The role of BMX in Lymphangiogenesis

描述（由申请人提供）：根据美国癌症协会，2007年将有50多万美国人死于癌症。尽管癌症研究已经付出了很多努力，但它仍然是美国第二大最常见的死亡原因。由于对癌症治疗的需求仍然存在，因此更需要更详细地研究癌细胞运作的基本机制。寻求对癌症更彻底的了解可以对比并加强我们对癌细胞扩散到身体其他部位的了解。黑色素瘤癌症模型已被验证用于研究癌症转移。它将在我们的系统中产生淋巴管生成反应的背景下进行研究。最近人们认识到，新的淋巴管的形成可以为癌细胞提供一条通往身体其他部位的逃逸途径。此外，通常被招募到肿瘤的巨噬细胞也可以在淋巴管生成中发挥作用。已经提出，这通过两种不同的机制发生：1)巨噬细胞直接并入现有的淋巴管；2)巨噬细胞产生VEGF-C，刺激淋巴管生成。通过缺乏蛋白酪氨酸激酶（Bmx -/-）的小鼠，我们计划确定Bmx在骨髓中的功能，并更广泛地确定骨髓来源细胞对肿瘤淋巴管生成的贡献。我们的初步结果表明骨髓中的Bmx对炎症反应中的迁移至关重要。我们将确定这些影响最终是由淋巴细胞迁移、单核细胞/巨噬细胞迁移缺陷介导的，还是两者兼而有之。我们计划在这些细胞类型中研究Bmx缺失后，癌细胞、巨噬细胞、淋巴内皮之间的相互作用和功能结局。具体来说，我们想研究Bmx是否会影响这些细胞的迁移和/或增殖能力，以及肿瘤淋巴管生成减少或增加的临床结果/意义（通过小鼠发病率和死亡率来衡量）。我们将通过使用绿色荧光蛋白（GFP）报告小鼠来测量体内迁移，这将使我们能够确定骨髓来源细胞对Bmx-/-小鼠淋巴管的贡献。我们计划将这种体内方法与其他体内和体外试验相结合，以确定巨噬细胞对淋巴管生成的作用机制。最终，针对Bmx的新型抑制剂分子可能在癌症治疗中有效。

DESCRIPTION (provided by applicant): According to the American Cancer Society, more than half a million Americans will die from cancer in 2007. Although much effort has been focused on cancer research, it remains the 2nd most common cause of death in the U.S. As the need for cancer therapy remains, there is also a greater need to study in greater detail the fundamental mechanisms of how cancer cells operate. Seeking a more thorough understanding of cancer can contrast with and reinforce the knowledge we have about the spread of cancer cells to other regions of the body. The melanoma cancer model has been validated to study cancer metastasis. It will be studied in our system in the context of generating a lymphangiogenic response. It has recently become appreciated that creation of new lymphatic vessels can provide an escape route for cancer cells en route to other parts of the body. Also, macrophages that are normally recruited to tumors can play role in lymphangiogenesis. It has been proposed that this occurs by two distinct mechanisms: 1) Direct macrophage incorporation into existing lymphatic vessels and 2) Macrophage production of VEGF-C which stimulates lymphangiogenesis. Through mice that are deficient in a protein tyrosine kinase, (Bmx -/-), we plan to determine the function of Bmx in the bone marrow and more broadly the contribution of bone marrow derived cells to tumor lymphangiogenesis. Our preliminary results indicate Bmx in the bone marrow is critical for migration in an inflammatory response. We will determine if these effects are ultimately mediated by a defect in lymphatic cell migration, monocyte/macrophage migration, or perhaps a combination of both. We plan to study the interactions between cancer cells, macrophages, lymphatic endothelium and the functional outcomes when Bmx is deleted in these cell types. Specifically, we want to investigate if Bmx affects the migratory and/or proliferative capacity of these cells and the clinical outcomes/significance of decreased or increased tumor lymphangiogenesis (measured by mice morbidity and mortality). We will measure migration in vivo by using green fluorescent protein (GFP) reporter mice which will allow us to determine the contribution of bone marrow derived cells to lymphatic vessels in Bmx-/- mice. We plan to combine this in vivo method with other in vivo and in vitro assays to determine the mechanism of macrophage contribution to lymphangiogenesis. Ultimately novel inhibitor molecules against Bmx may be effective in cancer therapy.