Fukumura D, Salehi H A, Witwer B, Tuma R F, Melder R J, Jain R K
Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital, Boston, USA.
Cancer Res. 1995 Nov 1;55(21):4824-9.
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.
肿瘤坏死因子α（TNF-α）局部注射或用于离体肢体灌注时可导致肿瘤消退，并且能增强各种治疗的杀瘤效果。TNF-α还可上调黏附分子，从而促进白细胞与正常血管的结合。本研究旨在调查在不同小鼠品系[C3H和严重联合免疫缺陷（SCID）]中，无论有无TNF-α激活，宿主白细胞在给定部位对不同肿瘤（MCaIV，一种小鼠乳腺腺癌；HGL21，一种人类恶性星形细胞瘤）的血管滚动和黏附程度，或者在不同部位（背部皮肤和颅骨）对同一肿瘤的血管滚动和黏附程度。在PBS处理的对照组和相应的TNF-α处理组之间，诸如红细胞速度、直径或剪切速率等血流动力学参数没有显著差异。在PBS对照条件下，C3H和SCID小鼠背部腔室中MCaIV肿瘤血管以及C3H小鼠颅骨窗口中白细胞的滚动计数显著低于正常血管（P<0.05），但正常血管和肿瘤血管之间的稳定细胞黏附情况相似。在以下情况中，TNF-α导致血管中白细胞与内皮细胞相互作用增加（P<0.05）：无论部位和品系的正常组织、C3H小鼠颅骨窗口中的MCaIV肿瘤以及SCID小鼠颅骨窗口中的HGL21肿瘤。然而，在C3H和SCID小鼠背部腔室以及C3H小鼠颅骨窗口中，MCaIV肿瘤对TNF-α反应的滚动和黏附增加显著低于相应的正常血管（P<0.05）。SCID小鼠颅骨窗口中的HGL21肿瘤显示白细胞滚动和黏附与正常软脑膜血管相当。这些发现表明：（a）一般来说，肿瘤血管中的基础白细胞滚动低于正常血管；（b）TNF-α介导的激活可增强肿瘤中的白细胞滚动和黏附；（c）TNF-α反应取决于肿瘤类型、移植部位和宿主品系。这些结果对于使用TNF-α基因转染的癌细胞或淋巴细胞进行癌症基因治疗具有重要意义。
