The thyroid gland is part of the endocrine system and is a hormone-producing gland that regulates the body's functions. Thyroid cancer (TC), which occurs in thyroid cells, is the most common endocrine - related cancer, accounting for about 1% of systemic malignancies.
Thyroid cancer is more common in females, and the ratio of females to males is 3:1 in most geographical regions and population groups [1], making it the fifth most common cancer among females. Most thyroid cancers are curable by surgery and other means.
3. Mechanisms of Disease Progression
4. Signaling Pathways and Gene Mutations
The thyroid gland is a butterfly-shaped gland located in front of the neck, under the throat, and above the clavicle. The thyroid gland is part of the endocrine system that controls heart rate, blood pressure, body temperature and metabolism by secreting hormones.
There are two main cell types in the thyroid gland: follicular cells and C cells.
Follicular cells use iodine in the blood to make thyroid hormones, which help regulate the body's metabolism. The amount of thyroid hormone released by the thyroid gland is regulated by the pituitary gland at the bottom of the brain, which promotes the release of thyroid hormone by producing a substance called thyroid stimulating hormone (TSH).
C cells (also known as parafollicular cells) produce calcitonin, a hormone that helps control how the body uses calcium.
Figure 1. Hormones produced by the thyroid gland
Thyroid cancer can be classified into four types according to the origin of cells and the rate of cancer cell division: papillary thyroid carcinoma, follicular thyroid cancer, medullary thyroid cancer, and anaplastic thyroid cancer.
It is the most common type of thyroid cancer, and 70% to 80% of thyroid cancers are papillary thyroid cancer. Although it can occur at any age, most occur between the ages of 30 and 60. The disease is three times more common in women than men, and is usually more aggressive for older patients.
Papillary thyroid cancer may spread, usually involving the neck lymph nodes, and less involving the lungs.
Most people with this type of cancer can be cured if they are diagnosed early.
Follicular thyroid cancer accounts for less than 15% of all thyroid cancers. Hürthle cells are variants of FTC. This type of thyroid cancer occurs mostly in adults between the ages of 40 and 60. Women get it more often than men. Cancer cells can invade blood vessels and travel to tissues such as bones or lungs.
PTC and FTC, as well as the less common Hürthle cell carcinoma, are classified as differentiated thyroid carcinoma (DTC) [2] [3], which originated from follicular epithelial thyroid cells. Both PTC and FTC are slow to progress and usually have a good prognosis, especially if diagnosed early.
It accounts for about 3% of all thyroid cancers [4]. It is developed by C-cells or parafollicular cells that produce calcitonin (which regulates calcium and phosphate levels in the blood and promotes bone growth) [5], and elevated levels of calcitonin indicate cancer. It is usually diagnosed between the ages of 40 and 50, and women and men are equally affected.
Compared to other types of thyroid cancer, it is more likely to run in the family (familial medullary thyroid carcinoma, FMTC).
Anaplastic thyroid cancer is a rare thyroid cancer, which accounts for less than 2% of all thyroid cancers (77% of women).
ATC originates from follicular cells, but it does not have its original biological characteristics [6]. Unlike other thyroid tumors, it is characterized by rapid growth and spread and aggressive. Therefore, anaplastic thyroid cancer (ATC) is the most invasive type of thyroid cancer among all thyroid cancers [7]. It usually occurs in patients over the age of 65, and women are slightly more affected than men. ATC is not sensitive to conventional treatment [8]. The prognosis was the worst, with a 5-year survival rate of 5% [9].
There's also thyroid lymphoma. This is a rare thyroid cancer that starts with immune system cells in the thyroid gland and grows very fast. Thyroid lymphoma usually occurs in the elderly.
Figure 2. Type of thyroid cancer
The development of thyroid cancer is a complex, multifactorial process involving intricate regulation and interactions at various levels. Genetic variations play a pivotal role in the pathogenesis of this disease. Evidence from familial clustering and genetic association studies suggests a close association between mutations in specific genes and thyroid cancer susceptibility [10]. For instance, BRAF gene mutations are frequently observed in thyroid cancer, particularly in papillary thyroid carcinoma (PTC), a finding corroborated by multiple studies [11].
Furthermore, environmental factors constitute a crucial element in the development of thyroid cancer. Studies have indicated a correlation between exposure to radioactive iodine isotopes and an increased risk of thyroid cancer [12]. Additionally, factors such as diet, chemical exposure, and lifestyle may also exert an influence on the formation of thyroid tumors.
Within the cellular milieu, aberrant activation of signaling pathways emerges as a key driving force propelling thyroid cancer progression. The dysregulated activation of pathways like RAF/MEK/ERK and PI3K/AKT is intricately linked to the malignant transformation of thyroid cancer [13]. Excessive activation of these signaling pathways can lead to dysregulation in biological processes such as cell growth, differentiation, and apoptosis, ultimately promoting tumor formation and development.
In the development of thyroid cancer, multiple signaling pathways and gene mutations have been identified as crucial drivers. A comprehensive understanding of these changes is paramount for both mechanistic research and the precision design of therapeutic interventions.
Firstly, aberrant activation of the RAF/MEK/ERK signaling pathway is widely observed in thyroid cancer. This pathway's hyperactivation is closely associated with tumor development and progression in numerous thyroid cancer patients [14]. Research indicates that BRAF gene mutations play a pivotal role in the activation of the RAF/MEK/ERK signaling pathway, particularly the BRAF V600E mutation, considered one of the most prevalent mutations in thyroid cancer [15]. Clinical trials targeting BRAF V600E with inhibitors like Vemurafenib and Dabrafenib have demonstrated therapeutic efficacy in a subset of patients [16].
Secondly, the PI3K/AKT signaling pathway also plays a significant role in the development of thyroid cancer. Aberrant activation of the PI3K/AKT pathway is associated with increased proliferation, survival, and invasive capabilities in thyroid cancer [17]. In some patients, the loss or mutation of the PTEN gene may lead to the excessive activation of the PI3K/AKT pathway, thereby promoting the occurrence of thyroid cancer. Consequently, inhibiting the PI3K/AKT signaling pathway is considered a potential therapeutic strategy.
Figure 3. PI3K-Akt signaling pathway
Furthermore, several other gene mutations are closely associated with the development of thyroid cancer. For instance, RET gene mutations are commonly found in some cases of familial medullary thyroid carcinoma (MTC), highlighting their significance in the genetic susceptibility to thyroid cancer [18].
The metabolic features of thyroid cancer exhibit distinct high energy demands and abnormal cell growth compared to normal cells. This characteristic is commonly referred to as "cancer metabolic reprogramming," involving the dysregulation of various metabolic pathways to provide signals for the survival and proliferation of tumor cells.
Firstly, thyroid cancer cells often demonstrate enhanced glycolysis, the process of converting glucose into lactate. Even under oxygen-rich conditions, thyroid cancer cells selectively adopt this "Warburg effect," enabling cells to rapidly generate ATP to meet their fast-paced proliferation demands [19].
Secondly, thyroid cancer cells also display enhanced lipid metabolism. The accelerated lipid metabolism provides the necessary raw materials for building cell membranes and supplying essential substances for survival. In thyroid cancer, the heightened lipid metabolism may be closely linked to the uncontrolled proliferation of tumor cells [20].
Additionally, thyroid cancer cells typically exhibit elevated levels of oxidative phosphorylation, indicating a stronger reliance on mitochondrial function to meet high energy demands. This phenomenon contrasts with the more energy-efficient oxidative phosphorylation levels in normal cells, emphasizing the abnormal regulation of metabolic pathways in thyroid cancer cells [21].
In-depth exploration of the metabolic characteristics of thyroid cancer contributes to uncovering crucial mechanisms for tumor growth and survival. Research in this field will provide vital clues for developing new therapeutic strategies, potentially involving drug interventions targeting specific metabolic pathways to effectively inhibit tumor growth and spread.
Cancer treatment strategies need to be developed according to the stage of the tumor.
These studies provide hope for developing more effective treatment strategies and personalized therapies, underscoring the need for an in-depth understanding of drug targets and continuous innovation.
References
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