Graduation Date

Fall 12-14-2018

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pathology & Microbiology

First Advisor

James E. Talmadge, Ph.D.

Second Advisor

Geoffrey M. Thiele, Ph.D.

Abstract

Omega (ω)-6 and ω-3 polyunsaturated fatty acids (PUFAs) are essential fatty acids (FAs) and the precursors of pro- and anti-inflammatory mediators respectively. Epidemiological studies have shown a lower incidence of breast cancer (BC) in the countries where long-chain (LC)-ω-3FAs consumption is higher; however, the role of ω-3FAs in BC growth and metastasis is poorly understood. We used isocaloric, isolipidic ω-6 and ω-3 (contains LC-ω-3FAs) diets and a pair-fed model to evaluate the effects of dietary PUFAs in mammary tumor metastasis. Our studies have resulted in several novel observations including that dietary LC-ω-3FAs modulate mammary gland (MG) microenvironments in non-tumor bearing (NTB) mice by lowering MG ductal density, epithelial cell proliferation, adipocyte hypertrophy and adipose tissue inflammation compared to the MGs in the ω-6 group. Similarly, we reported that dietary LC-ω-3FAs modulate the hepatic microenvironment (a common site of metastasis) by lowering hepatic steatosis, hepatocyte apoptosis, extramedullary myelopoiesis and NFκB expression relative to the respective observations in the ω-6 group. Finally, 4T1 mammary tumor studies in mice pre-exposed to these diets showed that, dietary LC-ω-3FAs delays mammary tumor induction and growth, and enhances survival of mice by lowering incidences/frequencies of spontaneous metastases to multiple organs including, lungs, liver, bone, heart, kidneys, ovaries and contralateral mammary glands compared to the respective analyses in the mice fed a ω-6 diet. In tumor microenvironments of mice fed a ω-3 diet, there were significantly lower numbers of proliferating tumor cells, neo-vascularization and a higher incidence of apoptotic tumor cells. Similarly, there was a significantly lower infiltration of myeloid cells including F-4/80+ macrophages and neutrophil elastase positive cell (granulocytes), and a higher infiltration of CD3+ T-Cells in tumors from mice fed an ω-3 diet relative to the ω-6 diet-fed group. There was a direct correlation between the neutrophil to T-cell ratio with tumor size and macrophage infiltration with neovascularization. There was also a direct correlation between T-cell infiltration and frequency of apoptotic tumor cells, indicating their roles in tumor growth. IL10 mRNA expression in tumors of mice fed an ω-3 diet was six fold higher, relative to the expression in the tumors from the ω-6 group, indicating a potential role of IL10 in the tumor growth suppression by dietary LC-ω-3FAs. In summary, our studies using isocaloric/isolipidic diets and a pair-fed model showed for the first time that dietary LC-ω-3FAs delay tumor growth and lower metastasis, and enhance survival by modulating the tissue microenvironments including MGs and liver.

Comments

Recommended Citations:

  1. S. Khadge, G. M. Thiele, J. G. Sharp, T. R. McGuire, L. W. Klassen, P. N. Black, C. C. DiRusso, and J. E. Talmadge, “Long-Chain Omega-3 Polyunsaturated Fatty Acids Modulate Mammary Gland Composition and Inflammation,” Journal of Mammary Gland Biology and Neoplasia, DOI: 10.1007/s10911-018-9391-5, March 2018
  2. S. Khadge, J. G. Sharp, G. M. Thiele, T. R. McGuire, L. W. Klassen, M. J. Duryee, H. C. Britton, A. J. Dafferner, J. Beck, P. Black, C. C. DiRusso, and J. E. Talmadge, “Dietary Omega-3 and Omega-6 Polyunsaturated Fatty Acids Modulate Hepatic Pathology,” The Journal of Nutritional Biochemistry, vol. 52, pp. 92-102, Feb. 2018
  3. S. Khadge, J. G. Sharp, T. R. McGuire, G. M. Thiele, and J. E. Talmadge, “Lipid Inflammatory Mediators in Cancer Progression and Therapy,” Tumor Immune Microenvironment in Cancer Progression and Cancer Therapy, Advances in Experimental Medicine and Biology, Springer, pp. 145-156, Dec. 2017

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