Tumor Cell-Microenvironment Interactions in the Molecular Pathogenesis of Multipl

多发性骨髓瘤（MM）的一个临床显著特征是可通过MRI检测到的局灶性肿瘤生长（作为局灶性病变）;这种肿瘤生长与化疗耐药性增加和通常的溶骨性骨病相关。我们的初步工作表明，局灶性病变，溶骨性骨病，并传播到髓外疾病与Wnt/β-连环蛋白信号抑制和β-连环蛋白和钙粘蛋白之间的相互作用，介导细胞粘附的分子事件。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MM患者的生存率和生活质量。微环境和骨髓瘤肿瘤细胞中的连环蛋白信号传导是MM自然史中的基本和关键事件。因此，对该信号传导轴的控制可能代表骨髓瘤治疗的范式转变。我们将通过以下具体目标来实现这一广泛的假设：（目的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）检查E-和N-钙粘蛋白及其与β-连环蛋白在MM发病机制中的相互作用，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是由间充质干细胞和成骨细胞中β-连环蛋白信号的诱导引起的;（目标4）建立MM中新型CYR 61亚型的衍生，并确定该CYR 61和天然CYR 61对骨髓瘤生长的体外和体内作用，骨病全面了解MM中Wnt/β-连环蛋白信号转导失调的分子事件将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.