Breast CSC sensitivity to particle beam radiation

Despite significant improvement in the treatment outcome due to the development of novel and effective therapeutic strategies, breast cancer is still one of the most common causes of cancer-related mortality among women worldwide. Radiation therapy (RT) plays an important role in the management of early and advanced breast cancer. This therapeutic approach markedly reduces risk of the local recurrences of breast cancer. However not all carcinoma cells are uniformly sensitive to the photon-based RT that is currently used in the breast cancer treatment. It is suggested that cells survived after radiation exposure could be responsible for further tumor regeneration and disease progression. These cells are called cancer stem cells (CSCs). Since CSCs are suggested as photon- resistant intratumoral cell subpopulation, perhaps other types of RT (ion beam RT) could effectively destroy and eliminate CSCs. It is suggested that proton beam RT could be equally or even more effective compared to photon RT, whereas carbon ion beam RT has been shown to be undoubtedly more effective than photon RT with less pronounced normal tissue reactions. However, there are only limited and sporadic reports presenting results on the anti-tumor efficacy of ion beam RT. Therefore new clinically-relevant radiobiological research is urgently needed. Although molecular background of breast carcinoma cell radioresistance is relatively well described, little is known whether photon- resistant breast cancer cells (including breast CSCs) could be sensitive to proton or carbon ion beam ionizing radiation. Furthermore, nothing is known about molecular signature(s) of breast carcinoma cells resistant to the heavy ion irradiation. This research project aims to elucidate molecular signatures of breast CSCs associated with their resistance to low-linear energy transfer (LET) (photons and protons), and high-LET (carbon ions) ionizing radiation. Specific inhibition of the molecular pathways affected in CSCs can help to overcome resistance of breast CSCs to either low- or high-LET RT, thereby resulting in the improvement of clinical outcome in breast cancer patients treated with RT.

Despite significant improvement in the treatment outcome due to the development of novel and effective therapeutic strategies, breast cancer is still one of the most common causes of cancer-related mortality among women worldwide. Radiation therapy plays an important role in the management of early and advanced breast cancer. This therapeutic approach markedly reduces risk of the local recurrences of breast cancer. However not all carcinoma cells are uniformly sensitive to the photon-based RT that is currently used in the breast cancer treatment. It is suggested that cells survived after radiation exposure could be responsible for further tumor regeneration and disease progression. These cells are called 'cancer stem cells' (CSCs). It is generally believed that CSCs could be resistant to the photon-based ionizing radiation (low-LET), and we have assumed that carbon ion irradiation (high-LET) could more effectively destroy and eliminate CSCs compared to photon-based irradiation. In order to prove this hypothesis, we have generated two in vitro models of metastatic and radioresistant breast carcinoma cells. Both breast carcinoma cell models have demonstrated an enrichment for the CSC content. Using the proteomic approach, we have found that the molecular signatures of the investigated metastatically active and radioresistant carcinoma cells can be used for the development of the putative biomarkers to predict response to photon-based ionizing radiation. In cooperation with NIRS (Chiba, Japan), we have checked the sensitivities of the metastatically active and photon-resistant breast carcinoma cells to the carbon ion irradiation. It was determined that cells belonging to different sybtypes of breast cancer execute their low- and high-LET radiation responses using distinct molecular mechanisms. Therefore, a suitable type of radiotherapy could correctly be selected for each subtype of breast carcinomas depending on the molecular profiling of carcinoma cells. It was additionally detected that chemical compounds targeting deregulated molecular pathways can markedly improve radiation responses in metastatically active and radioresistant breast carcinoma cells. Thus, metastatic and radioresistant breast carcinoma cells are characterized by affected lipid metabolism. This fact opens additional perspectives to improve radiotherapy outcomes in breast cancer patients with the locally or distantly relapsed tumors. Furthermore, we try to determine how abnormalities in lipid metabolism can be explored in the inhibition of metastatic properties of breast carcinoma cells. This research project allowed us to develop new strategies to make radiotherapy as a more personalized approach.