The Changing Face of in vitro Culture Models for Thyroid Cancer Research: A Systematic Literature Review

Abstract

Background: Thyroid cancer is the most common endocrine malignancy worldwide. Primary treatment with surgery and radioactive iodine is usually successful, however, there remains a small proportion of thyroid cancers that are resistant to these treatments, and often represent aggressive forms of the disease. Since the 1950s, in vitro thyroid culture systems have been used in thyroid cancer research. In vitro culture models have evolved from 2-dimensional thyrocyte monolayers into physiologically functional 3-dimensional organoids. Recently, research groups have utilized in vitro thyroid cancer models to identify numerous genetic and epigenetic factors that are involved with tumorigenesis as well as test the efficacy of cytotoxic drugs on thyroid cancer cells and identify cancer stem cells within thyroid tumors. Objective of Review: The objective of this literature review is to summarize how thyroid in vitro culture models have evolved and highlight how in vitro models have been fundamental to thyroid cancer research. Type of Review: Systematic literature review. Search Strategy: The National Institute for Health and Care Excellence (NICE) Healthcare and Databases Advanced Search (HDAS) tool was used to search EMBASE, Medline and PubMed databases. The following terms were included in the search: "in vitro" AND "thyroid cancer". The search period was confined from January 2008 until June 2019. A manual search of the references of review articles and other key articles was also performed using Google Scholar. Evaluation Method: All experimental studies and review articles that explicitly mentioned the use of in vitro models for thyroid cancer research in the title and/or abstract were considered. Full-text versions of all selected articles were evaluated. Experimental studies were reviewed and grouped according to topic: genetics/epigenetics, drug testing/cancer treatment, and side populations (SP)/tumor microenvironment (TME). Results: Three thousand three hundred and seventy three articles were identified through database and manual searches. One thousand two hundred and sixteen articles remained after duplicates were removed. Five hundred and eighty nine articles were excluded based on title and/or abstract. Of the remaining 627 full-text articles: Chew et al. Thyroid Cancer in vitro Models 24 were review articles, 332 related to genetic/epigenetics, 240 related to drug testing/treatments, and 31 related to SP/TME. Conclusion: In vitro cell culture models have been fundamental in thyroid cancer research. There have been many advances in culture techniques-developing complex cellular architecture that more closely resemble tumors in vivo. Genetic and epigenetic factors that have been identified using in vitro culture models can be used as targets for novel drug therapies. In the future, in vitro systems will facilitate personalized medicine, offering bespoke treatments to patients.

Adult mouse and human organoids derived from thyroid follicular cells and modeling of Graves’ hyperthyroidism

“…Submerging TFCs in suspension cultures, including extracellular matrix components, generates three-dimensionl (3D) polarized spheroids with a follicle architecture, but still cannot be maintained long term (9). Alternatively, mouse models have shown potential as model systems for thyroid biology and Graves' disease modeling.…”

The Immune Landscape of Papillary Thyroid Cancer in the Context of Autoimmune Thyroiditis

“…In the past years, the two-dimensional (2D) monolayer culture has been widely used for studying different kinds of tumors but cannot accurately reflect the in vivo tissue pattern. Conversely, the 3D cultures have been gaining in popularity and are closely able to mimic in vivo conditions [ 59 , 60 , 61 ]. Although different works are available using PTC-derived cell lines for studying the thyroid tumorigenesis [ 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 ], very few in vitro studies have been performed to increase knowledge of the relationship between thyroiditis and PTC.…”

“…In this paper, using a sensitive and specific reverse transcriptase-polymerase chain reaction (RT-PCR) assay, the authors were unable to find if chronic inflammation might facilitate the rearrangement, or conversely, RET/PTC rearrangement might promote chronic inflammation [ 94 ]. Since then, many studies, using in vitro strategy, have been carried out supporting this association [ 59 , 60 , 61 , 62 , 64 , 157 ]. Indeed, the relevance of RET/PTC in the association between thyroiditis and PTC is also underscored by a retrospective pathological study [ 158 , 159 , 160 ].…”

Different Expression of Thyroid-Specific Proteins in Thyroid Cancer Cells between 2-Dimensional (2D) and 3-Dimensional (3D) Culture Environment

“…Many drug candidates that show promising effects in vitro with cancer cells proceed to in vivo studies with animal models (mainly mice) for evaluating their effects within living organisms [ 5 , 6 ]. However, the results of these studies usually differ from those of in vitro studies [ 7 , 8 ]; thus, the accuracy of in vitro studies for predicting the efficacy of in vivo studies has remained controversial and remarkably delays the success of drug development [ 8 ].…”