CSF1 and CSF1R and Breast and Ovarian Carcinoma

在过去的14年里，我们的研究一直基于一个中心假设，即在肿瘤上皮细胞中激活CSF-1R会导致信号转导途径组件的激活状态、基因表达和一系列特定细胞表型的表达发生一致的变化，从而使非肿瘤上皮细胞“局部侵袭”和“具有转移能力”。这些变化是肿瘤上皮细胞对应的信号转导通路激活、基因表达水平的变化 而在巨噬细胞活化和胎盘着床过程中，非肿瘤性巨噬细胞和滋养层细胞中活化的CSF-1R诱导的细胞表型，生理上的正常、侵袭过程依赖于CSF-IR的激活。因此，我们的模型并没有暗示共同构成“局部侵袭”和“转移能力”表型的个体特征的获得是随机和随机的，而是提出乳腺、卵巢和其他肿瘤上皮细胞通过将一种 巨噬细胞激活时表达正常发育程序，胎盘着床时滋养层细胞表达正常发育程序，并受CSF-1Rs激活的调节。基于这一假设和我们已获得的支持这些假设的实验结果，我们建议测试是否在非肿瘤性上皮细胞中观察到的非肿瘤性上皮细胞在CSF-1R激活后基因表达水平和信号转导途径组件激活的至少部分变化也将在这些细胞被另一种细胞表面RTK(即受体酪氨酸激酶)转染时观察到，该RTK也使它们具有局部侵袭和转移能力，但当与其他不具有这种变化的RTK转染时，这些细胞不会被观察到。我们还将测试干扰这些基因表达水平变化和信号转导途径组件激活的药物或遗传操作是否能阻止HC11-FMS细胞的局部侵袭和转移扩散。最后，我们将测试这些CSF-1R的检测是否会导致人类乳腺和卵巢肿瘤标本的变化(其中 CSF-1R的表达，特别是其活化的酪氨酸磷酸化形式预测不良预后)也应与临床结果相关。

For the past 14 years, our research has been based on a central hypothesis that activation of CSF-1R in neoplastic epithelial cells induces coherent changes in the activation state of signal transduction pathway components, in gene expression, and in the expression of a set of specific cell phenotypes which render non-neoplastic epithelial cells "locally invasive" and "metastatically competent." These changes are the neoplastic epithelial cell counterparts of changes in activation of signal transduction pathways, levels of gene expression and cellular phenotype induced by activated CSF-1R in non-neoplastic macrophages and trophoblast during macrophage activation and placental implantation, physiologically normal, invasive processes dependent on the activation of CSF-IR. Thus, rather than implying that the acquisition of the individual traits which together comprise the phenotypes of "local invasiveness" and "metastatic competence" is random and stochastic, our model proposes that breast, ovarian, and other neoplastic epithelial cells acquire these phenotypes by coopting a normal developmental program expressed by macrophages during activation and by trophoblast cells during placental implantation and regulated by activation of CSF-1Rs. Based on this hypothesis and the experimental results we have obtained which support them, we propose to test whether at least some of the changes in levels of gene expression and signal transduction pathway component activation observed in non-neoplastic epithelial cells after activation of CSF-1R will also be observed when these cells are transfected with another cell surface RTK (i.e. receptor tyrosine kinase) which also renders them Iocally invasive and metastatically competent but not when transfected with other RTKs which do not. We also will test whether pharmacologic agents or genetic manipulations which interfere with these changes in levels of gene expression and signal transduction pathway component activation block local invasion and metastatic dissemination of HC11-fms cells. Finally, we will test whether assay of these CSF-1R-induced changes in human breast and ovarian tumor specimens (where expression of CSF-1R, particularly its activated tyrosine phosphorylated form predicts an adverse prognosis) should likewise correlate with clinical outcome.