Stackpole C W, Valle E F, Alterman A L
Department of Pathology, New York Medical College, Valhalla 10595.
Cancer Res. 1991 May 1;51(9):2444-50.
The mouse B16 melanoma metastasizes in two stages, first to the lungs and then from lung metastases to systemic organs. Despite widespread dissemination, visible metastases generally occur only in the brain, adrenals, kidneys, ovaries, pancreas, and mesentery. As a novel approach to investigate the basis of metastatic patterning in this system, the possibility was explored that an implantable "artificial organ" could serve as a site for the occurrence and experimental modulation of secondary-stage metastasis. Each implant consisted of a cellulose disc 4 mm in diameter, with a central 1-mm polymer pellet to effect local sustained release of angiogenic or growth factors in a s.c. environment. During the secondary spread of tumors initiated with the B16 melanoma clone G3.12 and with the more metastatic variant G3.12/BM2, metastatic involvement of implants containing angiogenic factors was mainly as invisible micrometastases demonstrable by bioassay; visible metastases were rare and were located in implant blood vessels. Metastasis occurred in about 30% (G3.12) and 50% (G3.12/BM2) of implants with vasculature induced by ethylene-vinyl acetate copolymer alone. Endothelial cell growth factor and heparin promoted greater vascularization but did not significantly alter metastatic involvement of implants. Release of tumor cell mitogenic activity from pellets containing a crude extract of mouse lungs increased the incidence of G3.12/BM2 metastasis in implants to over 70% and stimulated growth of visible metastases within the cellulose matrix. In contrast, liver extract inhibited metastasis growth. Colonization of implants following intracardiac injection of G3.12/BM2 cells was generally similar to metastasis, but visible colonies formed more readily and were less dependent on the influence of lung extract. These results indicate that metastasis and colonization can occur regularly in implants and that the relative favorability of the implant environment for secondary tumor growth can be altered by incorporation of tumor cell growth modulators.
小鼠B16黑色素瘤的转移分两个阶段，首先转移至肺部，然后从肺转移灶扩散至全身各器官。尽管肿瘤广泛播散，但可见转移灶通常仅出现在脑、肾上腺、肾、卵巢、胰腺和肠系膜。作为研究该系统转移模式基础的一种新方法，人们探讨了植入式“人工器官”能否作为二期转移发生及实验性调控的场所。每个植入物由一个直径4毫米的纤维素圆盘组成，圆盘中央有一个1毫米的聚合物小球，可在皮下环境中实现血管生成因子或生长因子的局部持续释放。在用B16黑色素瘤克隆G3.12及转移性更强的变体G3.12/BM2引发肿瘤的二期扩散过程中，含有血管生成因子的植入物的转移累及主要表现为通过生物测定可检测到的不可见微转移灶；可见转移灶很少，且位于植入物血管内。仅由乙烯-醋酸乙烯共聚物诱导血管生成的植入物中，约30%（G3.12）和50%（G3.12/BM2）发生了转移。内皮细胞生长因子和肝素促进了更多血管生成，但并未显著改变植入物的转移累及情况。含有小鼠肺粗提物的小球释放的肿瘤细胞促有丝分裂活性使植入物中G3.12/BM2转移的发生率增加至70%以上，并刺激了纤维素基质内可见转移灶的生长。相反，肝提取物抑制转移灶生长。心内注射G3.12/BM2细胞后植入物的定植情况通常与转移相似，但可见菌落形成更容易，且对肺提取物的影响依赖性较小。这些结果表明，转移和定植可在植入物中经常发生，并且通过加入肿瘤细胞生长调节剂可改变植入物环境对继发性肿瘤生长的相对适宜性。
