TUMOR-NECROSIS-FACTOR ALPHA-INDUCED LEUKOCYTE ADHESION IN NORMAL AND TUMOR VESSELS - EFFECT OF TUMOR TYPE, TRANSPLANTATION SITE, AND HOST STRAIN

Tumor necrosis factor alpha (TNF-alpha) can lead to tumor regression w hen injected locally or when used in an isolated limb perfusion, and i t can enhance the tumoricidal effect of various therapies. TNF-alpha c an also up-regulate adhesion molecules and, thus, facilitate the bindi ng of leukocytes to normal vessels. The present study was designed to investigate the extent to which the host leukocytes roll and adhere to vessels of different tumors (MCaIV, a murine mammary adenocarcinoma; HGL21, a human malignant astrocytoma) at a given site or to the same t umor at different sites (dorsal skin and cranium), in different mouse strains [C3H and severe combined immunodeficient (SCID)], both with an d without TNF-alpha-activation. There was no significant difference in hemodynamic parameters such as RBC velocity, diameter, or shear rate between PBS-treated control groups and corresponding TNF-alpha-treated groups. Under PBS control conditions, the leukocyte rolling count in MCaIV tumor vessels in the dorsal chamber in C3H and SCID mice and in the cranial window in C3H mice was significantly lower than that in no rmal vessels (P < 0.05), but stable cell adhesion was similar between normal and tumor vessels. TNF-alpha led to an increase (P < 0.05) in l eukocyte-endothelial interaction in vessels in the following cases: no rmal tissue regardless of sites and strains, MCaIV tumor in the dorsal chamber in C3H and SCID mice, MCaIV tumor in the cranial window in C3 H mice, and HGL21 tumor in the cranial window in SCID mice. However, t he increase in rolling and adhesion in the MCaIV tumor in response to TNF-alpha was significantly lower than in the corresponding normal ves sels (P < 0.05) in the dorsal chamber in C3H and SCID mice and in the cranial window in C3H mice. The HGL21 tumor in the cranial window in S CID mice showed leukocyte rolling and adhesion comparable to that in n ormal pial vessels. These findings suggest that (a) in general, basal leukocyte rolling is lower in tumor vessels than in normal vessels; (b ) leukocyte rolling and adhesion in tumors can be enhanced by TNF-alph a-mediated activation; and (c) the TNF-alpha response is dependent on tumor type, transplantation site, and host strain. These results have significant implications in the gene therapy of cancer using TNF-alpha -gene-transfected cancer cells or lymphocytes.