Tumor Cell-Microenvironment Interactions in the Molecular Pathogenesis of Multipl

多发性骨髓瘤（MM）的一个临床特征是局灶性肿瘤生长，MRI可检测为局灶性病变；这种肿瘤的生长与对化疗的抵抗力增加和常伴有溶骨性骨病有关。我们的初步研究表明，局灶性病变、溶骨性骨病和向髓外疾病的传播与Wnt/ β -连环蛋白信号的抑制以及p-连环蛋白和钙粘蛋白之间介导细胞粘附的相互作用有关。我们的长期目标是彻底了解Wnt/ β -catenin信号传导与骨髓瘤发病机制之间的关系，最终目标是发现新的治疗方法来控制骨髓瘤生长，提高骨髓瘤患者的生存和生活质量。我们假设微环境和骨髓瘤肿瘤细胞中Wnt/ β -catenin信号传导的解除是骨髓瘤自然历史中的一个基础和关键事件。控制这个信号轴可能代表了骨髓瘤治疗的范式转变。我们将通过以下具体目标来追求这一广泛的假设：（目标1）验证骨髓瘤肿瘤细胞中DKKI转录的升高与DKKI启动子的多态性/突变有关；（目的2）研究E-和N-cadherin及其与β -catenin的相互作用在MM发病机制中的作用，并确定它们是否代表可行的治疗靶点；（目的3）确定硼替佐米治疗的骨合成代谢效应是否源于间充质干细胞和成骨细胞中β -连环蛋白信号的诱导；（目的4）在MM中建立新的CYR61异构体的衍生，并确定该异构体和天然CYR61对骨髓瘤生长和骨病的体外和体内影响。全面了解MM中Wnt/ β -连环蛋白信号失调的分子事件，可能为控制骨髓瘤生长的创新治疗策略提供基础。

A clinically distinguishing feature of multiple myeloma (MM) is focal tumor growth detectable by MRI as focal lesions; this tumor growth is associated with increased resistance to chemotherapy and often osteolytic bone disease. Our preliminary work suggests that focal lesions, osteolytic bone disease, and dissemination to extramedullary disease are associated with molecular events resulting from suppression of Wnt/Beta-catenin signaling and from interactions between p-catenin and cadherin that mediate cell adhesion. Our long-term objective is to thoroughly understand the relationship between Wnt/Beta-catenin signaling and myeloma pathogenesis, with the ultimate goal of uncovering novel therapeutic approaches to control myeloma growth and improve survival and quality of life of patients with MM. We hypothesize that deregulation of Wnt/Beta-catenin signaling in both the microenvironment and the myeloma tumor cell is a fundamental and critical event in the natural history of MM. Therefore, control of this signaling axis may represent a paradigm shift in myeloma therapy. We will pursue this broad hypothesis through the following specific aims: (Aim 1) Verify that elevated transcription of DKKI in myeloma tumor cells is related to polymorphisms/mutations in the DKKI promoter; (Aim 2) Examine the roles of E- and N-cadherin and their interactions with Beta-catenin in MM pathogenesis and determine if they represent viable therapeutic targets; (Aim 3) Determine whether bone-anabolic effects of bortezomib treatment result from induction of Beta-catenin signaling in mesenchymal stem cells and osteoblasts; (Aim 4) Establish the derivation of a novel CYR61 isoform in MM and determine the in vitro and In vivo effects of this and native CYR61 on myeloma growth and bone disease. Comprehensive understanding of the molecular events surrounding dysregulation of Wnt/Beta-catenin signaling in MM will potentially provide the foundation for innovative therapeutic strategies to control growth of myeloma.