Influence of the mammary microenvironment on tumor progression: Identification of palmitoleic acid and osmotin as mediators of tumor cell growth

Therese S Salameh, Purdue University

Abstract

Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems. There are a number of factors that influence changes in body fat including diet, lifestyle, and genetics. Diet has been shown to be correlated to increased incidence of cancer and studies have shown that changes in fatty acid composition in diets are correlated with increased risk of a number of diseases including cancer. The main focus of these studies has been on understanding how diet, and dietary factors, influence tumor progression. In the first part of this study, a rat model was developed to study the effect of omega-3 or omega-6 polyunsaturated fatty acid rich diet on tumor development in prepubescent outbred female rats. Very few studies have evaluated the relationship between childhood diet and cancer, which is becoming increasingly important as childhood obesity is on the rise. Of the studies that have been completed, the focus has been on the effect of diet on tumor initiation and on the effect of in utero diet consumption on tumor development in offspring. Those studies have demonstrated that diets rich in omega-3 fatty acids are capable of inhibiting tumor initiation. Our work demonstrates that a diet rich in omega-3 fatty acids, given to a prepubescent rat from the time of weaning, has an adverse effect on tumor prevention. While the omega-3 group had increased tumor number, they had decreased tumor volume compared to the omega-6 group. Analysis of the fatty acid composition indicated that there was an increase in saturated fatty acid levels in the omega-3 fed group. Saturated fatty acids have been associated with an increase in breast cancer risk. Adipose tissue, the primary component of the tumor microenvironment, surrounds every organ in the human body. The tumor microenvironment has been shown to play a critical role in the growth and development of cancer. As obesity is associated with cancer incidence and diet influences obesity rates, understanding how diet changes the tumor microenvironment will provide insight into how obesity influences cancer incidence. Use of gas chromatography to analyze the fatty acid composition of mammary tissue has identified palmitoleic acid as a potential mediator of tumor cell growth. Follow up studies utilizing palmitoleic acid indicate that is in fact capable of promoting tumor cell growth and migration. Analysis of the mammary tissue from the omega fatty acid study indicate that palmitoleic acid levels were doubled in the omega-3 fed group compared to the omega-6 fed group. Analysis of mammary tissue from a previous animal study examining the effect of a western diet on tumor growth, indicated that the levels of palmitoleic acid were highest in the group containing the most aggressive types of tumors and the highest number of tumors. This provides the foundation for the development of palmitoleic acid as a potential cancer biomarker and potential molecular target for dietary intervention in cancer prevention. Contrary to the majority of adipocyte-secreted factors whose levels increase as adiposity increases and who promote tumorigenesis, adiponectin is an adipocyte-secreted factor whose levels decrease as adiposity increases and functions to inhibit tumorigenesis. Unfortunately, there are currently no known adiponectin-based therapies available to combat cancer. Osmotin, a plant protein identical in structure to adiponectin, has been identified as a potential alternative to an adiponectin-based therapy. The similarity in protein structure has allowed osmotin to initiate a similar physiological response in the cancer cell lines. Osmotin has been shown to inhibit tumor cell growth and induce apoptosis in the MCF-7 cell line. Further analysis indicates that osmotin inhibits cell cycle progression and decreases cyclinD1 activity. Osmotin was also shown to inhibit migration of MDA-MB-231 cells and U937 cells, a human macrophage cell line. Osmotin demonstrates a great deal of potential as a cancer therapeutic agent. It not only has antiproliferative properties, but has antimigratory properties which demonstrate its potential as an antimetastatic agent. There have been a number of advancements towards our understanding of how cancer works at the molecular level and a number of factors identified which initiate and promote cancer. Despite these advancements, there has been little progress in linking them to cancer preventions and treatments. Many studies have addressed the potential effects of diet on cancer incidence. Although a great deal of information has been gathered from these studies, there are still a lot of unknowns, thus providing a foundation for continued investigation into the role of diet and cancer.

Degree

Ph.D.

Advisors

Camarillo, Purdue University.

Subject Area

Biology|Womens studies|Oncology

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