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  • Review Article
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Pathogenesis of cancers derived from thyroid follicular cells

Nature Reviews Cancer volume 23, pages 631–650 (2023)Cite this article

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Abstract

The genomic simplicity of differentiated cancers derived from thyroid follicular cells offers unique insights into how oncogenic drivers impact tumour phenotype. Essentially, the main oncoproteins in thyroid cancer activate nodes in the receptor tyrosine kinase–RAS–BRAF pathway, which constitutively induces MAPK signalling to varying degrees consistent with their specific biochemical mechanisms of action. The magnitude of the flux through the MAPK signalling pathway determines key elements of thyroid cancer biology, including differentiation state, invasive properties and the cellular composition of the tumour microenvironment. Progression of disease results from genomic lesions that drive immortalization, disrupt chromatin accessibility and cause cell cycle checkpoint dysfunction, in conjunction with a tumour microenvironment characterized by progressive immunosuppression. This Review charts the genomic trajectories of these common endocrine tumours, while connecting them to the biological states that they confer.

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Fig. 1: Characteristics of BRAF-like and RAS-like differentiated thyroid cancers.
Fig. 2: Interactions between MAPK and cAMP signalling in thyroid cancer cells.
Fig. 3: Mechanisms of mutant eIF1A and RAS cooperation in thyroid tumorigenesis.
Fig. 4: Epigenetic reprogramming in thyroid cancer progression and differentiation.
Fig. 5: Adaptive responses of BRAF-mutant thyroid cancers to RAF kinase inhibitors.

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Acknowledgements

J.A.F. acknowledges funding from the NIH, Cycle for Survival and from the Frank Cohen, Jaymie and Peter Flowers and Salvatore Ranieri funds. I.L. acknowledges funding from the NIH. The authors are also grateful to B. Xu and R. Ghossein for providing histological images for Fig. 1.

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Authors and Affiliations

  1. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    James A. Fagin, Gnana P. Krishnamoorthy & Iñigo Landa

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  1. James A. Fagin
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  2. Gnana P. Krishnamoorthy
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  3. Iñigo Landa
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Glossary

Adaptive resistance

MAPK pathway oncoproteins activate downstream signalling networks, which in turn elicit negative regulatory events designed to dampen pathway output. Upon targeted inhibition of the oncoprotein with small molecules, the network adapts by relieving this negative feedback, causing intrinsic resistance to their action.

Adipogenesis

Differentiation process through which mesenchymal cells commit to preadipocytes, and these in turn differentiate into adipocytes.

Angiocrine factors

Growth factors, trophogens or membrane-bound paracrine factors supplied by endothelial cells to regulate neighbouring cell growth and homeostasis.

Capsular invasion

Invasion of tumour through the entire capsule distinguishes malignant from benign follicular-patterned thyroid neoplasms.

Cassette exon

Intervening exon between two other exons from the mature mRNA sequence that can be either included or skipped to generate two distinct protein isoforms.

Goitre

Abnormally enlarged thyroid gland.

Hyperthyroidism

Syndrome associated with excessive production of thyroid hormones by thyroid cells.

Non-homologous end joining

Pathway that repairs DNA double-stranded breaks without the need for a homologous template to ligate the break ends.

Non-synonymous somatic mutations

Mutations acquired postnatally that change the amino acid sequence of a protein.

Oncogene-induced senescence

Antiproliferative effects of oncoproteins mediated by a DNA damage response to DNA hyper-replication.

Open-label clinical trials

A type of study in which health providers and study subjects are aware of the treatment or drug being given.

Oxyphil cells

Cells with an eosinophilic cytoplasm containing abundant, abnormally large, mitochondria and large centrally located nuclei.

Radioactive iodine (RAI) therapy

Administration of iodine-131 to ablate thyroid tissue. In patients with thyroid cancer, it is used to destroy the remnants of thyroid after thyroidectomy as adjuvant therapy or to treat RAI-avid metastases.

RAI avidity

Refers to the cellular property of incorporating and retaining radioactive iodine isotopes.

Sleeping beauty (SB) transposon

Composed of a Sleeping Beauty transposase and a synthetic DNA transposon designed to integrate into the genome of vertebrates to introduce new phenotypes and identify the genes responsible for them.

SWI/SNF chromatin remodelling complexes

Multisubunit protein complexes that elicit a DNA-stimulated ATPase activity that destabilizes histone–DNA interactions to mobilize nucleosomes, which increases accessibility of transcription factors to chromatin to activate or repress gene expression.

Telomere crisis

When telomeres become critically short, they are unable to protect chromosome ends from the DNA damage response and repair pathways. Telomere shortening can enable cancer growth through telomere crisis, a state of extensive genomic instability causing translocations, amplifications and deletions.

Tetraploidy

A cell containing four homologous copies of all chromosomes.

Thyroglobulin

A glycoprotein produced by thyroid cells that is secreted into the lumen of the follicle. Tyrosine residues in thyroglobulin incorporate iodine through the action of thyroid peroxidase, which upon cleavage and coupling in lysosomes gives rise to thyroid hormones.

Thyroid follicular cells

The major cell type of the thyroid gland, derived from the endoderm, and responsible for the production and secretion of the thyroid hormones thyroxine and triiodothyronine.

Thyroid parafollicular or C cells

Neuroendocrine cells of the thyroid, which secrete calcitonin, a hormone that helps control the level of calcium in blood.

Thyroid-stimulating hormone

(TSH). Glycoprotein hormone secreted by the pituitary gland that binds to the TSH receptor on thyroid cells to stimulate cell growth and expression of iodine metabolism genes.

Thyrotrophs

Pituitary cells that secrete TSH.

Tumour microevolution

Cancer is commonly understood to develop as a microevolutionary process, whereby a mutation initially confers a cell with a growth advantage allowing it to clonally expand. Sequential acquisition of new mutations in turn provides further stepwise fitness to the emerging clones.

Uniparental disomy

(UPD). Refers to the presence of two copies of a chromosome (chromosomes) derived from a single parent. In cancer, it manifests as large blocks of homozygosity with normal copy number.

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Fagin, J.A., Krishnamoorthy, G.P. & Landa, I. Pathogenesis of cancers derived from thyroid follicular cells. Nat Rev Cancer 23, 631–650 (2023). https://doi.org/10.1038/s41568-023-00598-y

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