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      Papillary Thyroid Carcinoma and Inflammation

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          Abstract

          The relationship between cancer and inflammation is well known since 1863 when Rudolf Virchow, following the observation of leukocytes in neoplastic tissues, hypothesized that chronic inflammation could contribute to the tumorigenic process. In the following decades, several lines of evidence suggested a strong association between chronic inflammation and increased susceptibility to neoplastic transformation and cancer development. It was estimated that up to 20% of all tumors arise from conditions of persistent inflammation such as chronic infections or autoimmune diseases. Indeed, the associations are well known between cervical cancer and papilloma virus, gastric cancer and Helicobacter pylori induced gastritis, esophageal adenocarcinoma and Barrett's metaplasia, hepatocellular carcinoma, hepatitis B and C viral infections, and many others. Some of the mechanisms forming the basis of the relationship between inflammation and tumor have been recently elucidated. The inflammatory microenvironment of neoplastic tissues is characterized by the presence of host leukocytes both in the supporting stroma and among the tumor cells, with macrophages, dendritic cells, mast cells, and T cells being differentially distributed (Balkwill and Mantovani, 2001). Several cytokines (TNF, IL-1, IL-6) and chemokines that are produced by the tumor cells and by leukocytes and platelets associated with the tumor have been found to be able to maintain the invasive phenotype (Coussens and Werb, 2002). Tumor-associated macrophages (TAMs) are a major component of the leukocyte infiltrate, initially recruited by inflammatory chemokines (e.g., CCL2) and then sustained by cytokines present in the tumor microenvironment (e.g., CSFs, VEGF-A). In response to cytokines such as TGF-β, IL-10, and M-CSF, TAMs promote tumor proliferation and progression and stroma deposition and, indeed, the density of TAMs is increased in advanced thyroid cancers (Ryder et al., 2008). As far as papillary thyroid cancer (PTC) is concerned, this tumor is frequently associated with autoimmune thyroid diseases, Graves’ disease, and Hashimoto's thyroiditis. The frequency of association is extremely variable in the series from different countries, 0–9% for Graves’ and 9–58% for Hashimoto's (Figure 1). It is still debated whether association with an autoimmune disorder could influence the prognosis of PTC. Indeed a worse prognosis was reported in few series (Ozaki et al., 1990; Pellegriti et al., 1998), while the majority of the studies showed either a protective effect of thyroid autoimmunity (Matsubasyashi et al., 1995; Loh et al., 1999; Gupta et al., 2001) or a similar behavior between cancer with and without associated thyroiditis (Yano et al., 2007). These discrepancies can be due to either the low number of patients examined in those studies, the lack of a control group, the existence of different genetic and epidemiological backgrounds, or the use of inappropriate criteria to define remission or persistence/relapse. We recently produced data extending the knowledge about the tight relationships among thyroiditis and thyroid cancer. In particular, the clinical and molecular features, and the expression of inflammation-related genes, were investigated in a large series of PTCs divided in two groups according to the association or not of the tumor with thyroiditis (Muzza et al., 2010). Interestingly, no significant differences between the two groups were found, as far as age at diagnosis, gender distribution, TNM staging, histological variants, and outcome are concerned, suggesting that the association with an autoimmune thyroid process does not modify either the presentation or the clinical behavior of PTC. A crucial finding of the last few years concerns the genetic background of PTCs, since the concept has emerged that the inflammatory protumourigenic microenvironment of this cancer is elicited by the oncogenes responsible for thyroid neoplastic transformation (such as RET/PTC, BRAFV600E, and RASG12V; Borrello et al., 2005, 2008; Melillo et al., 2005; Mantovani et al., 2008). In particular, we recently demonstrated that the RET/PTC1 oncogene activates a transcriptional proinflammatory program in normal human primary thyrocytes (Borrello et al., 2005). Moreover, gene expression studies in cellular systems showed that not only RET/PTC but also RAS and BRAF proteins, all belonging to the RET–PTC/RAS/BRAF/ERK pathway, are able to induce the up-regulation of chemokines, which in turn could contribute to neoplastic proliferation, survival, and migration (Melillo et al., 2005). Consistently, other Authors demonstrated that RET/PTC3-thyrocytes express high levels of proinflammatory cytokines (Russel et al., 2003) and proteins involved in the immune response (Puxeddu et al., 2005). These data are well in agreement with our recent study which firstly showed that PTCs harbor a different genetic background according to the association or not with thyroiditis (Muzza et al., 2010). In particular, RET/PTC was more represented in patients with PTC and autoimmunity, while BRAF V600E was significantly more frequent in patients with PTC alone. Moreover, we showed that the expression of genes encoding three inflammation-related genes (CCL20, CXCL8, and l-selectin) was enhanced either in BRAF V600E or in RET/PTC tumors, compared with normal samples. Interestingly, non-neoplastic tissues with thyroiditis displayed the same levels of expression of CCL20 and CXCL8 compared to normal samples, suggesting that these inflammatory molecules could be associated with tumor-related inflammation, and not with the autoimmune process. Figure 1 Worldwide prevalence of papillary thyroid cancer in patients with Graves’ disease (Graves) and Hashimoto's thyroiditis (Hashi), corresponding to the sum of the data reported to date in the literature. References: Australia (Graves: Hales et al., 1992; Barakate et al., 2002); Austria (Graves: Rieger et al., 1989); China (Graves: Chou et al., 1993; Lin et al., 2003); Corea (Graves: Kim et al., 2004); Egypt (Hashimoto: Tamimi, 2002); France (Graves: Melliere et al., 1988; Ozoux et al., 1988; Kraimps et al., 1998; Kraimps, 2000; Mssrouri et al., 2008); Germany (Graves: Wahl et al., 1982); Great Britain (Graves: Hancock et al., 1977); Greece (Graves: Linos et al., 1997); Italy (Graves: Pacini et al., 1988; Belfiore et al., 1990; Miccoli et al., 1996; Pellegriti et al., 1998; Cantalamessa et al., 1999; Zanella et al., 2001; Gabriele et al., 2003; Cappelli et al., 2006; Hashimoto: Fiore et al., 2011); Turkey (Graves: Terzioglu et al., 1993); Japan (Graves: Kasuga et al., 1990; Ozaki et al., 1990; Yano et al., 2007; Hashimoto: Matsubayashi et al., 1995; Ohmori et al., 2007); Poland (Graves: Pomorski et al., 1996); Serbia (Graves: Zivaljević et al., 2008); Spain (Hashimoto: Pino Rivero et al., 2004); USA (Graves: Shapiro et al., 1970; Dobyns et al., 1974; Bradley and Liechty, 1983; Farbota et al., 1985; Behar et al., 1986; Razack et al., 1997; Carnell and Valente, 1998; Weber et al., 2006; Boostrom et al., 2007; Phitayakorn and McHenry, 2008; Hashimoto: Loh et al., 1999; Gupta et al., 2001; Kebebew et al., 2001; Larson et al., 2007). In conclusion, recent studies opened a new and extremely attractive scenario on the “connection” between thyroid autoimmunity, inflammation, and cancer. The interest is linked not only to the possibility of better understanding the communication between abnormally growing cells and their microenvironment, but also to the chance to pharmacologically interfere with such pro-tumor interactions.

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          Most cited references50

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          Induction of a proinflammatory program in normal human thyrocytes by the RET/PTC1 oncogene.

          Rearrangements of the RET receptor tyrosine kinase gene generating RET/PTC oncogenes are specific to papillary thyroid carcinoma (PTC), the most frequent thyroid tumor. Here, we show that the RET/PTC1 oncogene, when exogenously expressed in primary normal human thyrocytes, induces the expression of a large set of genes involved in inflammation and tumor invasion, including those encoding chemokines (CCL2, CCL20, CXCL8, and CXCL12), chemokine receptors (CXCR4), cytokines (IL1B, CSF-1, GM-CSF, and G-CSF), matrix-degrading enzymes (metalloproteases and urokinase-type plasminogen activator and its receptor), and adhesion molecules (L-selectin). This effect is strictly dependent on the presence of the RET/PTC1 Tyr-451 (corresponding to RET Tyr-1062 multidocking site). Selected relevant genes (CCL20, CCL2, CXCL8, CXCR4, L-selectin, GM-CSF, IL1B, MMP9, UPA, and SPP1/OPN) were found up-regulated also in clinical samples of PTC, particularly those characterized by RET/PTC activation, local extrathyroid spread, and lymph node metastases, when compared with normal thyroid tissue or follicular thyroid carcinoma. These results, demonstrating that the RET/PTC1 oncogene activates a proinflammatory program, provide a direct link between a transforming human oncogene, inflammation, and malignant behavior.
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            Coexisting chronic lymphocytic thyroiditis and papillary thyroid cancer revisited.

            The effect of chronic lymphocytic thyroiditis (CLT) on the behavior of papillary thyroid cancer (PTC) remains unclear. In recent studies the presence of CLT in patients with PTC was reported to be associated with a lower recurrence rate and an improved survival rate. Furthermore, patients with PTC and tumor infiltrating lymphocytes (TILs) have been reported to have lower recurrence rates and a lower frequency of distant metastases. Because of these and other observations, a tumor immune response in PTC has been suggested. The aim of our study was to determine: (1) the relative frequency of CLT in PTC; (2) the prognostic significance of CLT in patients with PTC; and (3) if TIL occurs independently or in association with CLT. A 10-year retrospective study of patients who underwent initial thyroidectomy for PTC from 1986 to 1996 was completed. The extent of thyroid lymphocytic infiltration was determined within the tumor, surrounding the tumor, and in the distant parenchyma by two independent observers blinded to the clinical data. Dense focal/diffuse lymphoid aggregates throughout the thyroid gland were diagnostic of CLT and when present within or surrounding the tumor were designated TILs. A total of 136 patients with PTC (typical and follicular variant of PTC histologic subtypes) were identified with a mean follow-up of 4.4 years and a 8% mortality rate at 10 years. Thirty percent of the patients with PTC had coexisting CLT, and 65% of these patients with CLT had positive anti-thyroglobulin antibodies. Patients with coexisting CLT and PTC were younger (p < 0.05), more likely to be female (p < 0.05), and more likely to have multicentric tumors (p < 0.001) compared to patients without CLT. Only 5% of patients had TILs without CLT, but 82.5% of patients with CLT had TILs identified (p < 0.0001). By univariate analysis CLT, age, gender, stage of PTC, tumor multicentricity, and tumor size were significant prognostic factors. Only age and TNM stage of PTC remained independent prognostic factors by multivariate analysis. We found a similar frequency (30%) of coexisting CLT and PTC as reported by others; but, more importantly, the presence of TILs primarily occurred in association with CLT. The presence of CLT in patients with PTC correlated with an improved prognosis. It was not an independent prognostic factor, however, and was not associated with a lower recurrence rate or a lower frequency of distant metastasis.
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              Increased incidence of well-differentiated thyroid cancer associated with Hashimoto thyroiditis and the role of the PI3k/Akt pathway.

              The link between inflammation and cancer is well-established, but the link between Hashimoto thyroiditis (HT) and thyroid cancer remains controversial. The purpose of our study was to determine the incidence of patients with thyroid cancer and associated HT at our institution, to correlate our patient population demographics with the Surveillance, Epidemiology and End Results (SEER) database, and to assess the expression of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in patients with HT. Demographic and histologic data were collected from patients undergoing thyroid resection at the University of Texas Medical Branch from 1987 to 2002 and compared with the SEER database. Immunohistochemistry for phosphorylated Akt (a marker of PI3K activity), Akt isoforms and PTEN (an inhibitor of PI3K) was performed on paraffin-embedded blocks of resected thyroid tissue. Our patient population demographics and thyroid cancer incidence by histologic type were similar to patients in the SEER database. Ninety-eight (37.7%) resected specimens had pathologic changes consistent with HT; 43 (43.8%) had an associated well-differentiated thyroid cancer. Increased phosphorylated Akt, Akt1, and Akt2 expression was noted in regions of HT and thyroid cancer compared with regions of normal surrounding thyroid tissue. Patients with HT were three times more likely to have thyroid cancer, suggesting a strong link between chronic inflammation and cancer development. PI3K/Akt expression was increased in both HT and well-differentiated thyroid cancer, suggesting a possible molecular mechanism for thyroid carcinogenesis.
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                Author and article information

                Journal
                Front Endocrinol (Lausanne)
                Front Endocrinol (Lausanne)
                Front. Endocrin.
                Frontiers in Endocrinology
                Frontiers Research Foundation
                1664-2392
                16 December 2011
                2011
                : 2
                : 88
                Affiliations
                [1] 1simpleEndocrine Unit, Department of Medical Sciences, Fondazione IRCCS Ca’ Granda, Università degli Studi di Milano Milan, Italy
                Author notes

                This article was submitted to Frontiers in Cancer Endocrinology, a specialty of Frontiers in Endocrinology.

                Article
                10.3389/fendo.2011.00088
                3355852
                22645512
                c69128da-ded0-4e7f-a234-4c0920292e4a
                Copyright © 2011 Fugazzola, Colombo, Perrino and Muzza.

                This is an open-access article distributed under the terms of the Creative Commons Attribution Non Commercial License, which permits non-commercial use, distribution, and reproduction in other forums, provided the original authors and source are credited.

                History
                : 08 September 2011
                : 14 November 2011
                Page count
                Figures: 1, Tables: 0, Equations: 0, References: 57, Pages: 3, Words: 3055
                Categories
                Endocrinology
                Original Research

                Endocrinology & Diabetes
                Endocrinology & Diabetes

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