Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
ReviewAdipose tissue and adipocytes support tumorigenesis and metastasis☆
Introduction
The role of adipose tissue, and more specifically adipocytes, in tumor initiation, growth, and metastasis, is a relatively new area of investigation. Adipose tissue has been traditionally regarded as an insulating and mechanically supportive site of energy storage, which is mobilized for peripheral organs during times of increased energy demand. However, after the discovery of leptin in 1994, the traditional role of adipose tissue has evolved to a fully functioning endocrine organ, capable of regulating systemic energy and metabolic homeostasis. A role for adipose tissue in cancer is emerging based on two key observations: (i) epidemiologic studies have demonstrated an association between obesity and some cancers (e.g. esophageal and endometrial), and (ii) adipocytes constitute a major component of the tumor microenvironment for breast and abdominally metastasizing cancers (e.g. gastric, colon, and ovarian), promoting tumor growth.
Several similarities can be drawn between an adipose tissue-dominated tumor microenvironment and the well-described function of adipose tissue in type 2 diabetes and obesity (Fig. 1). The two microenvironments share similar histologic features, including the presence of inflammatory cells, especially macrophages which secrete inflammatory cytokines. Adipocytes in both patients with obesity-associated type 2 diabetes and cancer, secrete adipokines, sustaining the activated state of the tissues, and promoting the progression of both diseases [1]. Expanding the analogy between the activated inflammatory adipose tissue in obesity and the cancer microenvironment, adipose tissue in obese patients is often characterized by chronic inflammation, while the tumor microenvironment is characterized by intratumoral inflammation which promotes progressive tumor growth and angiogenesis as described by Virchow (1863, “lymporeticular infiltrate in cancer”) and Dvorak (1986, “Tumors are wounds that do not heal”).
The expansion in cancer research from a cancer cell-centric approach to include adjacent “normal” cells that make significant contributions to cancer initiation and progression, has brought forth an exciting wave of research [2], [3], [4], [5]. This review will summarize what is known about how adipose tissue and adipocytes promote tumorigenesis. The first part of the review will discuss adipose tissue physiology, pathology, and biochemistry, which support the role of adipocytes in the tumor microenvironment. The latter part will review data from cancer-specific epidemiological and experimental studies on obesity and adipocytes in carcinogenesis. Our goal is to provide a concise synopsis of the complex reciprocal relationship between tumor cells and adipocytes, while highlighting interactions that may serve as unique clinical targets for cancer treatment and prevention.
Section snippets
Adipose tissue and adipocyte physiology and pathology
Adipose tissue is largely composed of adipocytes, but also contains a stromal vascular fraction made up of pericytes, endothelial cells, monocytes, macrophages, and pluripotent stem cells [6], [7]. Interestingly, adipocytes from different adipose tissue sites have unique metabolic functions, replicative and developmental potentials, cytokine production, and responses to external stimuli [8], [9]. For example, a proteomic analysis comparing human omental (i.e. visceral) and subcutaneous adipose
Adipocyte biochemistry
Adipocytes tightly control energy storage and utilization. Excess energy is stored in the form of triacylglycerol and the hydrolysis of triacylglycerol occurs during times of increased energy demands. The cycle of fatty acid storage and release is regulated, at least in part, by insulin. Insulin induces fatty acid uptake into adipocytes, inhibits lipolysis, and stimulates lipogenesis of triacylglycerol.
Triglyceride synthesis and storage occur in lipid droplets through the glycerol-phosphate
The role of obesity in tumorigenesis and cancer progression
Several epidemiological studies suggest an association between obesity and both cancer incidence and mortality [33], [34]. Not all cancers are associated with obesity and the relative risk (RR) seems to vary among cancer sites. In epidemiologic studies, cancer risk is often quantified as the proportional change in risk per 5 kg/m2 increase in body mass index (BMI), a measure of adiposity. Using this formula, the cancers most strongly associated with obesity are endometrial cancer (RR 1.52),
Adipocytes: active contributors to the tumor microenvironment
Tumorigenesis involves constant communication between tumor cells and neighboring normal cells. The tumor microenvironment, i.e. the normal cells that interact with premalignant and malignant cells, has recently been credited with supporting the acquisition of the necessary hallmark traits for tumorigenesis [49], [52], [53], [54]. In fact, an understanding of cancer is impossible without a comprehensive description of the tumor microenvironment. Most studies of the tumor microenvironment focus
Adipocytes and cancer
A number of tumors grow in the vicinity of adipocytes (e.g. breast cancer) or metastasize to the predominantly adipocyte-dominated host environment in the abdominal cavity (e.g. gastric and ovarian cancers). Studies linking adipocytes to tumorigenesis have increased in number over the last decade, most focused on breast, prostate, and colon cancer. A possible role for adipocytes in tumor development was first suggested in the mid-1960s with pioneering work by Spector (NIH, Bethesda). Dr.
Metabolic symbiosis in cancer
Cancer cells do not reside in plastic tissue culture dishes as solitary cell types where they are typically studied, or as Greenstein put it in 1954, “the tumor does not develop in a vacuum”. Tumor cells are part of a complex environment which defines their metabolism. As the tumor grows, regions evolve specific metabolic functions due to changes in their microenvironment. Dewhirst and colleagues (Duke University, Durham) first demonstrated that hypoxic regions of the tumor generate large
Conclusions and future areas of research
In summary, the current evidence clearly supports a model in which cancer cells reprogram adipocytes to CAA. Reprogrammed adipocytes produce growth promoting cytokines and provide lipids and other metabolites to cancer cells, promoting uncontrolled tumor growth.
The tumor promoting functions of adipocytes are a result of both the systemic actions of hormones involved in lipid hemostasis and local effects of adipocytes in the tumor microenvironment. Alterations in lipid metabolism during
Acknowledgements
Dr. Nieman is supported by a National Research Service Award from the National Cancer Institute. Dr. Romero is supported by grants from the Reproductive Scientist Development Program and the Prevent Cancer Foundation. Dr. Van Houten is supported by UPCI start-up and the Pennsylvania Department of Health, PA CURE. Dr. Lengyel is supported by a Clinical Scientist Award in Translational Research from the Burroughs Wellcome Fund, the Ovarian Cancer Research Fund, the National Cancer Institute, and
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This article is part of a Special Issue entitled Lipid Metabolism in Cancer.