Emodin as a chemopreventive agent for breast cancer - admin supp

项目总结 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患者的癌症转移。 病人。对此提出了两种理论。第一个假设是一些癌细胞是 在外科手术过程中从肿瘤中挤出进入循环，并移动到远处的器官形成 转移，几个月后生长为可检测到的转移。另一种假设是 亚临床微转移甚至在手术前就已经在远处的器官中种植了，但正在 免疫控制，一种称为转移休眠的状态，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。尽管有强有力的临床证据 支持第二种情况，通过假手术来直接测试这一点是不切实际和不道德的 患者的假说。最近在罗伯特·温伯格博士的实验室里进行的一项优雅的动物研究 支持此方案。利用一种独特的免疫原性同基因乳腺癌小鼠模型，他们 证明了手术创伤会导致全身炎症，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 促癌基因M-ΦS在促进转移建立的远处器官中的蓄积 通过手术前接种肿瘤细胞。更有趣的是，美洛昔康的围手术期给药， 非类固醇抗炎药(NSAID)，可显著抑制术后肿瘤生长， 抗炎止痛减少术后乳房的长期临床观察是否符合 癌症复发。因为非甾体抗炎药可能会造成免疫抑制、伤口愈合延迟等严重副作用 这种临床应用需要更安全的抗炎药物。在过去几年里，我们的实验室 发现一种中草药衍生的小分子化合物大黄素，具有上下文依赖的双 定向作用于MΦ激活，并可通过抑制乳腺癌的生长和转移 肿瘤相关M-ΦS的募集和类M2极化。我们建议大黄素可以作为 一种安全、低成本、有效的辅助药物用于围手术期以减轻手术负担 引发全身炎症反应，减少乳腺癌转移性复发。为了测试 在这一假设下，我们最近开发了一种4T1来源的细胞系，4T1-Luc2-RFP。原位肿瘤由以下方式形成 4T1-Luc2-RFP细胞生长较慢，对转移具有明显的抵抗力。这种新的细胞系将 提出了一个良好的模型和适当的时间窗口，以研究手术对肿瘤转移和 以开发治疗策略。提出了两个目标：1)测试大黄素是否能抑制手术创伤 加速乳腺癌的生长和转移，以及2)确定巨噬细胞在大黄素中的作用 对乳腺癌转移的作用。

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.