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

**Authors:** Benny Mosoane, Brandon S. Jackson, Michelle McCabe, Tebogo Marutha, Zodwa Dlamini

PMC · DOI: 10.3390/biomedicines14020453 · Biomedicines · 2026-02-18

## TL;DR

This review explores how cancer stem cells contribute to the progression and treatment resistance of anaplastic thyroid carcinoma, focusing on CD44 and related pathways.

## Contribution

The paper integrates molecular and microenvironmental factors to highlight CD44's role in cancer stemness and therapeutic resistance in ATC.

## Key findings

- CD44 and its variants are key players in cancer stemness, EMT, and metastasis in ATC.
- Signaling pathways like PI3K/AKT/mTOR and Wnt/β-catenin support CSC niches through interactions with the tumor microenvironment.
- Combination therapies targeting CSCs and the tumor microenvironment may improve outcomes in ATC.

## 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.

## Linked entities

- **Genes:** CD44 (CD44 molecule (IN blood group)) [NCBI Gene 960], PROM1 (prominin 1) [NCBI Gene 8842], ALDH1A1 (aldehyde dehydrogenase 1 family member A1) [NCBI Gene 216], PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) [NCBI Gene 5290], AKT1 (AKT serine/threonine kinase 1) [NCBI Gene 207], MTOR (mechanistic target of rapamycin kinase) [NCBI Gene 2475], MAPK (mitogen activated kinase-like protein) [NCBI Gene 7446652], Notch (neurogenic locus notch homolog) [NCBI Gene 100616083], Wnt (protein Wnt-2) [NCBI Gene 100641115], ctnnb1.S (catenin beta 1 S homeolog) [NCBI Gene 380441], shh.L (sonic hedgehog L homeolog) [NCBI Gene 398047]
- **Diseases:** anaplastic thyroid carcinoma (MONDO:0006468)

## Full-text entities

- **Genes:** EIF4E (eukaryotic translation initiation factor 4E) [NCBI Gene 1977] {aka AUTS19, CBP, EIF4E1, EIF4EL1, EIF4F, eIF-4E}, EPAS1 (endothelial PAS domain protein 1) [NCBI Gene 2034] {aka ECYT4, HIF2A, HLF, MOP2, PASD2, bHLHe73}, HSD3B7 (hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 7) [NCBI Gene 80270] {aka CBAS1, PFIC4, SDR11E3}, SHH (sonic hedgehog signaling molecule) [NCBI Gene 6469] {aka HHG1, HLP3, HPE3, MCOPCB5, SMMCI, ShhNC}, Prom1 (prominin 1) [NCBI Gene 19126] {aka 4932416E19Rik, AC133, CD133, Prom, Prom-1, Proml1}, CD44 [NCBI Gene 100126860], CSNK1A1 (casein kinase 1 alpha 1) [NCBI Gene 1452] {aka CK1, CK1a, CKIa, HEL-S-77p, HLCDGP1, PRO2975}, HIF1A (hypoxia inducible factor 1 subunit alpha) [NCBI Gene 3091] {aka HIF-1-alpha, HIF-1A, HIF-1alpha, HIF1, HIF1-ALPHA, MOP1}, CCND1 (cyclin D1) [NCBI Gene 595] {aka BCL1, D11S287E, PRAD1, U21B31}, ABCB1 (ATP binding cassette subfamily B member 1) [NCBI Gene 5243] {aka ABC20, CD243, CLCS, ENPAT, GP170, MDR1}, Cxcl5 (C-X-C motif chemokine ligand 5) [NCBI Gene 20311] {aka AMCF-II, Cxcl6, ENA-78, GCP-2, LIX, Scyb5}, IL2RG (interleukin 2 receptor subunit gamma) [NCBI Gene 3561] {aka CD132, CIDX, IL-2RG, IMD4, P64, SCIDX}, EGFR (epidermal growth factor receptor) [NCBI Gene 1956] {aka ERBB, ERBB1, ERRP, HER1, NISBD2, NNCIS}, Akt1 (Akt serine/threonine kinase 1) [NCBI Gene 11651] {aka Akt, LTR-akt, PKB, PKB/Akt, PKBalpha, Rac}, PPARG (peroxisome proliferator activated receptor gamma) [NCBI Gene 5468] {aka CIMT1, FPLD3, GLM1, NR1C3, PPARG1, PPARG2}, GSK3B (glycogen synthase kinase 3 beta) [NCBI Gene 2932], PIK3CB (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta) [NCBI Gene 5291] {aka P110BETA, PI3K, PI3KBETA, PIK3C1}, SMARCA4 (SWI/SNF related BAF chromatin remodeling complex subunit ATPase 4) [NCBI Gene 6597] {aka BAF190, BAF190A, BRG1, CSS4, MRD16, OTSC12}, AXIN2 (axin 2) [NCBI Gene 8313] {aka AXIL, ODCRCS}, STAT3 (signal transducer and activator of transcription 3) [NCBI Gene 733648], ABCG2 (ATP binding cassette subfamily G member 2 (JR blood group)) [NCBI Gene 9429] {aka ABC15, ABCP, BCRP, BMDP, CD338, CDw338}, HES1 (hes family bHLH transcription factor 1) [NCBI Gene 3280] {aka HES-1, HHL, HRY, bHLHb39}, CXCR4 (C-X-C motif chemokine receptor 4) [NCBI Gene 7852] {aka CD184, D2S201E, FB22, HM89, HSY3RR, LCR1}, PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) [NCBI Gene 5290] {aka CCM4, CLAPO, CLOVE, CWS5, HMH, MCAP}, CXCL11 (C-X-C motif chemokine ligand 11) [NCBI Gene 6373] {aka H174, I-TAC, IP-9, IP9, SCYB11, SCYB9B}, PREX1 (phosphatidylinositol-3,4,5-trisphosphate dependent Rac exchange factor 1) [NCBI Gene 57580] {aka P-REX1}, FOXO1 (forkhead box O1) [NCBI Gene 2308] {aka FKH1, FKHR, FOXO1A}, HDAC9 (histone deacetylase 9) [NCBI Gene 9734] {aka HD7, HD7b, HD9, HDAC, HDAC7B, HDAC9B}, AXIN1 (axin 1) [NCBI Gene 8312] {aka AXIN, CMDOH, PPP1R49}, ATF3 (activating transcription factor 3) [NCBI Gene 467], NANOG (Nanog homeobox) [NCBI Gene 79923], CD274 (CD274 molecule) [NCBI Gene 574058] {aka PDL1}, ASPM (assembly factor for spindle microtubules) [NCBI Gene 259266] {aka ASP, Calmbp1, MCPH5}, Trp53 (transformation related protein 53) [NCBI Gene 22059] {aka Tp53, bbl, bfy, bhy, p44, p53}, KRAS (KRAS proto-oncogene, GTPase) [NCBI Gene 3845] {aka 'C-K-RAS, C-K-RAS, CFC2, K-RAS2A, K-RAS2B, K-RAS4A}, Snai1 (snail family zinc finger 1) [NCBI Gene 20613] {aka Sna, Sna1, Snail, Snail1}, CTNNB1 (catenin beta 1) [NCBI Gene 1499] {aka CTNNB, EVR7, MRD19, NEDSDV, armadillo}, Slc2a1 (solute carrier family 2 (facilitated glucose transporter), member 1) [NCBI Gene 20525] {aka GT1, Glut-1, Glut1, M100200, Rgsc200}, CREB1 (cAMP responsive element binding protein 1) [NCBI Gene 1385] {aka CREB, CREB-1}, CHEK1 (checkpoint kinase 1) [NCBI Gene 1111] {aka CHK1, OZEMA21}, MAPK1 (mitogen-activated protein kinase 1) [NCBI Gene 5594] {aka ERK, ERK-2, ERK2, ERT1, MAPK2, NS13}, Sox2 (SRY (sex determining region Y)-box 2) [NCBI Gene 20674] {aka Sox-2, lcc, ysb}, Lin28a (lin-28 homolog A) [NCBI Gene 83557] {aka Gm10299, Lin-28, Lin28, Tex17, lin-28A}, IGF1R (insulin like growth factor 1 receptor) [NCBI Gene 3480] {aka CD221, IGFIR, IGFR, JTK13}, FN1 (fibronectin 1) [NCBI Gene 2335] {aka CIG, ED-B, FINC, FN, FNZ, GFND}, TWIST1 (twist family bHLH transcription factor 1) [NCBI Gene 7291] {aka ACS3, BPES2, BPES3, CRS, CRS1, CSO}, Tgfb1 (transforming growth factor, beta 1) [NCBI Gene 21803] {aka TGF-beta1, TGFbeta1, Tgfb, Tgfb-1}, IL6 (interleukin 6) [NCBI Gene 3569] {aka BSF-2, BSF2, CDF, HGF, HSF, IFN-beta-2}, TERT (telomerase reverse transcriptase) [NCBI Gene 7015] {aka CMM9, DKCA2, DKCB4, EST2, PFBMFT1, TCS1}, ALDH1A1 (aldehyde dehydrogenase 1 family member A1) [NCBI Gene 216] {aka ALDC, ALDH-E1, ALDH1, ALDH11, HEL-9, HEL-S-53e}, ALK (ALK receptor tyrosine kinase) [NCBI Gene 238] {aka ALK1, CD246, NBLST3}, Ctnnb1 (catenin beta 1) [NCBI Gene 12387] {aka Bfc, Catnb, Mesc}, MTOR (mechanistic target of rapamycin kinase) [NCBI Gene 2475] {aka FRAP, FRAP1, FRAP2, RAFT1, RAPT1, SKS}, EIF1AX (eukaryotic translation initiation factor 1A X-linked) [NCBI Gene 1964] {aka EIF1A, EIF1AP1, EIF4C, eIF-1A, eIF-4C}, CDH2 (cadherin 2) [NCBI Gene 1000] {aka ACOGS, ADHD8, ARVD14, CD325, CDHN, CDw325}, COL11A1 (collagen type XI alpha 1 chain) [NCBI Gene 1301] {aka CO11A1, COLL6, DFNA37, STL2}, TP63 (tumor protein p63) [NCBI Gene 8626] {aka AIS, B(p51A), B(p51B), EEC3, KET, LMS}, RBBP8 (RB binding protein 8, endonuclease) [NCBI Gene 5932] {aka COM1, CTIP, JAWAD, JWDS, RIM, SAE2}, NF1 (neurofibromin 1) [NCBI Gene 4763] {aka NFNS, VRNF, WSS}, Nanog (Nanog homeobox) [NCBI Gene 71950] {aka 2410002E02Rik, ENK, Stm1, ecat4}
- **Diseases:** necrosis (MESH:D009336), chyle fistula (MESH:D005402), glioblastoma (MESH:D005909), aneuploidy (MESH:D000782), nodular hyperplasia (MESH:D020518), benign thyroid lesions (MESH:D013959), hoarseness of voice (MESH:D006685), breast cancer (MESH:D001943), (IVB-IVC) (MESH:C567679), aggression (MESH:D010554), acute myeloid leukaemia (MESH:D054218), adenomatous polyposis coli (MESH:D011125), cytotoxicity (MESH:D064420), ulceration (MESH:D014456), multinodular goitres (MESH:C564546), dysphagia (MESH:D003680), metastasis (MESH:D009362), DTC (MESH:D013964), bladder, colon, and thyroid cancers (MESH:D015179), recurrent laryngeal nerve palsy (MESH:D014826), FTC (MESH:D018263), medullary thyroid carcinoma (MESH:C536914), thyroid (MESH:D013966), respiratory distress (MESH:D012128), SCID (MESH:D053632), cutaneous squamous cell carcinoma (MESH:D002294), Hypoxia (MESH:D000860), CSC (MESH:D018295), hypoxic (MESH:D002534), papillary thyroid carcinoma (MESH:D000077273), follicular adenomas and carcinomas (MESH:D000236), ATC (MESH:D065646), cancers (MESH:D009369), neck mass (MESH:D006258), familial medullary thyroid carcinoma (MESH:C536911), anaplastic transformation (MESH:D002277), injury to (MESH:D014947), inflammatory (MESH:D007249), MDR (MESH:D018088), WDTC (MESH:D015451)
- **Chemicals:** eosin (MESH:D004801), Anlotinib (MESH:C000625192), ellagic acid (MESH:D004610), tryptophan (MESH:D014364), ICG-001 (MESH:C492448), docetaxel (MESH:D000077143), plerixafor (MESH:C088327), RO4929097 (MESH:C545185), SB431542 (MESH:C459179), lipid (MESH:D008055), dabrafenib (MESH:C561627), PLX4720 (MESH:C528407), iodine (MESH:D007455), pioglitazone (MESH:D000077205), lenvatinib (MESH:C531958), iodine-131 (MESH:C000614965), VPA (MESH:D014635), BIWA-4 (-), GANT61 (MESH:C551027), pyrvinium pamoate (MESH:C024631), disulfiram (MESH:D004221), doxorubicin (MESH:D004317), retinoic acid (MESH:D014212), suberoylanilide hydroxamic acid (MESH:D000077337), Haematoxylin (MESH:D006416), artemisinin (MESH:C031327), Sorafenib (MESH:D000077157), decitabine (MESH:D000077209), ruxolitinib (MESH:C540383), HA (MESH:D006820), 5-FU (MESH:D005472), metformin (MESH:D008687), salinomycin (MESH:C010327), panobinostat (MESH:D000077767), iron (MESH:D007501), trametinib (MESH:C560077), paclitaxel (MESH:D017239), THZ531 (MESH:C000618758), 89Zr (MESH:C000615502), vemurafenib (MESH:D000077484), palbociclib (MESH:C500026), BEZ235 (MESH:C531198), vismodegib (MESH:C538724), MK-2206 (MESH:C548887)
- **Species:** Adenoviridae (family) [taxon 10508], Homo sapiens (human, species) [taxon 9606], Mus musculus (house mouse, species) [taxon 10090]
- **Mutations:** R273H, C/A, G/A, C228T, rs12898, R175H, rs12921862, S108delinsX, BRAFV600E, rs1805105, R273C, serine/threonine, C250T
- **Cell lines:** C643 — Homo sapiens (Human), Thyroid gland anaplastic carcinoma, Cancer cell line (CVCL_5969), SW1736 — Homo sapiens (Human), Thyroid gland anaplastic carcinoma, Cancer cell line (CVCL_3883), 8305C — Homo sapiens (Human), Thyroid gland anaplastic carcinoma, Cancer cell line (CVCL_1053), FTC-133 — Homo sapiens (Human), Thyroid gland papillary carcinoma, Cancer cell line (CVCL_6308)

## Full text

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## Figures

7 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12938669/full.md

## References

272 references — full list in the complete paper: https://tomesphere.com/paper/PMC12938669/full.md

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Source: https://tomesphere.com/paper/PMC12938669