Complement-mediated Stem Cell Recruitment to Breast Cancer
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: Breast cancers invoke a similar response of the body as wounds that fail to heal. In this scenario cells in the tumor environment such as mesenchymal stem cells (MSC) exploit the normal wound healing process to benefit the tumor. It was recently shown that MSC are recruited to developing breast cancers, where they contribute to tumor growth and metastasis. The factors involved in the process of MSC recruitment and in the interaction of these cells with breast cancer cells are largely unknown. It is hypothesized here that complement activation, which is part of the body’s defense against infection, contributes to this process: it has been shown that there is persistent complement activation in breast cancers, which leads to the production of two small proteins called C3a and C5a. We recently described that MSC express receptors for C3a and C5a called C3aR and C5aR, and that MSC migrate towards C3a and C5a. It is therefore hypothesized that C3a and/or C5a produced within breast tumors recruit MSC to the tumor. Once MSC enter the tumor, C3a and C5a could play a crucial role in increasing tumor growth and metastasis, since MSC stimulated with C3a or C5a produce increased amounts of factors that support the growth of tumor cells and blood vessels and that interfere with the immune response mounted by white blood cells.
 
 
 
 
 
 
 
 It is anticipated that C3aR-deficient mice receiving a mix of breast cancer cells with MSC from C3aR-deficient mice or C5aR-deficient mice receiving a mix of breast cancer cells with MSC from C5aR-deficient mice in the mammary fat pad will show diminished tumor growth, blood vessel growth and metastasis compared to ‘normal’ mice receiving a breast cancer cell/normal MSC mixture. For these studies, MSCs will be isolated from mouse bone marrow of normal mice or from mice that are deficient in the C3aR or the C5aR and fluorescently labeled. C3aR-deficient mice will be injected into the mammary fat pad with a breast cancer cell/C3aR-deficient MSC mixture, C5aR-deficient mice will receive a breast cancer cell/C5aR-deficient MSC mixture, and normal mice a breast cancer cell/normal MSC mixture. Additional groups of mice will receive only breast cancer cells. Tumor growth will be measured over time. After 30 days the excised tumors will be analyzed for the presence of fluorescent MSC, various white blood cell populations, and an indicator that shows that complement had been activated. Blood vessel growth will be assessed, growth factor production will be measured and tumor metastasis to the lung will be evaluated. If C3aR-deficient or C5aR-deficient mice show decreased tumor growth and metastasis, inhibitors of the C3aR of the C5aR would be a novel therapeutic target in metastatic breast cancer.
 
 
 
 
 
 
 
 The role of MSC in tumor growth and metastasis has only recently been recognized and MSC are a novel target in breast cancer research that may lead to innovative therapeutic approaches. More specifically, we recently recognized that MSC are recruited by C3a and C5a, and that C3a and C5a induce the production of growth factors in MSC, which suggests a potential for enhanced tumor growth and metastasis. However, none of this has been shown in the context of breast cancer, or any cancer. Therefore this project is based on an entirely novel concept.