Endocrine (2015) 48:353–354 DOI 10.1007/s12020-014-0379-7
LETTER TO THE EDITOR
Thyroid adiponcosis: more than an hypothesis Maurizio Bifulco • Mario Vitale
Received: 8 May 2014 / Accepted: 1 August 2014 / Published online: 2 September 2014 Ó Springer Science+Business Media New York 2014
To the Editor In recent decades, the incidence of cancer has increased along with a marked rise of pandemic diseases such as insulin resistance, metabolic syndrome, and obesity. The accumulating evidence of a causal relationship between obesity and increased cancer risk has brought researchers to the introduction of the new term ‘‘Adiponcosis’’, derived from the fusion of the words ‘‘adiposis’’ and ‘‘oncosis’’ [1]. The incidence of thyroid cancer, the most common endocrine cancer, has risen dramatically in recent decades. In addition to environmental and alimentary factors, the increased thyroid cancer occurrence has been associated to the marked increase of prevalence of obesity. Indeed, a correlation between the body mass index (BMI) and thyroid cancer incidence has been demonstrated in several reports. According to a pooled analysis of five prospective studies and more recently a pooled analysis of three casecontrol studies, a higher thyroid cancer risk occurs in individuals with high BMI and high body fat percentage [2, 3]. According to recent findings, not only obesity, defined as a BMI greater than 30 kg/m2, but also overweight (BMI, 25–29.9 kg/m2) has been linked to a higher thyroid cancer risk. Interestingly, this association is tumor type-specific being significant or near-significant for thyroid adenocarcinomas but not for medullary thyroid cancer, suggesting a specific carcinogenetic mechanism operating in follicular thyroid cells. The molecular mechanisms underlying this interesting relationship are unknown, and the hypotheses formulated include the upregulation of mitogenic
M. Bifulco M. Vitale (&) Department of Medicine and Surgery, University of Salerno, Via Allende, Baronissi, 84081 Salerno, Italy e-mail: [email protected]
pathways, low-grade inflammation, and oxidative stress. Adipose tissue is an immune and endocrine organ predisposing individuals to the development of inflammatory and proliferative diseases. Tumor necrosis factor alpha (TNFa), IL-6, IL-1b, CCL2, CXCL8, and CXCL9 are only some of the inflammatory cytokines which are elevated in the serum of obese patients. Conversely, adiponectin, an antiinflammatory hormone that improves insulin sensitivity, suppresses the effects of TNF-a, IL-6, and IFN-c is reduced in the serum of obese patients and is negatively associated with various types of cancer including lung, breast, prostate, and colorectal carcinomas. Insulin resistance and the consequent hyperinsulinemia are a common trait of obese individuals. TNF-a and resistin produced by macrophages in the stromal compartment of adipose tissue, induce insulin resistance, and the consequent hyperinsulinemia might increase the cancer risk through the Akt/PI3K/ mTOR cascade that promotes cell growth and proliferation. Notably, this signal pathway is also one of the signal mediators of obesity-associated factors, such as leptin, adiponectin, and inflammatory cytokines. Adipose tissue also functions as an endocrine organ with respect to steroid hormones. Aromatization of androgen precursors by CYP19 in adipose tissue is responsible for increased estrogen synthesis in obese subjects. Increased adipose tissue and elevated aromatase expression in adipose tissue have been suggested to contribute to the increased risk of developing estrogen receptor-positive cancer and worse prognosis in obese patients. This endocrine function of adipose tissue can have effects also on thyroid cells, which express estrogen receptors and may contribute to thyroid carcinogenesis. This hypothesis is supported by the demonstration in models on thyroid cancer cells that estrogen stimulates cell proliferation and reduces apoptosis. Besides these factors which might have a role in the mechanisms
123
354
responsible for the higher cancer risk in obese subjects, more specific factors could be involved in the higher risk for thyroid cancer. Leptin receptors are expressed in thyroid cancer cells, and their activation by the leptin produced by adipocytes has been demonstrated to promote cell survival and migration. Obesity is associated with higher serum concentration of thyroid-stimulating hormone (TSH) in caucasian individuals of both genders and in Japanese men. TSH plays a major role in the regulation of thyroid cell growth and function, and several studies have reported its association with thyroid cancer. A higher serum TSH level could increase the de novo thyroid oncogenesis, a possibility not confirmed in a large ultrasonographically screened population, or could stimulate the progression of thyroid cancers. While the molecular mechanisms have yet to be deciphered, they include obesity-related hormones, growth factors, modulation of energy production, and inflammatory processes. Accordingly, future studies should investigate the crosstalk between macrophages, adipocytes, endothelial cells, and epithelial cells and the effects of increased aromatase activity associated with obesity. To date, clinical studies strongly support the ‘‘thyroid
123
Endocrine (2015) 48:353–354
adiponcosis’’, one more reason to implement an appropriate policy for the prevention of obesity.
Conflict of interest There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
References 1. M. Bifulco, S. Pisanti, ‘‘Adiponcosis’’: a new term to name the obesity and cancer link. J. Clin. Endocrinol. Metab. 98(12), 4664–4665 (2013) 2. C.M. Kitahara, E.A. Platz, L.E. Freeman, A.W. Hsing, M.S. Linet, Y. Park, C. Schairer, A. Schatzkin, J.M. Shikany, A. de Berrington Gonzalez, Obesity and thyroid cancer risk among U.S. men and women: a pooled analysis of five prospective studies. Cancer. Epidemiol. Biomark. Prev. 20(3), 464–472 (2011) 3. L. Xu, M. Port, S. Landi, F. Gemignani, M. Cipollini, R. Elisei, L. Goudeva, J.A. Mueller, K. Nerlich, G. Pellegrini, C. Reiners, C. Romei, R. Schwab, M. Abend, E. Sturgis, Obesity and the risk of papillary thyroid cancer: a pooled analysis of three case-control Studies. Thyroid. (2014). doi:10.1089/thy.2013.0566
LETTER TO THE EDITOR
Thyroid adiponcosis: more than an hypothesis Maurizio Bifulco • Mario Vitale
Received: 8 May 2014 / Accepted: 1 August 2014 / Published online: 2 September 2014 Ó Springer Science+Business Media New York 2014
To the Editor In recent decades, the incidence of cancer has increased along with a marked rise of pandemic diseases such as insulin resistance, metabolic syndrome, and obesity. The accumulating evidence of a causal relationship between obesity and increased cancer risk has brought researchers to the introduction of the new term ‘‘Adiponcosis’’, derived from the fusion of the words ‘‘adiposis’’ and ‘‘oncosis’’ [1]. The incidence of thyroid cancer, the most common endocrine cancer, has risen dramatically in recent decades. In addition to environmental and alimentary factors, the increased thyroid cancer occurrence has been associated to the marked increase of prevalence of obesity. Indeed, a correlation between the body mass index (BMI) and thyroid cancer incidence has been demonstrated in several reports. According to a pooled analysis of five prospective studies and more recently a pooled analysis of three casecontrol studies, a higher thyroid cancer risk occurs in individuals with high BMI and high body fat percentage [2, 3]. According to recent findings, not only obesity, defined as a BMI greater than 30 kg/m2, but also overweight (BMI, 25–29.9 kg/m2) has been linked to a higher thyroid cancer risk. Interestingly, this association is tumor type-specific being significant or near-significant for thyroid adenocarcinomas but not for medullary thyroid cancer, suggesting a specific carcinogenetic mechanism operating in follicular thyroid cells. The molecular mechanisms underlying this interesting relationship are unknown, and the hypotheses formulated include the upregulation of mitogenic
M. Bifulco M. Vitale (&) Department of Medicine and Surgery, University of Salerno, Via Allende, Baronissi, 84081 Salerno, Italy e-mail: [email protected]
pathways, low-grade inflammation, and oxidative stress. Adipose tissue is an immune and endocrine organ predisposing individuals to the development of inflammatory and proliferative diseases. Tumor necrosis factor alpha (TNFa), IL-6, IL-1b, CCL2, CXCL8, and CXCL9 are only some of the inflammatory cytokines which are elevated in the serum of obese patients. Conversely, adiponectin, an antiinflammatory hormone that improves insulin sensitivity, suppresses the effects of TNF-a, IL-6, and IFN-c is reduced in the serum of obese patients and is negatively associated with various types of cancer including lung, breast, prostate, and colorectal carcinomas. Insulin resistance and the consequent hyperinsulinemia are a common trait of obese individuals. TNF-a and resistin produced by macrophages in the stromal compartment of adipose tissue, induce insulin resistance, and the consequent hyperinsulinemia might increase the cancer risk through the Akt/PI3K/ mTOR cascade that promotes cell growth and proliferation. Notably, this signal pathway is also one of the signal mediators of obesity-associated factors, such as leptin, adiponectin, and inflammatory cytokines. Adipose tissue also functions as an endocrine organ with respect to steroid hormones. Aromatization of androgen precursors by CYP19 in adipose tissue is responsible for increased estrogen synthesis in obese subjects. Increased adipose tissue and elevated aromatase expression in adipose tissue have been suggested to contribute to the increased risk of developing estrogen receptor-positive cancer and worse prognosis in obese patients. This endocrine function of adipose tissue can have effects also on thyroid cells, which express estrogen receptors and may contribute to thyroid carcinogenesis. This hypothesis is supported by the demonstration in models on thyroid cancer cells that estrogen stimulates cell proliferation and reduces apoptosis. Besides these factors which might have a role in the mechanisms
123
354
responsible for the higher cancer risk in obese subjects, more specific factors could be involved in the higher risk for thyroid cancer. Leptin receptors are expressed in thyroid cancer cells, and their activation by the leptin produced by adipocytes has been demonstrated to promote cell survival and migration. Obesity is associated with higher serum concentration of thyroid-stimulating hormone (TSH) in caucasian individuals of both genders and in Japanese men. TSH plays a major role in the regulation of thyroid cell growth and function, and several studies have reported its association with thyroid cancer. A higher serum TSH level could increase the de novo thyroid oncogenesis, a possibility not confirmed in a large ultrasonographically screened population, or could stimulate the progression of thyroid cancers. While the molecular mechanisms have yet to be deciphered, they include obesity-related hormones, growth factors, modulation of energy production, and inflammatory processes. Accordingly, future studies should investigate the crosstalk between macrophages, adipocytes, endothelial cells, and epithelial cells and the effects of increased aromatase activity associated with obesity. To date, clinical studies strongly support the ‘‘thyroid
123
Endocrine (2015) 48:353–354
adiponcosis’’, one more reason to implement an appropriate policy for the prevention of obesity.
Conflict of interest There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
References 1. M. Bifulco, S. Pisanti, ‘‘Adiponcosis’’: a new term to name the obesity and cancer link. J. Clin. Endocrinol. Metab. 98(12), 4664–4665 (2013) 2. C.M. Kitahara, E.A. Platz, L.E. Freeman, A.W. Hsing, M.S. Linet, Y. Park, C. Schairer, A. Schatzkin, J.M. Shikany, A. de Berrington Gonzalez, Obesity and thyroid cancer risk among U.S. men and women: a pooled analysis of five prospective studies. Cancer. Epidemiol. Biomark. Prev. 20(3), 464–472 (2011) 3. L. Xu, M. Port, S. Landi, F. Gemignani, M. Cipollini, R. Elisei, L. Goudeva, J.A. Mueller, K. Nerlich, G. Pellegrini, C. Reiners, C. Romei, R. Schwab, M. Abend, E. Sturgis, Obesity and the risk of papillary thyroid cancer: a pooled analysis of three case-control Studies. Thyroid. (2014). doi:10.1089/thy.2013.0566
