3.1.2. Activation of mTOR Pathway

The role of PKA as a key regulator of FTC has also been suggested by a recent study demonstrating a concurrent activation of PKA and mTOR. In this study a double *Prkar1a*-*Pten* knockout mouse (*DRP*-*Tpo*KO mice) with thyroid-specific deletion of both genes was generated and was compared to signaling alterations to human FTCs [1]; they found that mice developed aggressive FTC that exhibited 100% penetrance by 8 weeks of age. In addition, well-differentiated lung metastases appeared to be common in these mice (approximately one third of them), mimicking the human disease. The signaling pathways were analyzed and it was shown that PKA and the mammalian target of rapamycin (mTOR) pathways were consistently activated. mTOR has an essential role in promoting the metabolic changes that occur during tumorigenesis and is regulated by the AMPdependent protein kinase (AMPK) [47]. AMPK is activated under nutrition restriction or increase in the AMP/ATP ration in order to increase energy production [48].

It has been suggested before that mTOR could be activated by *Prkar1a* deletion and that it could possibly interact with Prkar1a directly [49], but the data remain controversial [50]. Furthermore, activation of mTOR by TSH has been suggested to be partly due to PKA phosphorylation of the target of rapamycin complex 1 complex member PRAS40 [51]. Mouse models have been developed over the years that recapitulate how human FTCs progress from benign follicular adenoma (at one year of age) in the *Pten-TpoKO* [23] to locally invasive FTC as in the *R1a-TpoKO* [46] and subsequently to invasive and distantly metastatic FTC. The authors identified PKA and mTOR as essential signaling pathways and showed that activation of mTOR can occur independently of Akt [1]. Further, the concurrent activation of PKA and mTOR that was observed in human FTCs led to the conclusion that PKA activates mTOR/p70S6K that results in thyroid cancer, indicating that PKA is a vital component regulating FTC in both mice and humans [1].

The same group reported that, in FTCs, both in mice and humans, AMPK and mTOR pathways are activated concomitantly [52]. They showed that the tumor suppressor that causes Peutz–Jeghers syndrome, LKB1, mediates the signaling from PKA to AMPK in driving tumorigenesis [53,54]. The role of AMPK in the development of cancer has not been determined yet; according to the literature, it can act either as tumor promoter or tumor suppressor [55,56]. LKB1, like AMPK, can act as tumor promoter/suppressor as well, depending on the context [55,57–61]. Even though it typically suppresses the activity of mTOR [56,62], there is evidence that it can also act as a tumor promoter [63–65], which means that its functions depend on the type of tissue and other intracellular signals that may be present.
