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Activating innate immunity to fight breast cancer
Risk, Prevention and Epidemiology
There has been debate as to whether human innate immune system is capable of constantly identifying and killing cancer cells and a failure of this system plays a role in cancer occurrence. Recently, a mutated mouse was found to have acquired systemic resistance to advanced malignancy apparently through leukocytes independently of lymphocyte-based immunity. Whether this innate immunity in mice can yield important clues to human cancer will await future studies. In an independent study, however, we demonstrated that the human complement system, an ancient innate immunity, could be specifically activated to kill breast cancer cells. We showed that human sera acquired an efficient killing feature specific to breast cancer cells by addition of an exogenous protein fraction, termed tumor specific complement activator or tsCA. The activated human serum completely lysed breast cancer cells within a few minutes, but had no effect on normal cells. We thus hypothesize that human complement lacks a crucial factor to specifically target breast cancer cells and initiate the proteolytic cascades. In this proposal, we plan to 1) characterize the exogenous factor (tsCA) that activates human serum and initiates tumor-specific cytolysis and 2) identify the target molecules on the surface of breast cancer cells. Based on the feature that tsCA specifically interacts with breast cancer cells, novel affinity approaches will be developed to identify the complex that initiates tsCA-mediated activation of human complement. Proteins in the complex will be identified with LC-MS/MS. Antibodies against the identified proteins will be raised and confirmed for their inhibitory activity. Our proposed study will have following potential outcomes and benefits: 1) existence of a novel mechanism for tsCA-mediated activation of human complement will be confirmed, which may lead to development of new strategies for drug discovery and cancer treatment; 2) the surface proteins on breast cancer cells may be used as new diagnostic markers and/or therapeutic targets for breast cancers; and 3) results of the proposed study will emphasize the role of complement in immune surveillance of breast cancer occurrence.
Our immune systems can efficiently identify and destroy abnormal cells. For many years, however, scientists have debated whether this immune surveillance can efficiently pickup cancer cells and destroy them spontaneously. It is encouraging that white blood cells from a naturally mutated mouse are recently found to kill aggressive cancer cells independently of adaptive immunity. Normal mice injected with these white blood cells acquired systemic resistance to aggressive cancers. Whether this phenomenon in mice can be found in humans needs further investigation. Markedly, we found in our laboratory that human blood acquired a specific activity to kill breast cancer cells by addition of a partially purified protein, termed tumor specific complement activator or tsCA. Our study demonstrated that this cancer killing activity acts through the Complement system, an ancient immune surveillance system to destroy infected and other abnormal cells. We thus hypothesize that human complement is capable of acquiring cancer-killing activity; however, it lacks a factor that specifically initiates the killing process. In this proposal, we plan to identify 1) the tsCA and 2) its target molecules on the surface of human breast cancer cells. Methodologies will involve development of novel affinity chromatographs and application of mass spectrometry-based proteomic approaches. These aims are straightforward and feasible based on our preliminary studies. Accomplishing these experiments will allow us to confirm the function of the factor and to characterize the mechanism underlying the phenomena of breast cancer-killing activity. It may explain, at least in part, why some people never get cancer. In addition, results of the proposed study will become a basis for novel diagnostic tools and new drugs to fight breast cancers.