**2. Molecular pathogenesis of thyroid cancer**

Thyroid cancers arise as a result of the accumulation of multiple genetic mutations that cause abnormal cellular proliferation and prolonged survival of malignant cells. Most thyroid cancers arise as a result of aberrant signaling involving the PI3K/Akt/ mTOR and MAPK signaling pathways. The PI3K and MAPK pathways are activated by receptor tyrosine kinase (RTK). The PI3K/Akt/mTOR pathway is classically activated by the induction of RTK at the cell membrane. Activated intracellular PI3K then phosphorylates and activates AKT. AKT then travels inside the nucleus to upregulate various other oncogenes as well the mTOR pathway, that later trigger tumorigenesis. MAPK signaling is stimulated first by activation of an RTK similar to the PI3K/Akt/ mTOR pathway. RTK then activates multiple other genes, including MEK, ERK, RAS, and BRAF. ERK ultimately enters the nucleus and then promotes tumorigenesis. The most common of genetic changes in Papillary Thyroid Cancers are point mutations in *BRAF* (40%) [4] and *RAS* (38%) genes [5]. Rearrangement of the *RET*/*PTC* protooncogene occurs in ~10–20% of papillary cancers [6]. Genetic rearrangements and mutations in anaplastic lymphoma kinase (*ALK*) [7] and neurotrophic tropomyosin receptor kinase *(NTRK)1-3* are also present [8], but only ~1–2% of cases. Point mutations of *RAS* and rearrangements of *PPARγ/PAX8* genes are the most common oncogenic alteration in follicular thyroid cancers. Mutations in members of the PI3K pathway, such as *PTEN* deletion/mutation and *PIK3CA*, have also been reported at low frequencies [9]. Both Anaplastic and Poorly Differentiated Thyroid Cancers also demonstrate a high prevalence of the *TP53* and *TERT* promoter mutations, which is usually associated with greater aggressiveness [10]. The most common genetic alterations found in Medullary Thyroid Cancer cells are the *RET*-activating point mutations [11], whereas *RAS* mutations, mainly the *HRAS* and *KRAS* mutations, have been reported in ~17%of cases [12].

Angiogenesis, being a very important process in tumor development is another attractive target for cancer therapy [9]. The vascular endothelial growth factor (VEGF) is overexpressed in the setting of intratumoral hypoxia via hypoxia-inducible

#### *Systemic Therapy in Thyroid Cancer DOI: http://dx.doi.org/10.5772/intechopen.106462*

factor-1*α* (HIF1*α*) and promotes angiogenesis. This transcription factor HIF1*α* is also upregulated by MAPK and PI3K/AKT pathways. An important target of HIF1*α* is the MET receptor, which is highly expressed in many thyroid cancers, promoting angiogenesis, cellular motility, invasion, and metastasis [13]. The above mentioned molecular pathways have been the basis for development of newer drugs and their testing in clinical trials in recent years and thereby provide attractive therapeutic targets for thyroid cancer.
