Distinct Tumor and Metastatic Collagen Microenvironments: Divergent Targeting Approaches

项目总结 原发肿瘤的转移进展是癌症死亡的主要原因。虽然最初的步骤是 转移级联被很好地定义，识别阻断这一过程的靶点仍然是主要的 临床挑战。以前的研究已经很好地研究了肿瘤细胞内在的机制贡献 促进膀胱尿路上皮癌转移的特性。然而，它的功能意义 肿瘤微环境及其对这一复杂过程的贡献尚未得到很好的表征，因此， 有理由进行调查。这项续订申请的长期目标是继续探索胶原蛋白-a 微环境的主要细胞外基质成分-充当配体，与他们的 肿瘤细胞上的受体促进转移级联反应。我们将调查下游监管 原发灶和转移灶中胶原受体信号转导机制的研究进展 监管程序，作为一种革命性的方法，目标转移。这种创新的方法扰乱了 胶原蛋白-癌症的串扰--不仅在原发肿瘤，而且在转移的壁龛--将推动这一领域 通过在转移性疾病治疗中提供新的概念而向前发展，并可能延伸到膀胱以外 癌症转移到其他癌症类型。

PROJECT SUMMARY Metastatic progression of the primary tumor accounts for the majority of cancer deaths. While the initial steps of the metastatic cascade are rather well defined, identification of targets to block this process remains a major clinical challenge. Previous studies have elegantly investigated the mechanistic contribution of tumor cell intrinsic properties that promote metastasis in bladder urothelial carcinomas. However, the functional significance of the tumor microenvironment and its contribution to this complicated process is not well characterized, and therefore, warrants investigation. The long-term goal of this renewal application is to continue explore how collagens—a major extracellular matrix component of the microenvironment—act as a ligand to mediate crosstalk with their receptor on tumor cells to facilitate the metastatic cascade. We will investigate the downstream regulatory mechanisms of collagen receptor signaling in both the primary tumor and metastatic sites, and to exploit these regulatory processes as a revolutionizing approach to target metastases. Such innovative approaches to perturb collagen-cancer crosstalk—not only at the primary tumor but also at the metastatic niche—will move the field forward by providing a new conception in metastatic disease management, and likely extend beyond bladder carcinomas to other cancer types.