GROWTH FACTORS AND HUMAN BLADDER CANCER

我们项目的长期目标是研究生长因子的作用 (GFs)及其受体在正常尿路上皮内稳态中的作用， 诱导和维持尿路上皮恶性肿瘤。 膀胱的 上皮细胞处于一个独特的位置， 天然存在的有丝分裂原如表皮生长因子（EGF）， 在尿液中以非常高的浓度排出， 生物活性形式。 尿路上皮细胞持续暴露于 这些物质可能导致连续刺激、连续细胞 分裂，最终失去生长控制。 因此， 对肿瘤和正常GF的研究将阐明诱导和 维持移行细胞癌（TCC）。 我们的工作是：（1）检测正常和恶性肿瘤细胞上生长因子受体， 移行上皮;（2）检测和表征由 人TCC（TCC-GF）;和（3）评估TCC-GF和其它GF对人TCC（TCC-GF）的作用。 正常和恶性尿路上皮细胞以及选定的其它细胞。 初步工作是 在体外进行。 直接和竞争性结合试验， 放射性同位素标记的配体被用于检测和定量 恶性和正常移行上皮细胞上的EGF受体， 并研究它们的结合动力学。 为了检查新鲜的 膀胱移行细胞癌的肿瘤分期，分级， 和预后，放射自显影正在使用。 生产要素 通过检测培养物中的生长刺激活性来记录 在无血清培养基中生长的TCC细胞系的上清液， 产生细胞本身、其他TCC细胞和非转化靶。 已经进行了初步调整，至少有两个不同的 已经记录了生长刺激活性的部分。 我们计划 表征其他选定的化学和物理性质， 我们可以将这些“活性”与其他GFs（包括EGF）进行比较。 活性组分已被测试其刺激生长的能力 正常成纤维细胞在软琼脂，这两个部分确实含有 转化能力。 正常生长因子的生化特性 （特别是EGF）和TCC-GF将被测试，包括能力， 刺激DNA合成，诱导鸟氨酸脱羧酶（ODC）活性， 改变靶细胞对多胺的需求。 另外由于 随着EGF的商业化应用，现在可以 将其结合和作用与标准（鼠）EGF对人 尿路上皮和TCC靶点。 （J）

Our project's long-term goal is to investigate the role of growth factors (GFs) and their receptors in normal urothelial homeostasis, and in the induction and maintenance of urothelial malignancy. The bladder's epithelium is in the unique position of being perpetually bathed by pools of naturally occurring mitogens such as epidermal growth factor (EGF), which are excreted in the urine in very high concentrations and in biologically active forms. The continuous exposure of urothelial cells to such substances may result in continuous stimulation, continuous cell division, and eventual loss of growth control. Thus, it is likely that the study of tumor and normal GFs will elucidate the processes which induce and maintain transitional cell carcinoma (TCC). We are: (1) examining growth factor receptors on normal and malignant transitional epithelium; (2) detecting and characterizing GFs produced by human TCC (TCC-GFs); and (3) assessing effects of TCC-GFs and other GFs on normal and malignant urothelium and selected other cells. Initial work is being performed in vitro. Direct and competitive binding assays with radioisotope-labeled ligands are being used to detect and quantitate receptors for EGF on malignant and normal transitional epithelial cells, and to study their binding kinetics. To examine the receptors on fresh urothelium and correlate their distribution on TCC with tumor stage, grade, and prognosis, autoradiography is being utilized. Factor production has been documented by detecting growth-stimulating activity in the culture supernates from TCC cell lines growing in serum-free medium, on the producing cells themselves, other TCC cells, and nontransformed targets. Preliminary sizing has already been performed, and at least two different fractions of growth-stimulating activity have been documented. We plan to characterize other selected chemical and physical properties which will allow us to compare these "activities" with other GFs, including EGF. Active fractions have been tested for their ability to stimulate the growth of normal fibroblasts in soft agar, and these two fractions do contain transforming ability. Biochemical properties of normal growth factors (particularly EGF) and TCC-GFs will be tested, including ability to stimulate DNA synthesis, induce ornithine decarboxylase (ODC) activity, and alter the polyamine requirements of target cells. In addition, because of the recent commercial availability of human EGF, it will now be possible to compare its binding and effects to that of standard (murine) EGF on human urothelial and TCC targets. (J)