Research Interests
Chemokines and their receptors are intimately involved in regulating organ-specific leukocyte trafficking and inflammation, and they have been implicated to play important roles in regulating cancer growth and metastasis. Fractalkine (CX3CL1) is a membrane bound chemokine that is upregulated on endothelial cells under inflammatory conditions as well as in malignant cells. The receptor for fractalkine is CX3CR1 and is found on monocytes, natural killer cells, and a subset of T cells. We have shown that CX3CR1 and fractalkine can mediate all three steps of leukocyte migration: rolling/capture, firm adhesion, and extravasation, in an integrin independent manner under physiological flow conditions[1]. Monocytes and NK cells have been shown to regulate tumor surveillance and regulating tumor metastasis. However, little is known about how they traffic from the blood into tissues to exert their anti-tumor effects. The hypothesis we are testing is that fractalkine and CX3CR1 regulate the host immune response to cancers by affecting immune cell trafficking and function. We also wish to examine the known gene polymorphisms of CX3CR1 and their role in different cancer subtypes.
Our laboratory has shown than animals lacking CX3CR1 have more tumor metastasis in a B16 melanoma cancer model than wildtype controls[2]. We have published that the mechanism for this finding is altered monocyte and NK cell trafficking to the lung in CX3CR1 deficient animals. The cytotoxic effects of NK cells are the same in wildtype and knockout animals; however, CX3CR1 deficient NK cells secrete less IFN- and more IL-6. This altered cytokine milieu could lead to a more tumor friendly microenvironment. Thus, our work shows that CX3CR1 is important in the regulation and spread of malignancy through its effects on immune cell trafficking and cytokine production. We are establishing cell lines from WT and KO animals to further study the role of CX3CR1 on cell subsets (ie leukocytes, endothelial cells) as it pertains to cancer development and progression.

CX3CR1 can function as both an adhesion receptor as well as a signaling molecule. We have identified amino acid residues which are important for these two separate functions of CX3CR1[3] and are generating knockin animals with these mutations to study the specific mechanistic defects in vivo. We will study mice expressing mutant CX3CR1 molecules known to be defective in either signaling (R127N) or adhesion (Y14F) and determine the contributions of CX3CR1 adhesion and signaling to tumor surveillance by NK cells and monocytes in vitro and in vivo. These animals are being generated by the UNC animal models core facility. Our collaboration with Dr. Alessandro Fatatis (Drexel University) will explore the effects of the CX3CR1 functional mutants in the development of prostate cancer.
We have hypothesized that a functional CX3CR1 molecule may be important for fighting off either the establishment of tumor or its metastasis. We have previously shown that a naturally occurring polymorphism of CX3CR1 (I249/M280) codes for a nonfunctional molecule[4]. These receptors are defective in both their adhesive as well as their signaling capabilities. Other studies have shown a correlation with this genotype and the development of a number of diseases such as coronary artery disease. Therefore, we were interested in whether this polymorphism had an effect on cancer. Our pilot studies in ovarian cancer have shown no correlation between the V249I/T280M CX3CR1 polymorphism with the onset, development, or progression of disease. However, our published data in the B16 mouse model have suggested that a more relevant site for action may be in the lung. Therefore, we have begun screening a lung cancer population to ascertain if a correlation exists. We have acquired DNA samples isolated from non small cell lung cancer patients in a cohort established by Dr. Michael Kelley (Duke University) to determine a possible correlation for this type of cancer.

In summary, my laboratory is interested in studying the role of CX3CR1 in the development and progression of cancer. Recently, other groups have shown that exogenously added fractalkine leads to a decrease in tumor size. Therefore, this ligand pair is also a potential target for anticancer therapies.

Recent Accomplishments and Honors
1985 Graduated cum laude
1992-1994 NIH Fellowship Award

Training
University of California Davis BS 1981-1985 Biological Science
University of California San Diego PhD 1985-1991 Biomedical Science

Publications
1. Fong, A.M., et al., Fractalkine and CX3CR1 mediate a novel mechanism of leukocyte capture, firm adhesion, and activation under physiologic flow. J Exp Med, 1998. 188(8): p. 1413-9.
2. Yu, Y.R., et al., Defective antitumor responses in CX3CR1-deficient mice. Int J Cancer, 2007. 121(2): p. 316-22.
3. Fong, A.M., et al., CX3CR1 tyrosine sulfation enhances fractalkine-induced cell adhesion. J Biol Chem, 2002. 277(22): p. 19418-23.
4. McDermott, D.H., et al., Chemokine receptor mutant CX3CR1-M280 has impaired adhesive function and correlates with protection from cardiovascular disease in humans. J Clin Invest, 2003. 111(8): p. 1241-50.

E-mail: afong@med.unc.edu
Telephone: 966-0544
FAX: 966-9269
Address: 4111 Thurston Chapel Hill, NC 27599

Click here to update this profile