PROGRESSIVE LOSS OF SENSITIVITY TO ENDOTHELIUM-DERIVED GROWTH-INHIBITORS EXPRESSED BY HUMAN-MELANOMA CELLS DURING DISEASE PROGRESSION
PROGRESSIVE LOSS OF SENSITIVITY TO ENDOTHELIUM-DERIVED GROWTH-INHIBITORS EXPRESSED BY HUMAN-MELANOMA CELLS DURING DISEASE PROGRESSION
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DOI：
10.1002/jcp.1041590208
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发表时间：
1994-05-01
影响因子：
5.6
通讯作者：
KERBEL, RS
中科院分区：
文献类型：
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作者：
RAK, JW;HEGMANN, EJ;KERBEL, RS
肿瘤进展通常与肿瘤细胞对旁分泌生长因子的反应性变化有关。实体瘤中这些旁分泌因子的潜在主要来源是内皮细胞，因为这种类型的细胞可以构成实体瘤细胞组成的相当大的一部分。作为检验内皮细胞相关生长因子对肿瘤细胞生长可能影响的第一步，一组代表肿瘤进展不同阶段的人类黑色素瘤细胞系被用于利用内皮细胞衍生的生长调节剂进行研究。在直接共培养实验中，分别来自脐静脉或皮肤的大血管或微血管人内皮细胞抑制黑色素瘤细胞的生长。这种抑制作用的效力随着黑色素瘤的进展而减弱。来自内皮细胞培养的条件培养基模拟了细胞共培养实验的效果，表明可溶性生长因子(s)的参与。通过加入白细胞介素-6 （IL-6）的中和抗体，大约50-75%的条件培养基抑制作用被消除。凝胶过滤层析显示内皮细胞条件培养基中存在额外的抑制剂。检测到两个活性峰，表观分子量约为100- 150kd和20- 30kd，后者含有IL-6活性。早期放射状生长期（RGP）原发性肿瘤源性黑色素瘤细胞对至少三种不同的高分子量或低分子量内皮产物（包括IL-6）敏感，而来自更晚期转移病变的黑色素瘤细胞对后一种活性有抗性，对高分子量抑制剂仅保留部分敏感性。更高级的垂直生长期（VGP）原发性黑色素瘤细胞系表达中等抑制敏感表型。因此，人类黑色素瘤的发展似乎与对内皮细胞产生的IL-6和其他因子的生长抑制作用的敏感性逐渐丧失有关。这可能是肿瘤细胞在血管生成过程中遇到邻近血管时的选择过程的结果。(C) 1994 Wiley-Liss, Inc。
Tumor progression is frequently associated with changes in responsiveness of tumor cells to paracrine growth factors. A potential major source of such paracrine factors in solid tumors are endothelial cells since this type of cell can constitute a sizeable fraction of the cellular composition of solid tumors. As an initial step to examining the possible effects of endothelial cell-associated growth factors on tumor cell growth, a panel of human melanoma cell lines representative of different stages of tumor progression was employed for studies utilizing endothelial cell-derived growth modulators. Macrovascular or microvascular human endothelial cells from umbilical vein or from skin, respectively, inhibited melanoma cell growth in direct coculture experiments. The potency of this inhibitory effect diminished as a function of melanoma progression. Conditioned media from endothelial cell cultures mimicked the effect of the cell coculture experiments, suggesting the involvement of soluble growth factor(s). Approximately 50-75% of the conditioned media inhibitory effect was abrogated by addition of the neutralizing antibody to interleukin-6 (IL-6). Gel filtration chromatography revealed the presence of additional inhibitors in endothelial cell conditioned medium. Two peaks of activity were detected with apparent molecular weights of approximately 100-150 Kd and 20-30 Kd, the latter containing IL-6 activity. Whereas early-stage radial growth phase (RGP) primary tumor-derived melanoma cells were sensitive to at least three different endothelial products of high or low molecular weight (including IL-6), melanoma cells from more advanced metastatic lesions were resistant to the latter activities, and retained only partial sensitivity to the high molecular weight inhibitor. More advanced vertical growth phase (VGP) primary melanoma cell lines expressed intermediate inhibition-sensitive phenotypes. Thus human melanoma development appears to be associated with progressive loss of sensitivity to the growth inhibitory effects of IL-6 and other factors produced by endothelial cells. This is likely to be a result of a selection process when tumor cells are confronted with adjacent vasculature during the progress of tu mor angiogenesis. (C) 1994 Wiley-Liss, Inc.