Leukocyte Recruitment, Angiogenesis and 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: In spite of advances in our current understanding and treatment of breast cancer, approximately 30% of breast cancer patients develop advanced, usually incurable metastatic disease. Unlike solid tumors, the metastatic micro-tumors originating from the breast are resistant to various therapies. Our interest is to study the immunopathology of metastatic breast cancer with the objective of enhancing or modulating the patient's own immune response to combat the disease. Recent studies with immune regulatory factors, such as cytokines and chemokines, have demonstrated their potential to eradicate experimentally induced tumors in animals. The inhibition of tumor growth in these studies was associated with enhanced infiltration of tumor killing lymphocytes. Thus, a better understanding of how immune cells interact with tumor microvessels in breast carcinomas will facilitate the development of strategies to target breast cancer.
 
 
 
 
 
 
 
 Our project will investigate the properties of metastatic micro-tumors, which stimulate local formation of blood vessels through a process called angiogenesis. Our experimental technique is called 'intravital microscopy', which can directly visualize the interaction of immune cells with the tumor microcirculation. For this, we implant a transparent window chamber in the dorsum of a female mouse. Tiny tumor spheroids of human breast carcinoma (e.g., MCF-7 cells) are introduced into the chamber, and this stimulates production of a localized network of blood vessels within 10-14 days. This now becomes our model system where we can introduce immune cells, inhibitory molecules to prevent their attachment to the vessels, and immune-stimulatory compounds, such as cytokines. Our first aim is to test whether leukocyte/T-cell attachment is prevented by (i) inducing the expression of endothelial cell adhesion molecules by stimulation with inflammatory cytokines and/or (ii) blockade of angiogenic factors released by tumors. Next, we will inject mouse T-cells (and CD8+ cells) that have the ability to kill tumor cells, and determine whether vessel stimulation with specific cytokines and chemokines will help in T-cell recruitment into the tumor vessels. Finally, one key step in immune recruitment is the ability of leukocytes to leave the tumor vessels and move into the space where the tumors reside. Using our model of tumor angiogenesis, it will be possible to expose the cytokine-activated tumor vessels to various compounds and examine if the leukocytes or T-cells move from the blood into sites of tumor growth.
 
 
 
 
 
 
 
 In cancer patients, immune cells continuously circulate in close proximity to cancer cells that spread and grow in different parts of the body. However, the ability of immune cells to stem the growth of these tumors appears to be compromised. It is hoped that new information will help in developing strategies to improve immune surveillance as a mechanism to effectively treat metastatic breast cancer.