CSF1 and CSF1R and Breast and Ovarian Carcinoma

在过去的14年中，我们的研究一直基于一个中心假设，即肿瘤上皮细胞中CSF-1 R的激活诱导信号转导通路组分的激活状态、基因表达和一组特定细胞表型的表达的一致变化，这使得非肿瘤上皮细胞具有“局部侵袭性”和“转移能力”。“这些变化是肿瘤上皮细胞对应的信号转导途径激活的变化，基因表达水平的变化， 以及在巨噬细胞活化和胎盘植入期间，在非肿瘤性巨噬细胞和滋养层中由活化的CSF-1 R诱导的细胞表型，生理上正常的侵入性过程依赖于CSF-1 R的活化。因此，我们的模型提出，卵巢上皮细胞和其他肿瘤上皮细胞获得这些表型， 在活化期间由巨噬细胞表达，在胎盘植入期间由滋养层细胞表达，并由CSF-1 R活化调节的正常发育程序。基于这一假设和我们已经获得的支持它们的实验结果，我们建议测试当用另一种细胞表面RTK转染这些细胞时，在CSF-1 R活化后在非肿瘤性上皮细胞中观察到的基因表达和信号转导途径组分活化水平的至少一些变化是否也将被观察到（即受体酪氨酸激酶），这也使它们具有局部侵袭性和转移能力，但当用不具有局部侵袭性和转移能力的其他RTK转染时，则不会。我们还将测试是否药物或遗传操作，干扰这些变化的基因表达水平和信号转导途径组件激活阻断局部侵袭和转移性传播的HC 11-fms细胞。最后，我们将测试这些CSF-1 R诱导的变化在人乳腺和卵巢肿瘤标本中的测定（其中 CSF-1 R的表达，特别是其活化的酪氨酸磷酸化形式预测不良预后）同样应该与临床结果相关。

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.