GROWTH FACTORS IN PROSTATE CANCER

在男性中，前列腺癌现在是最常见的（超过10万例 将于1991年被诊断出来）和癌症死亡的第二大原因。 这种疾病的特点是潜伏和显性形式，后者是 在40岁以上的尸检中有40 - 50%的人可以检测到。 述疾病是 进行性和临床形式随着年龄的增长而增加。 肝素结合 成纤维细胞生长因子（FGF）家族多肽及其受体 （FGF-R）已经被坚定地牵涉到支持前列腺上皮和 基质细胞生长和可能的分化。FGF和FGF-R家族 在分子水平上是非常异质的。 因子家族 由7个基因的同源产物组成，而受体家族 由四个基因的剪接变异组成， 对受体的大多数已知功能有影响的同种型（配体- 结合，二聚化，酪氨酸激酶活性，自磷酸化 酪氨酸、Ser/Thr上的外源磷酸化和代谢）。这 使该家族成为分子变化的绝佳候选者， 前列腺肿瘤进展期间生长和分化不受调节 也是其他生长因子调节的极佳靶点。 这 项目将确定七个成员的表达模式， FGF配体和bek FGF-R1和bek FGF-R2受体的剪接变体 模型大鼠前列腺肿瘤的上皮细胞和基质细胞中的基因， 它们从相对良性的分化状态发展到 高度致命的恶性转移状态 这将通过 细胞培养、体内可移植肿瘤、分子生物学 生物学和蛋白质化学技术。 它将检验这个假设 受体家族被正常的负调节因子修饰， 上皮细胞生长（TGF-β和其他细胞因子）和霍乱毒素， 是正常上皮细胞生长的人工刺激物， 通过肿瘤细胞。 待检验的关键假设是， 上皮细胞的生长和分化是由定向的 基质细胞到上皮细胞的旁分泌信号被 上皮细胞内自分泌环的激活。 变化 从有序的旁分泌控制到异常的自分泌控制 FGF配体和受体基因的同种型表达的变化， 后者主要是特定剪接变体的变化。

In males, prostate cancer is now the most common (more than 100,000 cases will be diagnosed in 1991) and the second leading cause of cancer death. The disease is characterized by latent and overt forms, the latter of which is detectable in 40-50% of autopsied men over 40. The disease is progressive and clinical forms increase with age. The heparin-binding fibroblast growth factor (FGF) family of polypeptides and its receptor (FGF-R) has been firmly implicated in support of prostate epithelial and stromal cell growth and possibly differentiation. The FGF and FGF-R family is extremely heterogenous at the molecular level. The factor family consists of homologous products of seven genes while the receptor family consists of splice variations of four genes which result in structural isoforms that have impact on most known functions of receptors (ligand- binding, dimerization, tyrosine kinase activity, autophosphorylation on tyrosine, exogenous phosphorylation on ser/thr, and metabolism). This makes the family an excellent candidate for molecular changes that lead to unregulated growth and differentiation during prostate tumor progression and an excellent target for regulation by other growth factors. This project will determine the expression pattern of the seven members of the FGF ligands and splice variants of the flg FGF-R1 and bek FGF-R2 receptor genes in the epithelial and stromal cells of model rat prostate tumors as they progress from the relatively benign differentiated state to the highly lethal malignant metastatic states. This will be accomplished by combinations of cell culture, transplantable tumor in vivo, molecular biology and protein chemistry technologies. It will test the hypothesis that the receptor family is modified by negative regulators of normal epithelial cell growth (TGF-B and other cytokines) and cholera toxin which is an artificial stimulant of normal epithelial cell growth that is by- passed by tumor cells. The key hypothesis to be tested is that normal epithelial cell growth and differentiation is controlled by directional stromal to epithelial cell paracrine signals that are subverted by activation of autocrine loops within the epithelial cells. Change from ordered paracrine control to abnormal autocrine control lies within changes in expression of isoforms of both FGF ligand and receptor genes, the latter of which is predominantly changes in specific splice variants.