Cancer Stemness and Dedifferentiation in Anaplastic Thyroid Carcinoma: Insights into a Multigenic, Microenvironmental Network and the Role of CD44

Abstract

Anaplastic thyroid carcinoma (ATC) is an aggressive and lethal malignancy that carries a poor prognosis. Moreover, there are limited therapeutic options for managing ATC. There is increasing evidence that implicates the role of cancer stem cells (CSCs) in the processes of dedifferentiation in the progression, therapeutic resistance, and metastatic potential of ATC. In this review, we integrate the molecular and cellular insights into the CSCs paradigm in ATC to highlight the role of stemness-associated markers that include CD44, CD133, and ALDH1. We put special emphasis on the role of CD44 and its variant isoforms (CD44v), which play a role in the interface of cancer stemness, tumour microenvironment crosstalk, modulation of epithelial-mesenchymal transition (EMT), chemoresistance, and metastasis. The contribution of signalling pathways (PI3K/AKT/mTOR, MAPK, Notch, Wnt/β-catenin, and Hedgehog) to hypoxia, cancer-associated fibroblasts (CAFs), and tumour-associated macrophages (TAMs) in sustaining CSC niches will be discussed. The review explores advances in molecular diagnostics, imaging technologies, and targeted therapeutic strategies with the potential to disrupt CSC-driven tumour maintenance. Through integration of multigenic, epigenetic, and microenvironmental perspectives, this review highlights the potential necessity of CSC-targeted and combination therapies to improve disease outcomes in ATC.

Keywords: CD44; anaplastic thyroid carcinoma; cancer stem cells; dedifferentiation.

Figure 1

Histological features of anaplastic thyroid carcinoma (ATC) arising in the background of differentiated thyroid carcinoma (DTC), specifically the follicular subtype of papillary thyroid carcinoma (PTC). The residual PTC displays follicular structures lined by tumour cells with optically clear “orphan Annie eye” nuclei and finely dispersed (powdery) chromatin. In the predominant ATC component, arrows indicate multinucleated tumour giant cells, while the stars denote areas of tumour necrosis. Haematoxylin and eosin staining, 10× magnification, captured using an Olympus BX41 microscope with a 10×/22 objective at the Department of Anatomical Pathology, University of Pretoria. The image is derived from anonymised archival diagnostic material and is included for illustrative purposes only.

Figure 2

This histological image shows a poorly differentiated thyroid carcinoma (PDTC). The main image shows a characteristic insular (nested) growth pattern (10× magnification). Inset (bottom right) displays a separate tumour field with extensive necrosis (20× magnification). Haematoxylin and eosin staining, images captured at the Department of Anatomical Pathology, University of Pretoria, using an Olympus BX41 microscope with a 10×/22 objective. The image is derived from anonymised archival diagnostic material and is included for illustrative purposes only.

Figure 3

This image illustrates the progression of thyroid follicular epithelial cells to anaplastic thyroid carcinoma (ATC). The transformation is driven by the stepwise accumulation of mutagenic events. Initial mutations such as RAS, BRAF, RET/PTC rearrangements, PPARγ fusions, and chromosomal aneuploidy commonly give rise to differentiated thyroid carcinomas (DTCs), including papillary and follicular subtypes. With further genetic alterations, including TP53 and RB1 inactivation or Wnt/β-catenin pathway activation, DTCs may dedifferentiate into ATC. In some cases, for well-differentiated carcinomas, progression may occur via an intermediate poorly differentiated thyroid carcinoma (PDTC) stage before culminating in ATC through SWI/SNF, TERT and TP53 mutations. Transformation of PDTC to ATC is postulated to mutations such as TP53, Wnt/β-catenin, Rb, FAP, TGFB1, and COL11A1.

Figure 4

Schematic representation of the gene and protein structure (across the cell membrane) of CD44.

Figure 5

CD44-mediated regulation of cancer cell plasticity. Subpopulations of cancer cells upregulate the iron transporter CD44, which facilitates epigenetic reprogramming and activation of gene expression programs associated with epithelial-to-mesenchymal transition (EMT), stemness, proliferation, and resistance to therapy, which serve as hallmarks of aggressive tumour behaviour.

Figure 6

Diagrammatic depiction of the localisation of cancer stem cells (CSCs) within tumour microenvironmental niches. CSCs reside within the extracellular matrix (ECM), which provides structural protection and promotes self-renewal through matrix remodelling. Their localisation within immune niches facilitates immune evasion via immunosuppressive signalling. In perinecrotic regions, CSCs are supported by hypoxia-induced paraphysiological adaptations that enhance survival.

Figure 7

Therapeutic resistance in anaplastic thyroid carcinoma (ATC) illustrating two clinical scenarios. Patient A: In the absence of cancer stem cells (CSCs), conventional therapies such as surgery, chemotherapy, and radioactive iodine effectively eradicate tumour cells. Patient B: In the presence of CSCs (depicted as larger cells with blue nuclei and bright yellow cytoplasm), conventional therapy eliminates bulk tumour cells but spares CSCs, leading to relapse and tumour regrowth. The addition of CSC-targeted therapies in Patient B enables elimination of both CSCs and differentiated tumour cells, reducing the risk of recurrence. Red T-bars denote therapeutic inhibition or blockade, red crosses indicate elimination of tumour cell populations and arrows indicate tumour progression or recurrence.