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.

PROJECT NARRATIVE Tumor resection surgery may accelerate breast cancer metastasis in some patients. We have discovered that a Chinese herb-derived small molecule compound, emodin, can inhibit breast cancer growth and metastasis by reducing recruitment and M2-like polarization of tumor-associated macrophages. 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.