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 when injected locally or when used in an isolated limb perfusion, and it can enhance the tumoricidal effect of various therapies. TNF-alpha can also up-regulate adhesion molecules, and thus, facilitate the binding 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 tumor at different sites (dorsal skin and cranium), in different mouse strains [C3H and severe combined immunodeficient (SCID)], both with and 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 normal 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 leukocyte-endothelial interaction in vessels in the following cases: normal tissue regardless of sites and strains, MCaIV tumor in the cranial window in C3H mice, and HGL21 tumor in the cranial window in SCID mice. However, the increase in rolling and adhesion in the MCaIV tumor in response to TNF-alpha was significantly lower than in the corresponding normal vessels (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 SCID mice showed leukocyte rolling and adhesion comparable to that in normal 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-alpha-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.
Fukumura
D
D
Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital, Boston, USA.
Salehi
H A
HA
Witwer
B
B
Tuma
R F
RF
Melder
R J
RJ
Jain
R K
RK
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002450:Cell Communication / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects; D004912:Erythrocytes / Q000502:physiology; D005909:Glioblastoma / Q000097:blood / Q000098:blood supply*; D006801:Humans; D007962:Leukocytes / Q000166:cytology* / Q000187:drug effects; D008325:Mammary Neoplasms, Experimental / Q000097:blood / Q000098:blood supply*; D051379:Mice; D008809:Mice, Inbred C3H; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D012867:Skin; D012886:Skull; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D014409:Tumor Necrosis Factor-alpha