Co-expression of interleukin-6 (IL-6) and interleukin-6 receptor (IL-6R) in thyroid nodules is associated with co-expression of CD30 ligand/CD30 receptor

Abstract

Data on the expression of interleukin 6 (IL-6)/interleukin 6 receptor (IL-6R) in thyroid nodules is scarce. Based on our recent data of CD30 ligand (CD30L)/CD30 receptor (CD30) in these nodules and on the knowledge that this signal stimulates IL-6 production in non-thyroid neoplasms, we wanted to evaluate the immunocytochemical expression of these 2 ligand/receptor systems in a large archival series of paraffin-embedded specimens. These specimens included 6 normal thyroids and 130 thyroid nodules. Co-expression of IL-6 and IL-6R in the epithelial (follicular) cells was observed solely in CD30L/CD30 positive nodules: 5/15 (33%) oncocytic adenomas; 6/30 (20%) follicular adenomas which belonged to 2 variants (4/4 microfollicular toxic and 2/2 hyalinizing trabecular); 9/30 (30%) papillary thyroid cancers (PTC), all belonging to the conventional variant. In PTC the proportion of tumor epithelial cells that were IL6 positive was inversely correlated with the pTNM staging (r=-0.549, p=0.01). All 15 follicular cancers (FTC), all 6 anaplastic cancers (ATC) were IL-6/lL-6R negative; 14/15 FTC and 5/6 ATC were CD30L/CD30 negative. In another oncocytic adenoma, another 4 conventional PTC and another 7 non-conventional PTC CD30L/CD30 expression was associated to expression of IL-6 only. IL-6 staining associated to absent expression of CD30L and CD30 was observed in 7 follicular adenomas (all belonging to variants different from toxic and hyalinizing trabecular), 2 oncocytic adenomas, 5 of the 30 colloid nodules and 2 normal thyroids. Of the 6 tumors arising from the parafollicular C cells (medullary thyroid cancer, MTC), all 3 that had metastasized were CD30L/CD30/IL-6 positive and IL-6R negative; only IL-6 expression was lost in both the local and distant metastases. This finding matched the loss of IL-6 expression in one PTC metastasis. All 3 non-metastasized MTC were IL-6/IL-6R negative, and 1/3 was CD30L positive/CD30 negative. We conclude that only in a subset of both benign and malignant thyroid nodules the IL-6/IL-6R signal could be induced by the CD30L/CD30. IL-6 expression is related with aggressiveness in both PTC and MTC. In the normal thyroid tissue, colloid nodules, and another subset of benign and malignant thyroid nodules, IL-6 expression is under control of signals other than CD30L/CD30.

Association of XIAP and P2X7 receptor expression with lymph node metastasis in papillary thyroid carcinoma

“…As discussed above, P2X 7 receptors are responsible for the release of IL-6 in human thyroid cancer cell lines [16]. It was revealed that the local expression of IL-6 is related to the aggressiveness of PTCs [34]. IL-6 could also increase mRNA and protein levels of XIAP in ovarian cancer cells, promoting chemoresistance by activating multiple signaling pathways including the PI3K/Akt pathway [35].…”

Programmed cell senescence: role of IL-6 in the pituitary

“…The protective role of IL-6 in OIS, as discussed below, occurs naturally in pituitary adenomas as a dynamic and slow mechanism, which results in a benign tumor with stable growth arrest. Interestingly, in other endocrine tumors like thyroid nodules, IL-6 (and its receptor) expression (Ruggeri et al 2002) and also OIS with an associated inflammatory secretome (Vizioli et al 2014) has been reported, suggesting that a senescence process involving IL-6 might also take place in thyroid tumor progression.…”

Multiplex analysis of cytokines as biomarkers that differentiate benign and malignant thyroid diseases

“…For example, IL-6 expression is related to aggressiveness of both papillary and medullary thyroid cancer [16]. Despite the growing number of reports indicating the complex interactions between inflammatory and angiogenic factors in the development of thyroid cancer, studies have concentrated on a small number of markers [17, 18]. Vesely et al [19] examined serum levels of IGF-I, HGF, TGF β 1, bFGF, and VEGF in 28 patients with thyroid gland tumors (14 adenomas, 14 papillary carcinomas) and compared these concentrations with those in healthy people.…”