, Volume 15, Issue 5, pp 484-498

Blood vessels in liver metastases from both sarcoma and carcinoma lack perivascular innervation and smooth muscle cells.

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Hepatic arterial infusion (HAI) chemotherapy as treatment for human colorectal liver metastases is promising, but not entirely satisfactory. Improved drug delivery during HAI may be achieved by manipulating the different control mechanisms of normal versus tumour blood vessels. The peptidergic/aminergic innervation of vessels in normal liver and in two animal models of liver metastasis (Lister Hooded rat with syngeneic MC28 sarcoma; athymic (nude) rat with human HT29 carcinoma) was investigated to assess the suitability of these models for future pharmacological studies. Normal liver and metastases were studied immunohistochemically for the presence of protein gene product 9.5 (PGP), neuropeptide Y (NPY), tyrosine hydroxylase (TH), calcitonin gene-related peptide (CGRP), vasoactive intestinal polypeptide (VIP) and substance P (SP). Perivascular innervation was also examined by transmission electron microscopy. In Lister rat normal livers, perivascular immunoreactive nerve fibres containing PGP, NPY, TH, CGRP and SP were observed around the interlobular blood vessels near the hilum and in the portal tracts. The highest density was seen for PGP, followed in decreasing order, by NPY, TH, CGRP and SP. VIP-immunoreactive nerves were absent. No immunoreactive nerves were observed in the hepatic lobule. In athymic rat livers, the pattern of innervation was similar, except that SP immunoreactivity was more sparse. No perivascular immunoreactive nerves were observed in either MC28 or HT29 tumours. Electron microscopy confirmed the absence of perivascular nerves. Smooth muscle cells were not observed in tumour blood vessel walls. These results are comparable with previous observations on human liver metastases and suggest that the animal models may be suitable for pharmacological studies on vascular manipulation of HAI chemotherapy.