Elucidating the role of bisphosphonates in the inhibition of breast cancer

阐明双膦酸盐在抑制乳腺癌中的作用

• 批准号: 9248790
• 负责人: Jessalyn Ubellacker
• 金额: $ 2.86万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9248790
• 关键词: Address; Adjuvant; Affect; Bone Marrow; Bone Marrow Cells; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer Prevention; Breast Carcinoma; Breast cancer metastasis; Cancer Model; Cells; Clinical; Coculture Techniques; Development; Diagnosis; Disease; Distant; Gene Expression; Gene Expression Profiling; Goals; Growth; Hematopoietic; Human; In Vitro; Indolent; Injection of therapeutic agent; Malignant Bone Neoplasm; Malignant Neoplasms; Mammary Neoplasms; Marrow; Mediating; Metastatic Neoplasm to the Bone; Metastatic breast cancer; Modification; Molecular; Mus; Neoplasm Metastasis; Organ; Osteoclasts; Osteoporosis; Outcome; Patient risk; Patients; Plasma; Primary Neoplasm; Process; Recurrence; Risk; Role; Route; Stimulus; Subcutaneous Injections; Supporting Cell; Tail; Testing; Therapeutic; Time; Tumor-Derived; Tumorigenicity; Veins; Woman; Work; Xenograft procedure; Zoledronic Acid; advanced disease; bisphosphonate; bone; bone cell; cancer recurrence; clinically relevant; cytokine; design; experience; experimental study; ineffective therapies; malignant breast neoplasm; mouse model; neoplastic cell; novel; osteopontin; patient population; pre-clinical; prevent; public health relevance; response; tool; tumor; tumor growth; tumor progression; tumorigenic

 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.

 描述（由申请人提供）：一些乳腺癌患者在最初诊断和治疗时没有转移性疾病的证据，但约30-40%的患者在数月甚至数年后会出现复发性乳腺癌，这表明这些播散性肿瘤可能在很长一段时间内未被检测到且不活跃2 -4。值得注意的是，很少有人知道的机制，调节生长的惰性肿瘤成为明显的，临床相关的疾病。我们发现，某些人乳腺癌（称为“煽动者”）促进生长，否则惰性肿瘤（称为“反应者”），已扩散到远处器官的过程称为“全身煽动”。全身性刺激由骨髓来源的细胞介导，这些细胞掺入到播散性肿瘤的微环境中，在那里它们支持肿瘤生长。重要的是，携带诱发性肿瘤的小鼠的造血BMC在其动员之前在骨髓中呈现促肿瘤发生。诱导肿瘤源性骨桥蛋白（OPN）是一种细胞因子，在转移性乳腺癌患者的血浆中升高，可预测不良结局，对于激活肿瘤支持性BMC是必要的5。双膦酸盐，包括唑来膦酸（ZOL），通过抑制骨破骨细胞的活性起作用，许多妇女用双膦酸盐治疗骨质疏松症。我们先前关于全身刺激的工作提供了一种可能的机制，通过这种机制，双膦酸盐可能发挥其抗乳腺癌活性以及预防乳腺癌的能力5。我的建议的目标是确定双膦酸盐ZOL的全身煽动过程中的效果，并阐明双膦酸盐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对骨微环境的影响通过抑制促肿瘤发生骨髓细胞的功能和抑制肿瘤细胞在骨中的定植来预防乳腺癌复发。