Emodin as a chemopreventive agent for breast cancer - admin supp

大黄素作为乳腺癌的化学预防剂 - 行政支持

• 批准号: 10027034
• 负责人: ELIZABETH ANGELA MURPHY
• 金额: $ 4.04万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10027034
• 关键词: 4T1; Absence of pain sensation; Animals; Anti-Inflammatory Agents; Blood Circulation; Breast cancer metastasis; Cancer Relapse; Cell Line; Cells; Chemopreventive Agent; Chinese Herbs; Clinical; Distant; Emodin; Excision; Growth; Immune; Immunosuppression; Impaired wound healing; Inflammation; Inflammatory; Laboratories; Micrometastasis; Modeling; Neoplasm Metastasis; Non-Steroidal Anti-Inflammatory Agents; Operative Surgical Procedures; Organ; Patients; Perioperative; Pharmaceutical Preparations; Relapse; Resistance; Role; Surgical wound; Testing; Therapeutic; Time; Travel; Tumor-associated macrophages; breast surgery; cancer cell; clinical application; cost; immunogenic; macrophage; malignant breast neoplasm; meloxicam; monocyte; mouse model; neoplastic cell; operation; recruit; side effect; small molecule; systemic inflammatory response; theories; tumor; wound

PROJECT SUMMARY It has long been suspected that tumor resection surgery may actually accelerate cancer metastasis in some patients. Two theories for this have been proposed. The first one hypothesizes that some cancer cells are squeezed out of the tumor into circulation during the surgical operation and travel to distant organs to form metastasis, which grow into detectable metastasis several months later. The other hypothesizes that subclinical micrometastases have already seeded in distant organs even before the surgery but are under immune control, a state called metastatic dormancy, and the surgery somehow may accelerate the growth of the micrometastases into macrometastases by breaking the dormancy. Although clinical evidences strongly favor the second scenario, it is impractical and unethical to perform pseudo-surgery to directly test this hypothesis in patients. A very recent elegant animal study in Dr. Robert Weinberg’s laboratory strongly supports this scenario. Using a unique immunogenic syngeneic breast cancer mouse model, they demonstrated that surgery wounding results in systemic inflammation, during which the inflammatory monocytes and their resulting pro-tumor M2 macrophages (MΦs) are mobilized into circulation, leading to accumulation of tumor-promoting MΦs in the distant organs where they facilitate the metastasis establishment by the pre-surgery seeded of tumor cells. More interestingly, perioperative administration of meloxicam, a nonsteroidal anti-inflammatory drug (NSAID), could significantly suppress post-surgery tumor outgrowth, which is in line with a long time clinical observation that anti-inflammatory analgesia reduces post-surgery breast cancer relapse. Because NSAIDs may cause immunosuppression, wound healing delay, and other severe side effects, safer anti-inflammatory drugs are needed for this clinical application. In the past few years, our labs discovered that a Chinese herb-derived small molecule compound, emodin, has context-dependent bi- directional effects on MΦ activation, and can inhibit breast cancer growth and metastasis by reducing recruitment and M2-like polarization of tumor-associated MΦs. We propose that emodin can be developed as a safe, low-cost, and effective complementary agent to be used perioperatively to alleviate the surgery triggered systemic inflammatory response and reduce resulting metastatic relapse of breast cancer. To test this hypothesis, we recently developed a 4T1-derived cell line, 4T1-Luc2-RFP. Orthotopic tumors formed by 4T1-Luc2-RFP cells display much slower growth and significant resistance to metastasis. This new cell line will present a good model with an appropriate time window to study the impact of surgery on tumor metastasis and to develop therapeutic strategies. Two aims are proposed: 1) to test if emodin can inhibit surgical wounding accelerated breast cancer growth and metastasis, and 2) to determine the role of macrophages in emodin’s actions on breast cancer metastasis.

项目摘要 长期以来一直怀疑肿瘤切除手术实际上可能在某些人中加速癌症转移 患者。提出了两种理论。第一个假设某些癌细胞是 在手术手术过程中，从肿瘤中挤出肿瘤，然后前往远处的器官形成 几个月后，转移生长成可检测的转移。其他假设是 甚至在手术前甚至在 免疫控制，一种称为转移性休眠的状态，手术可能会以某种方式加速 通过破坏休眠状态，微型转移到宏观变体中。尽管临床证据很强 偏爱第二种情况，进行伪手术以直接测试这是不切实际的和不道德的 患者的假设。罗伯特·温伯格博士的实验室中最近的一项非常优雅的动物研究强烈 支持这种情况。使用独特的免疫原性乳腺癌小鼠模型，它们 证明手术获胜会导致全身感染，在此期间炎症 单核细胞及其产生的促肿瘤M2巨噬细胞（MφS）被动员到循环中，导致 促进肿瘤的Mφ在远处的器官中积累了它们促进转移的建立 通过肿瘤细胞的术前种子。更有趣的是，定期给予Meloxiam，一个 非甾体类抗炎药（NSAID）可以显着抑制手术后的肿瘤生长，这 与长时间的临床观察一致，抗炎镇痛会减少手术后乳房 癌症缓解。因为NSAID可能会导致免疫抑制，伤口愈合延迟和其他严重的一面 这种临床应用需要效果，需要更安全的抗炎药。在过去的几年中，我们的实验室 发现一种中国草药衍生的小分子化合物Emodin具有上下文依赖性的双生 对Mφ激活的定向影响，可以通过减少抑制乳腺癌的生长和转移 肿瘤相关Mφ的募集和M2样偏振。我们建议可以开发Emodin作为 一个安全，低成本且有效的完整代理，可定期用于减轻手术 触发了全身性炎症反应并减少乳腺癌的转移性缓解。测试 这个假设，我们最近开发了4T1衍生的细胞系4T1-LUC2-RFP。原位肿瘤由 4T1-LUC2-RFP细胞显示出较慢的生长和对转移的明显抗性。这个新的单元线将 提出一个良好模型，其中有适当的时间窗口，以研究手术对肿瘤转移的影响和 制定理论策略。提出了两个目标：1）测试Emodin是否可以抑制手术逻辑 加速乳腺癌的生长和转移，以及2）确定巨噬细胞在Emodin中的作用 对乳腺癌转移的作用。