Role of Sympathetic Activation and RANKL/IL6 in Breast Cancer Bone Metastasis

描述(申请人提供)：乳腺癌的早期发现和新的治疗方法现已使患者的5年生存率超过99%，几乎所有乳腺癌死亡都是由于远处转移造成的，因此防止转移和复发具有重要的临床意义。这项工作的总体目标是研究慢性应激或抑郁诱导的交感神经系统(SNS)激活是否有助于乳腺癌患者的骨转移、复发和生存。我们实验室使用两种肿瘤骨转移模型积累的临床证据和实验数据支持这一假说。我们的数据还表明，成骨细胞衍生的细胞因子RANKL和IL6除了对破骨细胞生成和骨溶解有影响外，还是一个关键因素，促进了肿瘤细胞在SNS激活后在骨微环境中的定植。在这项应用中，我们建议表征这些SNS效应背后的细胞和分子机制(目标1和2)，并研究β-受体阻滞剂和RANKL阻滞剂是否对内源性交感神经激活的临床前小鼠模型的骨转移和生存有有益影响(目标3)。

DESCRIPTION (provided by applicant): Early detection of breast cancer and new treatments have now put the 5 year survival rate of patients above 99% and virtually all breast cancer deaths are the result of distal metastases, thus preventing metastasis and recurrence is of great clinical importance. The overall goal of this work is to address whether sympathetic nervous system (SNS) activation induced by chronic stress or depression in breast cancer patients contributes to bone metastasis, recurrence and survival. Clinical evidence and experimental data accumulated in our laboratory, using two mouse models of cancer metastasis to bone, support this hypothesis. Our data also point to osteoblast-derived cytokines RANKL and IL6 as a crucial factor promoting the colonization of cancer cells in the bone microenvironment in response to SNS activation, in addition to their effect on osteoclastogenesis and osteolysis. We propose in this application to characterize the cellular and molecular mechanisms underlying these SNS effects (Aim 1 and 2) and to address whether ?-blockers and RANKL blockade have beneficial effects on bone metastasis and survival in preclinical mouse models characterized by endogenous sympathetic activation (Aim 3).