Promotion of tumor invasion and pseudosenescence by the aging microenvironment

描述（由申请方提供）：恶性黑色素瘤是一种侵袭性疾病，治疗选择有限。特别地，与年轻个体相比，55岁以上的个体对于相同等级和阶段的黑色素瘤具有差得多的预后。迄今为止，还没有人解决这种差异的原因，黑色素瘤的侵袭性和转移的老年人。我们的长期目标是测试老化微环境驱动黑色素瘤细胞的局部侵袭性和系统性传播的假设。在以前的工作中，我们确定了一个关键的信号通路，调节黑色素瘤的侵袭性，分泌因子Wnt5a。我们发现，高Wnt5A的黑色素瘤具有间充质表型，增加的迁移和侵袭倾向，并与预后不良显著相关。在该应用的初步数据中，我们表明黑色素瘤与老年人（而不是年轻人）的成纤维细胞共培养会诱导它们表达高Wnt 5a水平、间充质表型和侵袭性增加。有趣的是，我们还发现，与老年而非年轻的成纤维细胞共培养的黑色素瘤显示出衰老样表型的证据。我们的初步数据暗示黑色素瘤与老年人成纤维细胞的共培养。我们发现，老化的成纤维细胞持续降低Klotho的表达，Klotho是Wnt5A信号传导和衰老的有效抑制剂。我们假设老年肿瘤微环境中Klotho表达的降低有助于老年人黑色素瘤中Wnt5A信号传导的增加和侵袭性的增加。拟议的研究将有助于更好地了解Klotho和衰老微环境在55岁以上患者黑色素瘤中的侵袭性和侵袭性增加中的作用。预期阐明Klotho和Wnt5a在衰老中的黑色素瘤中的作用将导致改善的治疗。

DESCRIPTION (provided by applicant): Malignant melanoma is an aggressive disease for which there are limited therapeutic options. In particular, individuals over the age of 55 have a much poorer prognosis for melanomas of equal grade and stage, compared to younger individuals. To date, no one has addressed the reasons for this disparity in melanoma aggressiveness and metastasis in aging individuals. Our long-term objective is test the hypothesis that the aging microenvironment drives the local aggressiveness and systemic dissemination of melanoma cells. In previous work we identified a critical signaling pathway that modulates melanoma invasiveness, by the secreted factor Wnt5a. We have found that melanomas with high Wnt5A have a mesenchymal phenotype, an increased propensity to migrate and invade, and are significantly associated with poorer prognosis. In preliminary data for this application we show that co-culture of melanomas with fibroblasts from aged individuals, but not young individuals, induces them to express high Wnt5a levels, a mesenchymal phenotype, and increased invasiveness. Interestingly, we have also discovered that melanomas co-cultured with aged but not young fibroblasts show evidence for a senescent-like phenotype. Our preliminary data implicate the co-culture of melanomas with fibroblasts from aged individuals. We find that aged fibroblasts consistently decrease their expression of Klotho, and that Klotho is a potent inhibitor of Wnt5A signaling and senescence. We hypothesize that the decreased expression of Klotho within the aged tumor micro-environment contributes to increased Wnt5A signaling and increased invasiveness in melanomas in the elderly. The proposed studies will lead to an improved understanding of the role of Klotho and the aging micro-environment in the increased aggressiveness and invasiveness seen in melanomas in patients over the age of 55. It is expected that elucidating the role of Klotho and Wnt5a in melanomas in aging will lead to improved therapy.