Radiation-Induced Migration of Breast Cancer Cells
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Non-technical overview of the research topic and relevance to breast cancer: 
 
 Despite advances in early detection and treatment, breast cancer continues to be a major health problem in the United States. Radiation therapy has undergone tremendous advances over the past half century, and is now used to treat more than half of all breast cancer patients. It is also relied upon to control tumors in patients when complete surgical removal of the tumor and its infiltrating cells is not possible. However aggressive tumors, such as triple-negative breast cancers, continue to exhibit limited response to treatment relative to less aggressive cancers. We have recently observed that radiotherapy to a tumor or post-surgical tumor bed may stimulate tumor cells that were circulating in the blood at the time of treatment, to return and re-grow, through a mechanism involving stimulation of granulocyte macrophage colony stimulating factor (GM-CSF). This is of prime interest for breast cancer radiotherapy, because this phenomenon may explain the persistence of local recurrences following radiotherapy in a subset of breast cancer patients. Moreover, the implication of GM-CSF raises concerns over delivery of this agent (trade name Leukine) to stimulate white blood cell production in breast cancer patients during treatment. Understanding this phenomenon may then allow it to be stopped, as well as optimization of a patient’s therapeutic regimen based on the characteristics of their individual disease. The objective of this project is to understand how radiation stimulates breast cancer cell migration, how GM-CSF facilitates this process, and the significance of this phenomenon in human breast cancers. 
 
 
 
 
 
 
 
 The question(s) or central hypotheses of the research: 
 
 Our main hypothesis is that radiation of tumors and normal tissue stimulates expression of a protein factor that attracts circulating breast cancer cells. A secondary hypothesis of this work is that GM-CSF, the factor we have identified as responsible for this process, is a potential target for drug development that, when inhibited, may slow or stop the recurrence of tumors following radiotherapy. 
 
 
 
 
 
 
 
 The general methodology: 
 
 We will use a variety of mouse models with metastatic triple-negative breast cancer to characterize this phenomenon, and how different doses of radiation stimulate it. We will use a florescent imaging “label” on the tumor cells that allows us to monitor and count their migration before and after radiation. Model systems of different radiation doses, timing, and surgical interventions will be used to assess how this phenomenon may function in human breast cancer patients undergoing treatment. We will examine the role of GM-CSF in this process both in cells in a petri dish, in animal models, as well as in blood and tissue samples from breast cancer patients. After gaining an understanding of this process at the molecular level, we will test the ability of anti-GM-CSF antibodies to slow or stop this process and improve tumor response to radiation. 
 
 
 
 
 
 
 
 Innovative elements of the project: 
 
 The proposed project utilizes novel imaging methods, biological models, and preclinical radiotherapy techniques to evaluate a hypothesis that challenges traditional thinking in radiobiology. It is therefore innovative on a number of levels. The concept that tumors re-grow after radiation therapy in part because tumor cells that had entered the circulation and left the primary mass return and proliferate, is a departure from conventional radiobiology. This project will develop and apply a variety of novel techniques and models to answer its research questions. The most notable of these are the multiple mouse tumor models in which tumor cell migration can be monitored by imaging. We will not only elucidate a novel molecular mechanism through which radiation-induced tumor self-seeding operates and establish its clinical significance, but will also produce unique therapeutic approaches towards inhibiting this phenomenon and improving the cure of breast cancers by radiotherapy.