 26, differed from the responses of vessels of a similar age in non-neoplastic tissue. These results appear to suggest that the different angiogenic stimuli released from tumour tissue may markedly influence pharmacological reactivity of newly formed blood vessels.Tumour angiogenesis, the formation of capillary vessels induced by neoplastic cells with eventual development of a functional microcirculatory network within the growing mass, is a process analogous to the formation of capillary vessels in granulation tissue during wound repair (Warren, 1979). Morphological abnormalities in vessels in either situation have frequently been reported (Schoelfl, 1963;Warren, 1979;Jain 1988;Vaupel et al., 1989). However, compared to other angiogenic stimuli, tumours induce a very intense and persistent response (Folkman & Klagsbrun, 1987) so that more severe abnormalities may be observed in tumour vessels; this tendency is accentuated in rapidly growing neoplasms (Vaupel et al., 1989). Pharmacological as well as anatomical abnormalities have been documented in tumour blood vessels, though the situation is far from clear-cut. Thus, experimental studies have suggested either increased (Young et al., 1979;Tveit et al., 1981), similar (Mattsson et al., 1982) or decreased (Wickersham et al., 1977) sensitivity to vasoactive stimuli in the tumour vascular bed compared to normal tissue. These differences have been attributed to the transplantation area of the tumour, the type of tumour and the different techniques used for measuring blood flow (Suzuki et al., 1984). The washout of locally injected radioactive '33Xe (Peterson, 1979) has been shown to be a reliable index of tumour blood flow when applied to relatively small, superficially located cancers (Kallman et al., 1972). This technique has also been used for examining the influence of vasoactive drugs on local blood flow in tumours and normal subcutaneous tissue (Mattsson et al., 1980;198...

Innervation and neurokinin receptors during angiogenesis in the rat sponge granuloma

“…However, neovasculature may differ from mature blood vessels, with a reduced sensitivity to vasoactive substances (Andrade et al, 1992;Boura et al, 1994). Maturation of neurovascular regulatory systems is associated with healing of skin wounds, and prevention of innervation delays wound healing (Kjartansson et al, 1987;Manek et al, 1993).…”

Sequential development of angiotensin receptors and angiotensin I converting enzyme during angiogenesis in the rat subcutaneous sponge granuloma

“…The development of vasoactive regulatory systems during angiogenesis remains incompletely defined. The neovascu‐lature responds differently to vasoactive agents compared with mature blood vessels (Andrade et al , 1992), and receptors for the sensory neuropeptide substance P appear on maturing microvessels before innervation provides an endogenous source of the peptide (Walsh et al , 1996). Maturation of mi‐crovascular AII systems may also be sequential, since ACE expression is low in immature endothelial cells, and is upre‐gulated during maturation in vitro (Shai et al , 1992).…”

Pharmacological reactivity of neoplastic and non‐neoplastic associated neovasculature to vasoconstrictors

“…Andrade and W.T.Beraldo early changes in blood flow within the implants even before growth of the tumour mass is evident (Andrade et al 1992a;Hu et al 1996). For studying tumour angiogensis the well defined, initially acellular and avascular compartment offers a valuable experimental opportunity to host proliferating tumour cells.…”

“…The activated cells produce angiogenic factors like basic fibroblast growth factor (bFGF), tumour necorosis factor-a (TNF-a), vascular permeability factor/vascular endothelial growth factor (VPF/|VEGF) by low oxygen tension which occurs in the depths of a wound and in hypoxic centre of a tumour (Knighton et al 1993;Neeman et al 1997). Furthermore, the resulting tumour-induced blood vessels have been shown to have altered reactivity to vasoactive agents when compared to pre-existing vascular beds (Peterson 1991;Andrade et al 1992a). It seems that the onset of tumour angiogenesis is associated with increased permeability of local blood vessels mediated at least, in part by the tumour product VPF/VEGF (Nagy et al 1988) whereas physiological angiogenesis in the healing processes is associated with wounding or ischemia (Folkman & Shing 1992), and unlike the vessels of the inflammatory granulation tissue, tumour vessels undergo endless proliferation and are characterized by a steady progression to necrosis without an intervening stable maturation phase (Suzuki et al 1984).…”