Discipline: Biological Sciences
Subcategory: Cancer Research
Mikala D. Jones - Jackson State University
Co-Author(s): Jessica Webber, Samantha He, Thomas Kelly, and Steven R. Post, University of Arkansas for Medical Sciences
Introduction: Understanding the factors that contribute to the inflammation associated with many diseases is important for developing new and more effective approaches for their treatment. To a large extent, inflammation is regulated by communication between cells. Cell-cell communication mediated by the release of soluble factors, such as growth factors and cytokines, is well studied. Less well appreciated are inflammatory responses mediated via the deposition and modification of extracellular matrix (ECM). We reported that proteolytic cleavage of the ECM component collagen by fibroblast activation protein-alpha (FAP), which is expressed by activated fibroblasts, creates an adhesion substrate that is recognized by the class A scavenger receptor (SR-A) on macrophages. In cancer, the tumor microenvironment resembles the inflammatory response associated with wound healing where killing of tumor cells by the immune system is suppressed. Macrophages are key regulators of inflammation and presumably signal for immune suppression versus immune activation and tumor cell killing.
Hypothesis: We hypothesize that a novel communication pathway involving FAP, collagen, and SR-A regulates macrophage function and inflammation in the setting of chronic disease.
Methods and controls: To test this hypothesis, we used genetically-modified mice which lack either SR-A (SRA -/-) or FAP (FAP -/-) to assess their role in the pathology associated with tumor growth in mouse models of human breast cancer. We used three different strains of mice: C5BL6/J (Inbred background strain), SRA -/- (SRA knockout mice) and FAP -/- (FAP knockout mice). Each mice (male and female) was injected with E0771 cells (mice breast cancer cells derived from the C57BL6/J mice). Particularly 14-21 days after injection, tumors grew at injection sites. Tumors were collected, cleaned, weighed and analyzed for histology purposes.
Results: Tumors that were implanted in the flank of male mice grew at a faster rate in the wild type animals than those implanted in either FAP KO or SR-A KO mice. Similarly, tumors that were implanted in the fat pads of female mice grew faster in the wild type animals grew than those growing in either FAP KO or SR-A KO mice. There was no pronounced immune response in any of the tumors isolated from the injected mice.
Conclusion and future research questions: No obvious differences in the inflammatory response were observed using this method. In future work we will develop a protocol for isolation of viable cells from tumors. These will be subjected to flow cytometry to determine the inflammatory cell populations present in the tumor. Using this strategy, it can be conclusively determined if FAP and/or SR-A encourage tumor growth by altering the immune response to the tumor.
Funder Acknowledgement(s): LSAMP Bridge to Doctorate, NSF; UAMS Summer Undergraduate Research Program to Increase Diversity in Research, NIH, Grant 5R25HL108825
Faculty Advisor: Clement Yedjou, firstname.lastname@example.org
Role: The part of research I did included the methods and control: I didn't actually inject the mice. I took tumor measurements and analyzed the tumors by means of histology purposes. I also cultured the cells (E0771) and made sure there were enough available for each mice injection.