Final Activity Report Summary - NEURONS AND CANCER (The role of nervous system in progression of breast cancer: focusing on neuropeptides released from sensory neurons and inflammatory mediators) Breast cancer is the second leading cause of death in women. Patients die because of distant metastasis which is the spread of tumour cells to other organs. Understanding mechanisms of metastasis is crucial to design new treatments. Psychology of the patients and their attitude toward disease is very important and may significantly affect the response to treatment. This suggests that nervous system plays an important role in progression of the cancer. We have previously demonstrated that activation of certain neurons, specifically capsaicin-sensitive sensory neurons decreased the metastasis of breast cancer by altering gene expression. These findings suggested that mediators released from these nerve endings protects against metastasis and can be used for treatment. The effects of neurons on response to different treatments were not also known. Substance P (SP) is a neuromediator which is found in sensory neurons. We here demonstrated for the first time that physiological fragments of substance P inhibited growth of breast carcinoma cells as well as cells metastasised to vital organs e.g. heart. These findings clearly demonstrated that physiological fragments of SP were important in the suppression of tumour growth and this might partly explain the mechanisms of enhanced metastases following inactivation of sensory neurons. We unexpectedly found that tumour suppressor effects of SP fragments were not inhibited by SP, but rather SP itself inhibited tumour growth. Because these findings were not in accordance with previously published results, we planned new experiments to clarify exact role of SP in tumour developments and metastases. SP as well as SP 9-11 enhanced anti-tumoural effects of radiotherapy. Furthermore, in order to determine the possible mechanisms involved in anti-tumoural effects of SP 9-11 fragment (the one seemed to be most effective in previous studies) we determined the proteins interacting with SP 9-11. We found several novel proteins which will help us to design novel treatments. We also extended our study to include melanoma which is a highly aggressive tumour. There is no effective treatment for advanced melanoma. Excitingly, P effectively decreased cell survival in B16F10 cells and potentiated the anti-tumoural effects of radiotherapy (RT). These results demonstrated for the first time that substance P and SP 9-11 induces cancer cell death and could be used in cancer treatment in future.
