Elucidating the role of bisphosphonates in the inhibition of breast cancer

 描述(申请人提供)：一些乳腺癌患者在最初诊断和治疗时没有转移疾病的证据，但~30%-40%的患者在几个月甚至几年后会经历复发的乳腺癌，这表明这些播散的肿瘤可能在较长的时间内保持不被发现和惰性。值得注意的是，人们对惰性肿瘤发展为临床相关疾病的调节机制知之甚少。我们发现，某些人类乳腺癌(称为“煽动者”)促进了原本不起作用的肿瘤(称为“反应者”)的生长，这些肿瘤已经扩散到远处的器官--这一过程被称为“全身性煽动”。全身刺激是通过骨髓来源的细胞结合到播散性肿瘤的微环境中来介导的，在那里它们支持肿瘤的生长。重要的是，携带肿瘤的小鼠的造血性骨髓细胞在动员之前在骨髓中表现为促肿瘤形成。肿瘤衍生的骨桥蛋白(OPN)是一种细胞因子，在转移性乳腺癌患者的血浆中升高，并预示着不良的预后，对于激活支持肿瘤的BMC是必要的。双膦酸盐，包括唑来膦酸(ZOL)，通过抑制破骨细胞的活性而起作用，许多妇女都被双膦酸盐治疗骨质疏松症。我们之前关于全身激发的工作提供了一种可能的机制，通过这种机制，双膦酸盐既可以发挥其抗乳腺癌活性，又可以发挥其预防乳腺癌的能力5。我建议的目的是确定双膦酸类ZOL在全身激发过程中的作用，并阐明双膦类药物影响肿瘤支持骨髓细胞和肿瘤细胞骨定植的机制。我推测，ZOL对骨微环境的影响是通过抑制促肿瘤骨髓细胞的功能和抑制肿瘤细胞在骨骼中的定植来防止乳腺癌复发的。

 DESCRIPTION (provided by applicant): Some breast cancer patients have no evidence of metastatic disease at the time of their original diagnosis and treatment, yet ~30-40% of patients will experience recurrent breast cancer months or even years later, suggesting that these disseminated tumors can remain undetected and indolent for extended periods of time2-4. Remarkably little is known about the mechanisms that regulate outgrowth of indolent tumors into overt, clinically relevant disease. We found that certain human breast carcinomas (termed "instigators") facilitate growth of otherwise-indolent tumors (termed "responders") that had disseminated to distant organs-a process termed "systemic instigation". Systemic instigation is mediated by bone marrow- derived cells that incorporate into the microenvironment of the disseminated tumors where they support tumor growth. Importantly, hematopoietic BMCs of mice bearing instigating tumors are rendered pro-tumorigenic in the marrow prior to their mobilizations. Instigating tumor-derived osteopontin (OPN), a cytokine that is elevated in the plasma of patients with metastatic breast cancer and is predictive of poor outcome, is necessary for activating the tumor supportive BMCs5. Bisphosphonates, including zoledronic acid (ZOL), work by inhibiting the activity of bone osteoclasts and many women are treated with bisphosphonates for osteoporosis. Our previous work on systemic instigation provides a possible mechanism by which bisphosphonates might exert both its anti-breast cancer activity as well as its breast cancer prevention ability5. The goal of my proposal is to determine the effect of the bisphosphonate ZOL on the systemic instigation process and elucidate mechanisms by which bisphosphonates affect tumor-supportive bone marrow cells and tumor cell bone colonization. I hypothesize that ZOL's effect on the bone microenvironment prevents breast cancer recurrence by inhibiting the function of pro-tumorigenic bone marrow cells and by inhibiting tumor cell colonization in the bone.