ENDOTHELIAL GROWTH FACTOR IN PROSTATE CANCER METASTASIS

背景和意义：Paget最初对肿瘤转移的模式有了认识，他提出了“种子(癌细胞)和土壤(转移器官)”假说来解释这种现象的器官趋向性。在这一点上，前列腺癌(CAP)有很强的骨转移倾向，其他部位很少涉及。然而，即使癌细胞一旦寄生在遥远的器官中，如果没有血管生成的过程，它也无法生长2毫米。因此，由于所有器官的“种子”都是相同的，所以每个器官的“土壤”必须不同，才能允许转移细胞生长。综上所述，这些观察结果构成了我们指导性假说的基础，我们可以这样说：CAP的器官趋向性的潜在原因是器官特异性的血管生成诱导。例如，CAP细胞可能解释不正常的细胞环境，如转移部位，与正常细胞不同。虽然正常的前列腺上皮细胞在前列腺微环境中茁壮成长，但它不会在骨基质中茁壮成长。相反，CAP细胞可以在这两种微环境中生长，但不能在肝组织中生长，这在一定程度上解释了CAP转移的器官取向。我们最近发现，血管生成因子VEGF也可以通过CAP中的细胞表面接触来调节。粘着斑激酶(FAK)、Src、PI3K、Raf和MEK是RAS非依赖性信号通路中的关键效应因子。这种新的细胞表面介导的信号通路可能是恶性肿瘤细胞增强其血管生成潜能的重要途径，并可能解释CAP转移的器官特异性。由于抑制这一过程可能对CAP患者具有潜在的治疗应用，我们建议通过检验以下假设来进一步描述和剖析通过细胞表面接触诱导VEGF的机制：1)器官特异性VEGF诱导是CAP生长和转移的器官趋向性的关键决定因素；2)FAK、Src、PI3K、Raf、Rap1和MEK信号网络负责体内器官趋性CAP VEGF的诱导；3)新的细胞内信号网络和启动子基序负责细胞表面介导的VEGF诱导。为了验证这些假说，并为人类疾病的翻译联系奠定基础，我们提出了以下具体目标的研究：1)确定在转移的CAP细胞中诱导血管内皮生长因子是否具有器官特异性，以及在动物模型中血管内皮生长因子是否是器官趋向性的介导者；2)确定FAK、Src、PI3K、Raf、Rap1和MEK信号网络的复杂性及其在体内器官特异性血管内皮生长因子诱导或转移器官趋向性中的相关性；3)发现新的细胞内信号网络和启动子基序负责细胞表面介导的血管内皮生长因子诱导。结论：这些特定目标的成功完成将为调节血管内皮生长因子诱导的信号通路提供生物学上相关的分子信息，并可能增强我们对前列腺癌转移的器官特异性的理解，并为干扰这种致命且过于流行的疾病患者的这一过程的新疗法的开发奠定基础。

Background and Significance: The pattern of cancer metastasis was initially appreciated by Paget, who proposed the "seed (cancer cell) and soil (organ of metastasis)" hypothesis to explain the observed organ tropism of this phenomenon. In this regard, prostate cancer (CaP) has a strong predilection for bone metastasis with other sites being only rarely involved. However, even once lodged in a distant organ, a cancer cell cannot grow >2mm without the process of angiogenesis. Therefore, since the "seed" is the same in all organs, the "soil" must be different in each organ, in order to permit the metastatic cells to grow. Taken together, these observations form the basis of our Guiding Hypothesis can be stated as: the underlying reason for organ tropism of CaP is an organ specific induction of angiogenesis. For example, CaP cells may interpret abnormal cellular environments such as a metastatic site, differently than a normal cell. While a normal prostate epithelial cell thrives in the prostate microenvironment, it does not in the bone stroma. Conversely, a CaP cell may thrive in both microenvironments but not in that of liver tissue, explaining in part the organ tropism of CaP metastasis. We have recently discovered, that the angiogenic factor VEGF can also be regulated by cell surface contact in CaP. Focal adhesion kinase (FAK), Src, PI3K, Raf and MEK were found to be key effectors in this Ras- independent signaling pathway. This novel cell surface mediated signaling pathway may constitute an important way which malignant cells employ to enhance their angiogenic potential and may explain the organ specificity of CaP metastasis. Because of the potential therapeutic applications that inhibition of this process may have on patients with CaP, we propose to further delineate and dissect the mechanisms underlying VEGF induction by cell surface contact by testing the following Hypotheses: 1) Organ specific VEGF induction is a key determinant of organ tropism of CaP growth and metastasis in animal models; 2) FAK, Src, PI3K, Raf, Rap1 and MEK signaling networks are responsible for organ tropic CaP VEGF induction in vivo, 3) Novel intracellular signaling networks and promoter motifs are responsible for cell surface mediated VEGF induction. To test these hypotheses and additionally to lay the ground work for translational connections to human disease, we propose studies with the following Specific Aims: 1) Determine if VEGF induction in metastatic CaP cells is organ specific and whether VEGF is a mediator of organ tropism of CaP metastasis in animal models; 2) Determine the complexity of FAK, Src, PI3K, Raf, Rap1 and MEK signaling networks and their relevance in either organ specific VEGF induction in vivo or organ tropism of metastasis; 3) Discover novel intracellular signaling networks and promoter motifs responsible for cell surface mediated VEGF induction. Conclusions: Successful completion of these specific aims will provide biologically relevant molecular information on the signaling pathways regulating VEGF induction and may both enhance our understanding of the organ specificity of prostate tumor metastasis and provide a foundation for the much-needed development of novel therapies that interfere with this process in patients with this lethal and far too prevalent disease.