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，人们一直怀疑肿瘤切除手术实际上可能会加速某些人的癌症转移。 患者对此提出了两种理论。第一个假设是一些癌细胞 在手术过程中从肿瘤中挤出进入血液循环，并转移到远处的器官， 转移，几个月后发展成可检测的转移。另一种假设是， 亚临床微转移甚至在手术前就已经在远处器官中播种， 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肿瘤的生长。 通过打破休眠将微转移转化为大转移。虽然临床证据强烈 我倾向于第二种情况，进行伪手术来直接测试这一点是不切实际和不道德的 患者的假设。罗伯特温伯格博士的实验室最近进行的一项优雅的动物研究强烈地表明， 支持这种情况。他们使用一种独特的免疫原性同基因乳腺癌小鼠模型， 表明手术创伤导致全身性炎症，在此期间， 单核细胞及其产生的促肿瘤M2巨噬细胞（MΦ）被动员到循环中，导致 促进肿瘤的MΦ在远处器官中的积累，在那里它们促进转移的建立 通过手术前接种肿瘤细胞。更有趣的是，围手术期给予美洛昔康， 非甾体抗炎药（NSAID），可以显着抑制术后肿瘤生长， 与长期临床观察一致，抗炎镇痛可减少术后乳房 癌症复发因为NSAIDs可能引起免疫抑制、伤口愈合延迟等严重副作用 因此，这种临床应用需要更安全的抗炎药物。在过去的几年里，我们的实验室 发现一种中药衍生的小分子化合物大黄素，具有上下文依赖性的双- 定向作用于MΦ活化，并可通过减少乳腺癌的生长和转移， 肿瘤相关MΦ的募集和M2样极化。我们建议大黄素可以被开发为 一种安全、低成本、有效的辅助剂，可在围手术期使用，以减轻手术 引发的全身炎症反应，并减少乳腺癌的转移复发。测试 基于这一假设，我们最近开发了4 T1衍生的细胞系，4 T1-Luc 2-RFP。原位肿瘤形成于 4 T1-Luc 2-RFP细胞显示出慢得多的生长和显著的转移抗性。这种新的细胞系将 提供了一个具有适当时间窗的良好模型，以研究手术对肿瘤转移的影响， 来开发治疗策略。本研究的目的有二：1）探讨大黄素对外科创伤的抑制作用 加速乳腺癌的生长和转移，和2）确定巨噬细胞在大黄素的作用， 对乳腺癌转移的作用。