Abstract
After apparently successful excision of breast cancer, risk of local recurrence remains high mainly in the area surrounding the original tumor, indicating that wound healing processes may be implicated. The proportional reduction of this risk by radiotherapy does not depend on the extent of surgery, suggesting that radiotherapy, in addition to killing tumor cells, may influence the tumor microenvironment. We studied how normal and mammary carcinoma cell growth and motility are affected by surgical wound fluids (WF), collected over 24 h following breast-conserving surgery in 45 patients, 20 of whom had received additional TARGeted Intraoperative radioTherapy (TARGIT), immediately after the surgical excision. The proteomic profile of the WF and their effects on the activation of intracellular signal transduction pathways of breast cancer cells were also analyzed. WF stimulated proliferation, migration, and invasion of breast cancer cell lines. The stimulatory effect was almost completely abrogated when fluids from TARGIT-treated patients were used. These fluids displayed altered expression of several cytokines and failed to properly stimulate the activation of some intracellular signal transduction pathways, when compared with fluids harvested from untreated patients. Delivery of TARGIT to the tumor bed alters the molecular composition and biological activity of surgical WF. This novel antitumoral effect could, at least partially, explain the very low recurrence rates found in a large pilot study using TARGIT. It also opens a novel avenue for identifying new molecular targets and testing novel therapeutic agents.
Highlights
Breast-conserving surgery followed by external radiotherapy is the current standard treatment for localized cancer of the breast [1, 2]
We observed that the stimulation of the growth of mammary carcinoma cell lines by wound fluids (WF) was significantly higher than that produced by the respective peripheral blood serum (PS) (Fig. 1 and Supplementary Fig. S1)
Residual tumor cells may still be present even when meticulous care is taken to ensure that excision margins are microscopically free of tumor, it is difficult to explain why radiotherapy reduces the risk of recurrence by the same proportional extent wide the excision is
Summary
Breast-conserving surgery followed by external radiotherapy is the current standard treatment for localized cancer of the breast [1, 2]. Targeted intraoperative radiotherapy (TARGIT) is the first of such techniques and enables delivery of radiotherapy to the tumor bed immediately after surgical excision of the tumor. The TARGIT technique offers a unique opportunity to study the immediate effect of radiotherapy on human tissues in vivo. We carried out preliminary proteomic analyses of the fluids to assess which factors may be responsible for the observed effects. By these experimental approaches, we tried to answer two clinical/biological questions: First, why do local recurrences arise mainly in the tumor bed irrespective of the margin status? Does intraoperative radiotherapy have an immediate effect on the local tumor microenvironment? We tried to answer two clinical/biological questions: First, why do local recurrences arise mainly in the tumor bed irrespective of the margin status? Second, does intraoperative radiotherapy have an immediate effect on the local tumor microenvironment? Is it conceivable that in addition to killing residual tumor cells (‘‘the seed’’), radiotherapy alters the microenvironment (‘‘the soil’’), making it less favorable for tumor cell growth and invasion in humans, as already shown in animal models [22]?
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