**3.8. Other C-cell secreted peptides**

The data presented here describe, according to our criteria, the most significant regulatory factors produced by C cells and their effects and pathways involved on follicular-cell activity according to the literature. Nevertheless, as illustrated in the present review, the list of C-cell secreted peptides and their putative paracrine functions on follicular cells is constantly being enlarged.

In addition to those described along the present chapter, and despite the fact that there is still limited evidence in the literature, there is a small group of regulatory factors such as bombesin/GRP, CCK (cholecystokinin) and helodermin, that should be observed as potential new candidates for thyroid local-modulators.

68 Thyroid Hormone

gland [212-214].

HIOMT and, moreover, melatonin membrane receptors have also been found in the rat thyroid gland, specifically, on follicular-cell and C-cell membranes [209] (see Figure 8).

**Figure 8.** Immunolocalization of AANAT in a rat C-cell line (CA77) (A), and melatonin receptor (MT1)

Many effects of melatonin on the thyroid gland have been described so far in the literature. In rodents, high doses of melatonin inhibit basal and TSH-stimulated mitotic activity of thyroid follicular cells *in vivo* and in primary culture [210]. Besides, melatonin has a direct inhibitory effect on T4 secretion and, also, depresses the response of the thyroid to TSH [211]. Furthermore, melatonin plays a protective role against oxidative stress in the rat thyroid

As regard to the latter, reactive oxygen species (ROS) are deeply involved in cellular processes of the thyroid gland. Follicular cells are subjected to high oxidative stress since they require hydrogen peroxide (H2O2) for thyroid hormones biosynthesis and moreover, a large number of diseases associated with H2O2 accumulation in the thyroid gland have been described. For example, H2O2 participates in the Wolff-Chaikoff's effect and in hypothyroidism caused by iodine excess in the thyroid [213]. Melatonin has been suggested to be able to directly scavenge H2O2 [215]; in accordance to this last point melatonin synthesized by C cells might play a role in thyroid antioxidant defense against oxidative stress. Endogenous synthesized intrathyroidal melatonin could, thus, be a kind of local

regulator that could regulate redox homeostasis and modulate thyroid function [216].

The data presented here describe, according to our criteria, the most significant regulatory factors produced by C cells and their effects and pathways involved on follicular-cell activity according to the literature. Nevertheless, as illustrated in the present review, the list of C-cell secreted peptides and their putative paracrine functions on follicular cells is

in a follicular-cell line (PC-Cl3) (B) by immunofluorescence.

**3.8. Other C-cell secreted peptides** 

constantly being enlarged.

Bombesin/GRP (gastrin-releasing peptide) was first described as being expressed by neoplastic C cells from MTCs by the group of Kameya et al. In 1983 [217]. Moreover, Ahren in 1989 [57] confirmed that GRP had the capacity to stimulate both basal and TSHstimulated thyroid hormone secretion in mice. Furthermore, differences in GRP synthesis among developing thyroid C cells, normal adult C cells, and neoplastic C cells led Sunday et al [32] to hypothesize that C-cell GRP gene-expression might play a role in both normal and neoplastic growth processes.

In the case of CCK, its expression in C cells was described by Arias et al. in rat thyroid gland [42]. Recently, its receptor CCK2R, which is shared with gastrin, has been described to be expressed at different intensities in normal and malignant C cells by Blakër et al. [218]. No additional data has been published with regard to the putative functional role of CCK signalling in thyroid, however, there are initial encouraging therapeutic results with the use of CCK/Gastrin R2-binding peptides in patients with MTC [219, 220].

The last factor from this "other" group is the amidated peptide helodermin. Originally isolated from *Heloderma suspectum* [221, 222], helodermin was described to be expressed by rat C cells by Grunditz et al. in 1999 [35]. Furthermore, these authors reported dose and time course experiments which showed a consistent stimulatory effect of helodermin on thyroid hormone synthesis.

Although some of these data seemed to have well-characterized new pathways for C-cell and thyrocytes interrelationships, surprisingly no further studies that illustrated new insights for this evidence have been reported so far. Therefore, to our knowledge, future studies are still necessary to finally clarify their involvement in thyroid function and homeostasis.

**Figure 9.** Schematic diagram of the different mechanisms of regulation of the synthesis of thyroid hormones by follicular cells.
