ENDOTHELIAL GROWTH FACTOR IN PROSTATE CANCER METASTASIS

背景和意义：癌症转移的模式最初是由佩吉特认识到的，他提出了“种子（癌细胞）和土壤（转移器官）”假说来解释观察到的这种现象的器官向性。在这方面，前列腺癌（CaP）具有骨转移的强烈偏好，其他部位很少涉及。然而，即使癌细胞在远处器官中停留，如果没有血管生成过程，癌细胞也不能生长> 2 mm。因此，由于“种子”在所有器官中是相同的，因此“土壤”在每个器官中必须不同，以允许转移细胞生长。综上所述，这些观察结果形成了我们的指导假设的基础，可以表述为：CaP的器官嗜性的根本原因是血管生成的器官特异性诱导。例如，CaP细胞可以与正常细胞不同地解释异常细胞环境，例如转移部位。虽然正常的前列腺上皮细胞在前列腺微环境中茁壮成长，但它不在骨基质中。相反，CaP细胞可以在这两种微环境中生长，但不能在肝脏组织中生长，这部分解释了CaP转移的器官嗜性。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、PI 3 K、Raf和MEK被发现是该Ras非依赖性信号通路中的关键效应子。这种新的细胞表面介导的信号通路可能构成了一个重要的方式，恶性肿瘤细胞采用，以提高其血管生成的潜力，并可能解释器官特异性的钙磷转移。由于抑制该过程可能对CaP患者具有潜在的治疗应用，我们建议通过测试以下假设来进一步描述和剖析细胞表面接触诱导VEGF的潜在机制：1）在动物模型中，器官特异性VEGF诱导是CaP生长和转移的器官嗜性的关键决定因素; 2）FAK、Src、PI 3 K、Raf、Rap 1和MEK信号网络负责体内器官嗜性CaP VEGF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。为了检验这些假设并另外为翻译与人类疾病的联系奠定基础，我们提出了具有以下特定目的的研究：1）确定转移性CaP细胞中的VEGF诱导是否是器官特异性的，以及VEGF是否是动物模型中CaP转移的器官嗜性的介体; 2）确定FAK、Src、PI 3 K、Raf、Rap 1和MEK信号网络的复杂性及其在体内器官特异性VEGF诱导或转移的器官向性中的相关性; 3）发现负责细胞表面介导的VEGF诱导的新的细胞内信号传导网络和启动子基序。结论：这些特定目标的成功完成将提供调节VEGF诱导的信号传导途径的生物学相关分子信息，并可能增强我们对前列腺肿瘤转移的器官特异性的理解，并为急需开发的新疗法提供基础，这些新疗法干扰患有这种致命且过于普遍的疾病的患者的这一过程。

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.