The Thyroid Gland: A Crossroad in Inflammation-Induced Carcinoma? An Ongoing Debate with New Therapeutic Potential.

Abstract

Chronic infection and inflammation contribute to around 25% of cancer cases worldwide. While a direct link between several types of human malignancies and inflammation has now been established, in particular at the gastrointestinal level, the relationship between inflammation and thyroid cancer and the pathophysiology of chronic inflammation that induces papillary thyroid carcinoma (PTC) are still subjects of debate. However, several epidemiological and morphological studies have strongly suggested an increased risk of PTC in patients with Hashimoto's thyroiditis (HT). As in HT, an intense immune infiltrate is associated with certain PTC and might play a critical role in the regulation of carcinogenesis and in carcinoma progression. Proinflammatory molecules, such as cytokines and chemokines, which are produced by immune infiltrate in the tumor microenvironment, contribute to the regulation of key cellular processes for cancer onset and progression, in particular for tumor cell proliferation, apoptosis, autophagy, angiogenesis and metastasis. Molecular studies have identified activation of the RET/PTC rearrangement-induced MAPK signaling pathway as the driving force in the development of PTC in the context of HT. These genetic alterations may be favored by chronic inflammation. In this regard, the RET oncoprotein and its downstream effectors, such as those implicated in the activation of the MAPK pathway, as well as inflammatory molecules of the tumor microenvironment could be promising molecular targets for new therapeutic strategies for thyroid cancer. This review focuses on the complex link between thyroid cancer and chronic inflammation and highlights the different current hypotheses regarding the role of the immune cell microenvironment in the initiation and progression of PTC.

Identification of Functionally Distinct TRAF Proinflammatory and Phosphatidylinositol 3-Kinase/Mitogen-activated Protein Kinase/Extracellular Signal-regulated Kinase Kinase (PI3K/MEK) Transforming Activities Emanating from RET/PTC Fusion Oncoprotein

“…This longstanding observation has led to the hypothesis that HT is a risk factor for PTC and furthermore that HT is a precancerous condition (2,3). For the various reasons discussed, we suggest the converse, the autoimmune component is the result rather than the cause of RET/PTC transformation.…”

“…For all experiments, PCCL3 cells were treated in a 1:1 ratio of F-12 media and D10. All cells were maintained in a 37°C incubator at 9% CO 2 .…”

“…In contrast, the more aggressive FDTCs usually harbor oncogenic RAS or BRAF point mutations and are associated with a poorer prognosis and higher recurrence rate (2,8).…”

Hashimoto’s Thyroiditis And Cancer: A Review

“…At the molecular level, activation of the mitogen activated protein kinase (MAPK) signaling pathway may represent the key molecular event linking autoimmune thyroiditis and thyroid cancer [25]. Larson and colleagues found increased phosphorylated protein kinase B (AKT) expression in regions of HT and thyroid cancer [26].…”

Advances in Research on the Role of Chemokines in Occurrence and Development of Autoimmune Thyroid Disease

“…In-depth clinical and basic experimental studies enable detection of serum chemokine changes [22,23] . Related products of chemokines and their receptors are important topics for clinical research, which are expected to bring new diagnostic and therapeutic methods for AITD, organ-specific autoimmune diseases, and tumors [24][25][26][27][28][29][30] . Pathogenesis of AITD remains to be clarified.…”