Wound Fluid Induces Cancer Cell Growth: A Mechanism for Recurrence?

Background: The process of wound healing after surgical resection of breast cancer may contribute to the development of local recurrence and possibly even metastases. Local recurrence after lumpectomy or mastectomy occurs most frequently near the surgical scar, leading to the hypothesis that the wound itself may promote the growth of residual disease. Some studies even suggest that removal of the primary tumor can accelerate progression of occult metastases. Two studies have shown that wound fluid can stimulate the growth of cancer cells and that differing cancer cell lines may be stimulated by differing wound fluid. A major criticism of these studies is that the activity of the wound fluid was compared to either the patient serum, which is likely less inflammatory than the wound fluid, or to serum free media. Thus, these studies did not define whether the inflammatory component of wound fluid alone is sufficient to stimulate cancer cell growth or whether the ability was specific to breast derived wound fluid. In this pilot study wound fluid was collected from 10 patients who had undergone unilateral mastectomy with abdominal flap reconstruction or bilateral mastectomy where one breast had known cancer and the contralateral did not. In the unilateral mastectomy patients, the fluid from the involved breast was compared to the fluid from the abdominal drain. In the bilateral mastectomy patients the fluid from the breast with cancer was compared with the fluid from the prophylactically removed breast. The effect of wound fluid on the growth of breast cancer cells was analyzed for each patient.Methods: Fluid from each breast and abdominal drain were collected 24 and 48 hours after surgery and their ability to promote growth of 6 different breast cancer cell lines was tested. In addition, the ability of the 48 hour wound fluid to stimulate colony formation of HBL-100 cells (ER-) on matrigel was established. The cytokine profile of the different wound fluid was also analyzed.Results: We found that when the ER – cells were cultured on matrigel, the breast derived fluid led to growth of invasive, branching colonies, while abdominal fluid from the same patient led to small round colonies. Further, we found that wound fluid derived from the breast where a tumor was present led to the formation of more invasive colonies than the wound fluid derived from the normal breast. Thus, we speculate that in addition to the normal cytokines and matrix metalloproteases associated with inflammation, breast wound fluid may contain additional proteins from the tumor bed microenvironment. In support of this model, we found that the protein composition of wound fluid varies from one site to another in the same patient.Conclusion: The biological activity and protein composition of wound fluid from the breast and abdomen is drastically different—such that breast wound fluid promotes growth and invasion of breast cancer cells. Thus, we hypothesize that residual disease may be stimulated to grow during the window of time after surgery when the wound fluid is produced. This transient stimulation may result in local recurrence if the nature of the residual disease is a foci cancer or acceleration of metastasis if the residual disease is disseminated into the surrounding lymph nodes or blood vessels. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3146.