Gene expression profiling has indicated that the up-regulation of specific subsets of chemokines/cytokine/ growth factors is often linked to poorer prognosis for women with invasive mammary carcinoma. Chemokines are important for the recruitment of leukocytes to the tumor microenvironment (TME) which can affect invasion and metastasis. It has been proposed that specific chemokines released by circulating tumor cells signal to leukocytes in the pre-metastatic niche and entrain myeloid cells to exhibit an anti-tumorigenic phenotype. The entrainment process is thought to require activation of neutrophil NADPH oxidase to ultimately generate extracellular H2O2, which is toxic to tumor cells. This process is reported to be dependent upon activation of PI3 kinase. The goal of this research is evaluate mechanisms of entrainment and to characterize the role of inhibition of PI3 kinase in chemokine mediated entrainment of leukocytes. We hypothesize that perisurgical delivery of entraining chemokines to cancer patients may reduce recurrence and metastasis. Moreover, current PI3K inhibitor therapies for breast cancer patients might fail if they reverse this entrainment, counteract the effect of anti-tumor leukocytes, and thus promote metastasis. There are three specific aims for this study: 1) Using an immunocompetent mouse model we will determine whether manipulation of CCL2, CCL5, CXCL1, CXCL12 and/or TGF-beta levels will differentially effect the recruitment of anti- or pro-tumor leukocytes into the primary tumor and the pre-metastatic niche.
Aim1 B. We will determine whether blocking the receptors for each of these chemokines will facilitate or disrupt the metastatic capacity of mammary carcinoma;2) Using immunocompetent mice, intravital imaging, and ex-vivo micro-bioreactors we will determine whether current therapeutics for breast cancer that inhibit PI3K are able to block or facilitate chemokine-mediated 'entrainment" of myeloid cells in tumor bearing mice;We will deliver PI3K inhibitors to tumor bearing mice, isolate myeloid cells, and determine whether neutrophils respond to entraining chemokines with induction of H2O2 and have the capacity to kill tumor cells;3) We will evaluate changes in the myeloid 'entrainment'status of cancer patients before and after chemotherapy and determine whether leukocytes can be entrained 'ex vivo'. Using a humanized mouse model and implanted patient tumors, we will determine whether drug induced alterations in myeloid entrainment that result in reduced tumor cell killing and/or enhanced metastasis correlates with time to progression in the patient. In humanized mice, we will also compare the effects of ex vivo treatment with chemokines or PI3K inhibitors on 'entrainment'properties of circulating myeloid cells of cancer patients prior to surgery, after surgery, or perisurgery to determine the appropriate time to deliver entraining chemokines or PI3K inhibitors.

Public Health Relevance

Using novel methodologies, we will define the chemokine mediated signals that are needed to entrain leukocytes to kill tumor cells in the pre-metastatic niche and inhibit establishment of metastatic breast cancer lesions. Results will reveal strategies to most effectively teach the immune system to better protect tissues from cancer metastasis.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Woodhouse, Elizabeth
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Vanderbilt University Medical Center
Anatomy/Cell Biology
Schools of Medicine
United States
Zip Code
Raman, Dayanidhi; Sai, Jiqing; Hawkins, Oriana et al. (2014) Adaptor protein2 (AP2) orchestrates CXCR2-mediated cell migration. Traffic 15:451-69
Ciombor, Kristen K; Feng, Yang; Benson 3rd, Al Bowen et al. (2014) Phase II trial of bortezomib plus doxorubicin in hepatocellular carcinoma (E6202): a trial of the Eastern Cooperative Oncology Group. Invest New Drugs 32:1017-27
Crowder, Spencer W; Horton, Linda W; Lee, Sue Hyun et al. (2013) Passage-dependent cancerous transformation of human mesenchymal stem cells under carcinogenic hypoxia. FASEB J 27:2788-98
Neel, Nicole F; Sai, Jiqing; Ham, Amy-Joan L et al. (2011) IQGAP1 is a novel CXCR2-interacting protein and essential component of the "chemosynapse". PLoS One 6:e23813
Rhodes, Lyndsay V; Short, Sarah P; Neel, Nicole F et al. (2011) Cytokine receptor CXCR4 mediates estrogen-independent tumorigenesis, metastasis, and resistance to endocrine therapy in human breast cancer. Cancer Res 71:603-13
Raman, Dayanidhi; Sobolik-Delmaire, Tammy; Richmond, Ann (2011) Chemokines in health and disease. Exp Cell Res 317:575-89
Richmond, Ann (2011) Chemokine research moves on. Exp Cell Res 317:553-5
Richmond, Ann; Yang, Jinming; Su, Yingjun (2009) The good and the bad of chemokines/chemokine receptors in melanoma. Pigment Cell Melanoma Res 22:175-86
Wang, Dingzhi; Dubois, Raymond N; Richmond, Ann (2009) The role of chemokines in intestinal inflammation and cancer. Curr Opin Pharmacol 9:688-96
Liu, Yuxin; Sai, Jiqing; Richmond, Ann et al. (2008) Microfluidic switching system for analyzing chemotaxis responses of wortmannin-inhibited HL-60 cells. Biomed Microdevices 10:499-507

Showing the most recent 10 out of 42 publications