Zugmaier G, Lippman M E, Wellstein A
Vincent T. Lombardi Cancer Research Center, Georgetown University Medical Center, Washington, DC 20007.
J Natl Cancer Inst. 1992 Nov 18;84(22):1716-24. doi: 10.1093/jnci/84.22.1716.
In a proliferating tumor, locally secreted polypeptide growth factors, which have autocrine and paracrine functions, induce vascularization essential for tumor growth and metastasis. These growth factors may serve as targets for tumor therapy. We have shown that the heparinoid pentosan polysulfate (PPS) can block growth of subcutaneous human tumor xenografts in nude mice and angiogenesis induced by the heparin-binding, Kaposi's sarcoma-derived fibroblast growth factor (K-FGF).
The purpose of this study was to determine whether PPS might also interfere with stimulation of endothelial cells by other growth factors released from tumor cells and whether the promising antitumor effects of PPS extend to other human tumor cell lines. We studied the effects of PPS on stimulation by heparin-binding growth factors released from seven human tumor cell lines in vitro and on tumors growing from these cell lines in athymic nude mice.
Seven human cell lines established from breast, prostate, epidermoid, and lung carcinomas and rhabdomyosarcoma were used in in vivo as well as in vitro studies of the effects of PPS. We also studied in vitro the effects of PPS on growth factor-induced colony formation of normal rat kidney fibroblasts and human adrenal carcinoma cells.
The tumor cell lines released growth factors into their media that stimulated growth of endothelial and epithelial cells as well as fibroblasts. Heparin-affinity chromatography showed that heparin-binding growth factors contributed substantially to this paracrine activity and that PPS inhibited this stimulus. Six of the seven tumor cell lines were resistant to PPS in soft-agar cloning assays and hence did not appear to depend on autocrine stimulation by the heparin-binding growth factors. In contrast to this in vitro resistance, subcutaneous growth of tumors from all cell lines in athymic nude mice was inhibited in a dose-dependent fashion by daily intraperitoneal injections of PPS.
We conclude that heparin-binding growth factors contribute substantially to tumor growth in vivo and that PPS acts by blocking the paracrine effects of heparin-binding growth factors released from the tumor cells.
PPS could become a novel treatment tool targeting tumor growth factors.
在增殖性肿瘤中，具有自分泌和旁分泌功能的局部分泌的多肽生长因子可诱导肿瘤生长和转移所必需的血管生成。这些生长因子可能成为肿瘤治疗的靶点。我们已经表明，类肝素戊聚糖多硫酸盐（PPS）可阻断裸鼠皮下人肿瘤异种移植物的生长以及由肝素结合的卡波西肉瘤衍生的成纤维细胞生长因子（K-FGF）诱导的血管生成。
本研究的目的是确定PPS是否也可能干扰肿瘤细胞释放的其他生长因子对内皮细胞的刺激，以及PPS有前景的抗肿瘤作用是否扩展到其他人类肿瘤细胞系。我们研究了PPS对7种人类肿瘤细胞系释放的肝素结合生长因子在体外刺激作用的影响，以及对无胸腺裸鼠中由这些细胞系生长的肿瘤的影响。
从乳腺癌、前列腺癌、表皮样癌、肺癌和横纹肌肉瘤建立的7种人类细胞系用于PPS作用的体内和体外研究。我们还在体外研究了PPS对生长因子诱导的正常大鼠肾成纤维细胞和人肾上腺癌细胞集落形成的影响。
肿瘤细胞系将生长因子释放到其培养基中，这些生长因子刺激内皮细胞、上皮细胞以及成纤维细胞的生长。肝素亲和层析表明，肝素结合生长因子对这种旁分泌活性有很大贡献，并且PPS可抑制这种刺激。在软琼脂克隆试验中，7种肿瘤细胞系中有6种对PPS耐药，因此似乎不依赖于肝素结合生长因子的自分泌刺激。与这种体外耐药性相反，无胸腺裸鼠中所有细胞系肿瘤的皮下生长可通过每日腹腔注射PPS以剂量依赖性方式受到抑制。
我们得出结论，肝素结合生长因子对体内肿瘤生长有很大贡献，并且PPS通过阻断肿瘤细胞释放的肝素结合生长因子的旁分泌作用发挥作用。
PPS可能成为一种针对肿瘤生长因子的新型治疗工具。
