Restricted accessReview articleFirst published online 2026-2
Comprehensive Analysis of CD44 in Colorectal Cancer: Molecular Mechanisms,Isoform Interactions,and Targeted Treatments to Address Tumorigenesis and Chemoresistance
Cluster of differentiation 44 (CD44), a versatile transmembrane glycoprotein, plays a crucial role in the progression, metastasis, and therapeutic resistance of colorectal cancer (CRC). This review clarifies CD44’s essential function in CRC via connections with the extracellular matrix (ECM), particularly hyaluronic acid (HA), and important signaling pathways, such as Ras/mitogen-activated protein kinase/extracellular signal-regulated kinase and phosphoinositide 3-kinase/protein kinase B (PI3K/Akt). The overexpression of CD44, especially its variant isoforms (CD44v), is associated with aggressive tumor characteristics, increased cancer stem cell (CSC) traits, and unfavorable outcomes in CRC patients. CD44 enhances tumor cell attachment, movement, infiltration, and epithelial–mesenchymal transition, facilitating metastasis and resistance to chemotherapy. Its interactions with ECM elements and receptors, such as the epidermal growth factor receptor, enhance tumor growth and survival signaling. Therapeutic approaches aimed at CD44, such as monoclonal antibodies, small interfering RNAs, and nanoparticles targeting CD44 (e.g., CSA-SS-CXB@CPT, A@HAP), show encouraging antitumor effectiveness by interrupting CD44-HA interactions and the subsequent signaling pathways. Preclinical studies emphasize the benefits of pairing anti-CD44 therapies with PI3K/Akt or Wnt/β-catenin inhibitors to improve results. This review combines CD44’s molecular mechanisms, isoform-specific functions, and CSC regulation in CRC, highlighting the potential as a biomarker and therapeutic target to enhance patient outcomes.
MukkavilliV, RamakrishnanG, GujjulaKR, et al.Molecular understanding and pharmacological potency of plant-derived compounds in Colorectal Cancer (CRC): A critical analysis and future perspectives. Cell Biochem Biophys, 2024; 82(3):1777–1795; doi: 10.1007/s12013-024-01370-1
2.
MundelR, DhadwalS, BhartiS, et al.A comprehensive overview of various cancer types and their progression. In: Handbook of Oncobiology: From Basic to Clinical Sciences. (SobtiRC, GangulyNK, KumarR eds.) Springer Nature Singapore: Singapore; 2024; pp. 189–205.
3.
HamdyNM, ZakiMB, RizkNI, et al.Unraveling the ncRNA landscape that governs colorectal cancer: A roadmap to personalized therapeutics. Life Sci, 2024; 354:122946; doi: 10.1016/j.lfs.2024.122946
4.
LiC, DuX, ZhangH, et al.Knockdown of ribosomal protein L22-like 1 arrests the cell cycle and promotes apoptosis in colorectal cancer. Cytojournal, 2024; 21:45; doi: 10.25259/Cytojournal_29_2024
5.
BiradarMS, ThapaS, ShindeSS, et al.Understanding colon cancer: causes, prevention, and complementary therapies including therapeutic foods, beverages, and meditation. In: Systems Biology Approaches: Prevention, Diagnosis, and Understanding Mechanisms of Complex Diseases. (JoshiS, RayRR, NagM eds.) Springer Nature Singapore: Singapore; 2024; pp. 467–487.
6.
MaedehB. Correlation between miR-27 rs895819 and miR-423 rs6505162 Polymorphisms and Susceptibility to Colorectal Cancer in the Iranian Population: A Case-Control Study. Ejmo, 2024; 8(3):348–357.
7.
SunDY, HuYJ, LiX, et al.Unlocking the full potential of memory T cells in adoptive T cell therapy for hematologic malignancies. Int Immunopharmacol, 2025; 144:113392; doi: 10.1016/j.intimp.2024.113392
8.
TongG, PengT, ChenY, et al.Effects of GLP-1 receptor agonists on biological behavior of colorectal cancer cells by regulating PI3K/AKT/mTOR signaling pathway. Front Pharmacol, 2022; 13:901559; doi: 10.3389/fphar.2022.901559
9.
XuX, MeiX, HanK, et al.The deubiquitinating enzyme USP1 is auto-ubiquitinated and destabilized by ML323 in colorectal cancer cells. Eurasian J Med Oncol, 2023; 7:174–179.
10.
KimSG, DuongTV, LeeS, et al.Synergistic inhibition of colorectal cancer cells by autocrine motility factor peptide and Glycyrrhetinic acid. Discov Med, 2024; 36(189):2063–2070; doi: 10.24976/Discov.Med.202436189.190
11.
Abd El FattahYK, AbulsoudAI, AbdelHamidSG, et al.CCDC144NL-AS1/hsa-miR-143-3p/HMGA2 interaction: In-silico and clinically implicated in CRC progression, correlated to tumor stage and size in case-controlled study; step toward ncRNA precision. Int J Biol Macromol, 2023; 253(Pt 2):126739; doi: 10.1016/j.ijbiomac.2023.126739
12.
HuangJ, MengP, LiangY, et al.Tubular CD44 plays a key role in aggravating AKI through NF-κB p65-mediated mitochondrial dysfunction. Cell Death Dis, 2025; 16(1):119; doi: 10.1038/s41419-025-07438-x
13.
HanJ, LeeC, JeongH, et al.Tumor necrosis factor-inducible gene 6 protein and its derived peptide ameliorate liver fibrosis by repressing CD44 activation in mice with alcohol-related liver disease. J Biomed Sci, 2024; 31(1):54; doi: 10.1186/s12929-024-01042-5
14.
WangY, DingG, ChuC, et al.Genomic biology and therapeutic strategies of liver metastasis from gastric cancer. Crit Rev Oncol Hematol, 2024; 202:104470; doi: 10.1016/j.critrevonc.2024.104470
15.
DuJ, MengX, YangM, et al.NGR-Modified CAF-Derived exos targeting tumor vasculature to induce Ferroptosis and overcome Chemoresistance in osteosarcoma. Adv Sci (Weinh), 2025; 12(12):e2410918; doi: 10.1002/advs.202410918
16.
LinX, YuT, ZhangL, et al.Silencing Op18/stathmin by RNA interference promotes the sensitivity of nasopharyngeal carcinoma cells to taxol and high-grade differentiation of Xenografted Tumours in nude mice. Basic Clin Pharmacol Toxicol, 2016; 119(6):611–620; doi: 10.1111/bcpt.12633
17.
LinX, LiaoY, ChenX, et al.Regulation of Oncoprotein 18/Stathmin signaling by ERK concerns the resistance to Taxol in Nonsmall cell lung cancer cells. Cancer Biother Radiopharm, 2016; 31(2):37–43; doi: 10.1089/cbr.2015.1921
18.
TangF, ZhuY, ShenJ, et al.CD44+ cells enhance pro-tumor stroma in the spatial landscape of colorectal cancer leading edge. Br J Cancer, 2025; 132(8):703–715; doi: 10.1038/s41416-025-02968-9
19.
ZhangQ, WangX, LiuY, et al.Pan-cancer and single-cell analyses identify CD44 as an immunotherapy response predictor and regulating macrophage polarization and tumor progression in colorectal cancer. Front Oncol, 2024; 14:1380821.
20.
HamdyNM, BasaliousEB, El-SisiMG, et al.Advancements in current one-size-fits-all therapies compared to future treatment innovations for better improved chemotherapeutic outcomes: A step-toward personalized medicine. Curr Med Res Opin, 2024; 40(11):1943–1961; doi: 10.1080/03007995.2024.2416985
21.
AkceM, ZakkaK, PenleyM, et al.Impact of high-risk features for stage II adenocarcinoma of the appendix. Cancer Treat Res Commun, 2021; 27:100329; doi: 10.1016/j.ctarc.2021.100329
22.
HeZ, YangC, DiaoD, et al.Anatomic patterns and clinical significance of gastrocolic trunk of Henlé in laparoscopic right colectomy for colon cancer: Results of the HeLaRC trial. Int J Surg, 2022; 104:106718; doi: 10.1016/j.ijsu.2022.106718
23.
YangR, ZhengG, RenD, et al.The clinical significance and biological function of tropomyosin 4 in colon cancer. Biomed Pharmacother, 2018; 101:1–7; doi: 10.1016/j.biopha.2018.01.166
24.
MärklB, RößleJ, ArnholdtHM, et al.The clinical significance of lymph node size in colon cancer. Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc, 2012; 25(10):1413–1422; doi: 10.1038/modpathol.2012.92
25.
KimHG, LeeS-H, JeonSR, et al.Clinical significance of the first surveillance colonoscopy after endoscopic early colorectal cancer removal. Hepatogastroenterology, 2013; 60(125):1047–1052; doi: 10.5754/hge11998
26.
LiZ, FanJ, XiaoY, et al.Essential role of Dhx16-mediated ribosome assembly in maintenance of hematopoietic stem cells. Leukemia, 2024; 38(12):2699–2708; doi: 10.1038/s41375-024-02423-3
27.
YangJ, ZhuJ, LuS, et al.Transdermal psoriasis treatment inspired by tumor microenvironment-mediated immunomodulation and advanced by exosomal engineering. J Control Release, 2025; 382:113664; doi: 10.1016/j.jconrel.2025.113664
28.
ParkJH, KimYH, ShimS, et al.Radiation-Activated PI3K/AKT pathway promotes the induction of cancer stem-like cells via the upregulation of SOX2 in colorectal cancer. Cells, 2021; 10(1):135; doi: 10.3390/cells10010135
29.
Gonzalez-ValdiviesoJ, VallejoR, Rodriguez-RojoS, et al.CD44-targeted nanoparticles for co-delivery of docetaxel and an Akt inhibitor against colorectal cancer. Biomater Adv, 2023; 154:213595; doi: 10.1016/j.bioadv.2023.213595
30.
GaoL, LuY, ChenHN, et al.Deciphering the clinical significance and kinase functions of GSK3α in colon cancer by proteomics and Phosphoproteomics. Mol Cell Proteomics, 2023; 22(5):100545; doi: 10.1016/j.mcpro.2023.100545
31.
MüllerS, SindikubwaboF, CañequeT, et al.CD44 regulates epigenetic plasticity by mediating iron endocytosis. 2019.
32.
HummelM, Hegewisch-BeckerS, NeumannJHL, et al.BRAF testing in metastatic colorectal carcinoma and novel, chemotherapy-free therapeutic options. Pathologe, 2021; 42(Suppl 1):98–109; doi: 10.1007/s00292-021-00946-5
33.
GuoQ, YangC, GaoF. The state of CD44 activation in cancer progression and therapeutic targeting. Febs J, 2022; 289(24):7970–7986; doi: 10.1111/febs.16179
34.
MatsunagaT, OkumuraN, SaitoH, et al.Significance of aldo-keto reductase 1C3 and ATP-binding cassette transporter B1 in gain of irinotecan resistance in colon cancer cells. Chem Biol Interact, 2020; 332:109295; doi: 10.1016/j.cbi.2020.109295
35.
LuoW, LuT. A commentary on “Anatomic patterns and clinical significance of gastrocolic trunk of Henlé in laparoscopic right colectomy for colon cancer: Results of the HeLaRC trial. Int J Surg, 2022; 107:106965; doi: 10.1016/j.ijsu.2022.106965
36.
DerwingerK, GustavssonB. A study of lymph node ratio in stage IV colorectal cancer. World J Surg Oncol, 2008; 6:127; doi: 10.1186/1477-7819-6-127
37.
EbrahimiN, AfshinpourM, FakhrSS, et al.Cancer stem cells in colorectal cancer: Signaling pathways involved in stemness and therapy resistance. Crit Rev Oncol Hematol, 2023; 182:103920; doi: 10.1016/j.critrevonc.2023.103920
38.
WangH, LiuS, ZhangX, et al.Tu1919 clinical significance of NIBP expression in human colon cancer tissues. Gastroenterology, 2013; 144(5):S-881; doi: 10.1016/S0016-5085(13)63275-8
39.
XuH, NiuM, YuanX, et al.CD44 as a tumor biomarker and therapeutic target. Exp Hematol Oncol, 2020; 9(1):36; doi: 10.1186/s40164-020-00192-0
40.
Hassn MesratiM, SyafruddinSE, MohtarMA, et al.CD44: A multifunctional mediator of cancer progression. Biomolecules, 2021; 11(12):1850.
41.
DevetziM, TrangasT, ScorilasA, et al.Parallel overexpression and clinical significance of kallikrein-related peptidases 7 and 14 (KLK7KLK14) in colon cancer. Thromb Haemost, 2013; 109(4):716–725; doi: 10.1160/th12-07-0518
42.
XiaK, HuW, WangY, et al.Extracellular matrix stiffness modulates the mechanophenotypes and focal adhesions of colon cancer cells leading to their invasions via YAP1. Mechanobiol Med, 2024; 2(2):100062; doi: 10.1016/j.mbm.2024.100062
43.
Pihlmann KristensenM, KorsgaardU, TimmS, et al.The prognostic value of tumor budding in a thoroughly characterized stage II colon cancer population in the context of a national screening program. Hum Pathol, 2024; 146:15–22; doi: 10.1016/j.humpath.2024.02.010
44.
KangK, HuangH, ChenZ. Identification and validation of the prognostic signature of a novel demethylation-related gene associated with the clinical features of colon cancer. Int Immunopharmacol, 2024; 139:112798; doi: 10.1016/j.intimp.2024.112798
45.
ZhuS, ZouM, LiC, et al.MC1R regulates T regulatory cell differentiation through metabolic reprogramming to promote colon cancer. Int Immunopharmacol, 2024; 138:112546; doi: 10.1016/j.intimp.2024.112546
46.
LiD, QuG, LingS, et al.A cuproptosis-related lncRNA signature to predict prognosis and immune microenvironment of colon adenocarcinoma. Sci Rep, 2023; 13(1):6284; doi: 10.1038/s41598-023-33557-6
47.
AnwarMM, AlbaneseC, HamdyNM, et al.Rise of the natural red pigment ‘prodigiosin’ as an immunomodulator in cancer. Cancer Cell Int, 2022; 22(1):419; doi: 10.1186/s12935-022-02815-4
48.
ZhangX, YangL, LeiW, et al.Single-cell sequencing reveals CD133(+)CD44(-)-originating evolution and novel stemness related variants in human colorectal cancer. EBioMedicine, 2022; 82:104125; doi: 10.1016/j.ebiom.2022.104125
49.
JoostenSPJ, SpaargarenM, CleversH, et al.Hepatocyte growth factor/MET and CD44 in colorectal cancer: Partners in tumorigenesis and therapy resistance. Biochim Biophys Acta Rev Cancer, 2020; 1874(2):188437; doi: 10.1016/j.bbcan.2020.188437
50.
XieZ, ZhengG, NiuL, et al.SPP1+ macrophages in colorectal cancer: Markers of malignancy and promising therapeutic targets. Genes Dis, 2025; 12(3):101340; doi: 10.1016/j.gendis.2024.101340
51.
AokiK, NishitoY, MotoiN, et al.Tumor-infiltrating Leukocyte profiling defines three immune subtypes of NSCLC with distinct signaling pathways and genetic alterations. Cancer Res Commun, 2023; 3(6):1026–1040; doi: 10.1158/2767-9764.Crc-22-0415
52.
SunR, SunC, YueZ, et al.Astragali Radix-Curcumae Rhizoma herb pair reduces the stemness of colorectal cancer cells through HIF-2α/β-catenin pathway. Phytomedicine, 2024; 132:155824; doi: 10.1016/j.phymed.2024.155824
53.
Sadat KalakiN, AhmadzadehM, NajafiM, et al.Systems biology approach to identify biomarkers and therapeutic targets for colorectal cancer. Biochem Biophys Rep, 2024; 37:101633; doi: 10.1016/j.bbrep.2023.101633
54.
SasakiN, AsanoY, SorayamaY, et al.Promoting biological similarity by collagen microfibers in 3D colorectal cancer-stromal tissue: Replicating mechanical properties and cancer stem cell markers. Acta Biomater, 2024; 185:161–172; doi: 10.1016/j.actbio.2024.07.001
55.
YusupovM, Privat-MaldonadoA, CordeiroRM, et al.Oxidative damage to hyaluronan–CD44 interactions as an underlying mechanism of action of oxidative stress-inducing cancer therapy. Redox Biol, 2021; 43:101968; doi: 10.1016/j.redox.2021.101968
56.
KumarS, KimlingerT, MoriceW. Immunophenotyping in multiple myeloma and related plasma cell disorders. Best Pract Res Clin Haematol, 2010; 23(3):433–451; doi: 10.1016/j.beha.2010.09.002
GuoL, KeH, ZhangH, et al.TDP43 promotes stemness of breast cancer stem cells through CD44 variant splicing isoforms. Cell Death Dis, 2022; 13(5):428; doi: 10.1038/s41419-022-04867-w
59.
DzoboK, DandaraC. The extracellular matrix: Its composition, function, remodeling, and role in tumorigenesis. Biomimetics (Basel, Switzerland), 2023; 8(2); doi: 10.3390/biomimetics8020146
60.
FuD, HuZ, XuX, et al.Key signal transduction pathways and crosstalk in cancer: Biological and therapeutic opportunities. Transl Oncol, 2022; 26:101510; doi: 10.1016/j.tranon.2022.101510
61.
PhiLTH, SariIN, YangYG, et al.Cancer Stem Cells (CSCs) in drug resistance and their therapeutic implications in cancer treatment. Stem Cells Int, 2018; 2018:5416923; doi: 10.1155/2018/5416923
62.
WolfKJ, ShuklaP, SpringerK, et al.A mode of cell adhesion and migration facilitated by CD44-dependent microtentacles. Proceedings of the National Academy of Sciences of the United States of America, 2020; 117(21):11432–11443; doi: 10.1073/pnas.1914294117
63.
FanS, QiM, QiQ, et al.Targeting FAPα-positive lymph node metastatic tumor cells suppresses colorectal cancer metastasis. Acta Pharm Sin B, 2024; 14(2):682–697; doi: 10.1016/j.apsb.2023.11.002
64.
AylaS, KarakocE, ByrneYY, et al.Splicing variants of versican in CD133+/CD44+ prostate cancer stem cells. Pathol Res Pract, 2024; 260:155440; doi: 10.1016/j.prp.2024.155440
65.
MallaR, JyosthsnaK, RaniG, et al.CD44/PD-L1-mediated networks in drug resistance and immune evasion of breast cancer stem cells: Promising targets of natural compounds. Int Immunopharmacol, 2024; 138:112613; doi: 10.1016/j.intimp.2024.112613
66.
SaundersMP, GrahamJ, CunninghamD, et al.CXD101 and nivolumab in patients with metastatic microsatellite-stable colorectal cancer (CAROSELL): A multicentre, open-label, single-arm, phase II trial. ESMO Open, 2022; 7(6):100594; doi: 10.1016/j.esmoop.2022.100594
67.
NarihiroS, YoshidaM, OhdairaH, et al.Effectiveness and safety of tumor site marking with near-infrared fluorescent clips in colorectal laparoscopic surgery: A case series study. Int J Surg, 2020; 80:74–78; doi: 10.1016/j.ijsu.2020.06.014
68.
ZhangS, LiX, ZhuL, et al.CD163+ macrophages suppress T cell response by producing TGF-β in pediatric colorectal polyps. Int Immunopharmacol, 2021; 96:107644; doi: 10.1016/j.intimp.2021.107644
69.
HeiserCN, SimmonsAJ, RevettaF, et al.Molecular cartography uncovers evolutionary and microenvironmental dynamics in sporadic colorectal tumors. Cell, 2023; 186(25):5620–5637.e16; doi: 10.1016/j.cell.2023.11.006
70.
PrimeauxM, GowrikumarS, DhawanP. Role of CD44 isoforms in epithelial-mesenchymal plasticity and metastasis. Clin Exp Metastasis, 2022; 39(3):391–406; doi: 10.1007/s10585-022-10146-x
71.
YanY, ZuoX, WeiD. Concise review: Emerging role of CD44 in cancer stem cells: A promising biomarker and therapeutic target. Stem Cells Transl Med, 2015; 4(9):1033–1043; doi: 10.5966/sctm.2015-0048%J
72.
FontanellaRA, SideriS, Di StefanoC, et al.CD44v8-10 is a marker for malignant traits and a potential driver of bone metastasis in a subpopulation of prostate cancer cells. Cancer Biol Med, 2021; 18(3):788–807; doi: 10.20892/j.issn.2095-3941.2020.0495
73.
HerishanuY, GibelliniF, NjugunaN, et al.Activation of CD44, a receptor for extracellular matrix components, protects chronic lymphocytic leukemia cells from spontaneous and drug induced apoptosis through MCL-1. Leuk Lymphoma, 2011; 52(9):1758–1769; doi: 10.3109/10428194.2011.569962
YangC, ShengY, ShiX, et al.CD44/HA signaling mediates acquired resistance to a PI3Kα inhibitor. Cell Death Dis, 2020; 11(10):831; doi: 10.1038/s41419-020-03037-0
76.
SzatanekR, Baj-KrzyworzekaM. CD44 and Tumor-Derived Extracellular Vesicles (TEVs) possible gateway to cancer metastasis. Int J Mol Sci, 2021; 22(3):1463; doi: 10.3390/ijms22031463
77.
HouH, ChenD, ZhangK, et al.Gut microbiota-derived short-chain fatty acids and colorectal cancer: Ready for clinical translation? Cancer Lett, 2022; 526:225–235; doi: 10.1016/j.canlet.2021.11.027
78.
ShanE, HuoY, WangH, et al.Differentiated embryonic chondrocyte expressed gene-1 (DEC1) enhances the development of colorectal cancer with an involvement of the STAT3 signaling. Neoplasia, 2022; 27:100783; doi: 10.1016/j.neo.2022.100783
79.
Fernández-TabaneraE, García-GarcíaL, Rodríguez-MartínC, et al.CD44 modulates cell migration and invasion in Ewing sarcoma cells. Int J Mol Sci, 2023; 24(14):11774.
80.
FaresJ, FaresMY, KhachfeHH, et al.Molecular principles of metastasis: A hallmark of cancer revisited. Signal Transduct Target Ther, 2020; 5(1):28; doi: 10.1038/s41392-020-0134-x
81.
ZhouH-M, ZhangJ-G, ZhangX, et al.Targeting cancer stem cells for reversing therapy resistance: Mechanism, signaling, and prospective agents. Signal Transduct Target Ther, 2021; 6(1):62; doi: 10.1038/s41392-020-00430-1
82.
WuF, YangJ, LiuJ, et al.Signaling pathways in cancer-associated fibroblasts and targeted therapy for cancer. Signal Transduct Target Ther, 2021; 6(1):218; doi: 10.1038/s41392-021-00641-0
SabnisAJ, BivonaTG. Principles of resistance to targeted cancer therapy: Lessons from basic and translational cancer biology. Trends Mol Med, 2019; 25(3):185–197; doi: 10.1016/j.molmed.2018.12.009
85.
IshimotoT, NaganoO, YaeT, et al.CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc− and thereby promotes tumor growth. Cancer Cell, 2011; 19(3):387–400; doi: 10.1016/j.ccr.2011.01.038
86.
McFarlaneS, McFarlaneC, MontgomeryN, et al.CD44-mediated activation of α5β1-integrin, cortactin and paxillin signaling underpins adhesion of basal-like breast cancer cells to endothelium and fibronectin-enriched matrices. Oncotarget, 2015; 6(34):36762–36773; doi: 10.18632/oncotarget.5461
87.
ZeilstraJ, JoostenSP, VermeulenL, et al.CD44 expression in intestinal epithelium and colorectal cancer is independent of p53 status. PLoS One, 2013; 8(8):e72849; doi: 10.1371/journal.pone.0072849
88.
TianY, WangX, CramerZ, et al.APC and P53 mutations synergise to create a therapeutic vulnerability to NOTUM inhibition in advanced colorectal cancer. Gut, 2023; 72(12):2294–2306; doi: 10.1136/gutjnl-2022-329140%J
89.
ReganJL, SchumacherD, StaudteS, et al.Identification of a neural development gene expression signature in colon cancer stem cells reveals a role for EGR2 in tumorigenesis. iScience, 2022; 25(7):104498; doi: 10.1016/j.isci.2022.104498
90.
KimM, BakytL, AkhmetkaliyevA, et al.Re-Sensitizing cancer stem cells to conventional chemotherapy agents. Int J Mol Sci, 2023; 24(3):2122.
91.
DalerbaP, DyllaSJ, ParkIK, et al.Phenotypic characterization of human colorectal cancer stem cells. Proceedings of the National Academy of Sciences of the United States of America, 2007; 104(24):10158–10163; doi: 10.1073/pnas.0703478104
92.
HongI, HongSW, ChangYG, et al.Expression of the cancer stem cell markers CD44 and CD133 in colorectal cancer: An Immunohistochemical staining analysis. Ann Coloproctol, 2015; 31(3):84–91; doi: 10.3393/ac.2015.31.3.84
93.
TodenS, KunitoshiS, CardenasJ, et al.Cancer stem cell-associated miRNAs serve as prognostic biomarkers in colorectal cancer. JCI Insight, 2019; 4(6):e125294; doi: 10.1172/jci.insight.125294
94.
LinZ, ChenQ, ZhouJ, et al.Transcriptomic analysis reveals immune infiltration status and potential biomarkers of canine colorectal cancer. Vet Immunol Immunopathol, 2023; 262:110622; doi: 10.1016/j.vetimm.2023.110622
95.
ZhangX, YangL, LeiW, et al.Single-cell sequencing reveals CD133+CD44−originating evolution and novel stemness related variants in human colorectal cancer. EBioMedicine, 2022:82.
96.
PrimeauxM, LiuX, GowrikumarS, et al.Claudin-1 interacts with EPHA2 to promote cancer stemness and chemoresistance in colorectal cancer. Cancer Lett, 2023; 579:216479; doi: 10.1016/j.canlet.2023.216479
97.
XuH, TianY, YuanX, et al.The role of CD44 in epithelial-mesenchymal transition and cancer development. Onco Targets Ther, 2015; 8:3783–3792; doi: 10.2147/ott.S95470
98.
ZhangJ, ZhuZ, MiaoZ, et al.The clinical significance and mechanisms of REG4 in human cancers. Front Oncol, 2020; 10:559230; doi: 10.3389/fonc.2020.559230
99.
MehnerLM, Munoz-SagredoL, SonnentagSJ, et al.Targeting CD44 and other pleiotropic co-receptors as a means for broad inhibition of tumor growth and metastasis. Clin Exp Metastasis, 2024; 41(5):599–611; doi: 10.1007/s10585-024-10292-4
100.
CossoF, LavacchiD, FancelliS, et al.Long-term response of more than 9 years to regorafenib in a heavily pretreated patient with metastatic colorectal cancer. Anticancer Drugs, 2023; 34(3):451–454; doi: 10.1097/cad.0000000000001410
101.
KimR, PanX, OstojicH, et al.Real-world (RW) study in patients (pts) with metastatic colorectal cancer (mCRC) with long-term responses to regorafenib in the USA. Jco, 2024; 42(3_suppl):48; doi: 10.1200/JCO.2024.42.3_suppl.48
102.
DucreuxMP, Ben AbdelghaniM, TougeronD, et al.3O PRODIGE 68 - UCGI 38 - SOREGATT: A randomized phase II study comparing the sequences of regorafenib (reg) and trifluridine/tipiracil (t/t) after failure of standard therapies in patients (pts) with metastatic colorectal cancer (mCRC). Annals of Oncology, 2024; 35:S3; doi: 10.1016/j.annonc.2024.05.014
103.
DucreuxM, ParzyA, Ben AbdelghaniMII,et al.508TiP PRODIGE 68 - UCGI 38 - SOREGATT: A randomized phase. Study comparing the sequences of regorafenib (reg) and trifluridine/tipiracil (t/t) after failure of standard therapies in patients (pts) with metastatic colorectal cancer (mCRC). Annals of Oncology, 2021; 32:S580–S581; doi: 10.1016/j.annonc.2021.08.1027
104.
BishnupuriKS, SainathanSK, CiorbaMA, et al.Reg4 interacts with CD44 to regulate proliferation and stemness of colorectal and pancreatic cancer cells. Mol Cancer Res, 2022; 20(3):387–399; doi: 10.1158/1541-7786.Mcr-21-0224
105.
GrotheyA, BlayJ-Y, PavlakisN, et al.Evolving role of regorafenib for the treatment of advanced cancers. Cancer Treat Rev, 2020; 86:101993; doi: 10.1016/j.ctrv.2020.101993
106.
SninskyJA, BishnupuriKS, GonzálezI, et al.Reg4 and its downstream transcriptional activator CD44ICD in stage II and III colorectal cancer. Oncotarget, 2021; 12(4):278–291; doi: 10.18632/oncotarget.27896
107.
LiJ, QinS, XuR, et al.; CONCUR Investigators. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol, 2015; 16(6):619–629; doi: 10.1016/s1470-2045(15)70156-7
108.
TsunekuniK, KonnoM, HaraguchiN, et al.CD44/CD133-Positive colorectal cancer stem cells are sensitive to Trifluridine exposure. Sci Rep, 2019; 9(1):14861; doi: 10.1038/s41598-019-50968-6
109.
ElliottVA, RychahouP, ZaytsevaYY, et al.Activation of c-Met and upregulation of CD44 expression are associated with the metastatic phenotype in the colorectal cancer liver metastasis model. PLoS One, 2014; 9(5):e97432; doi: 10.1371/journal.pone.0097432
110.
XiaopingL, XiaoweiZ, LeizhenZ, et al.Expression and significance of CD44 and p-AKT in pancreatic head cancer. World J Surg Oncol, 2015; 13(1):334; doi: 10.1186/s12957-015-0746-8
111.
ChenC, ZhaoS, ZhaoX, et al.Gemcitabine resistance of pancreatic cancer cells is mediated by IGF1R dependent upregulation of CD44 expression and isoform switching. Cell Death Dis, 2022; 13(8):682; doi: 10.1038/s41419-022-05103-1
112.
ZhaoS, ChenC, ChangK, et al.CD44 expression level and isoform contributes to pancreatic cancer cell plasticity, invasiveness, and response to therapy. Clin Cancer Res, 2016; 22(22):5592–5604; doi: 10.1158/1078-0432.CCR-15-3115%JClinical Cancer Research
113.
ZhengHC, XueH, ZhangCY. REG4 promotes the proliferation and anti-apoptosis of cancer. Front Cell Dev Biol, 2022; 10:1012193; doi: 10.3389/fcell.2022.1012193
114.
HoshinoY, NishidaJ, KatsunoY, et al.Smad4 decreases the population of pancreatic cancer-initiating cells through transcriptional repression of ALDH1A1. Am J Pathol, 2015; 185(5):1457–1470; doi: 10.1016/j.ajpath.2015.01.011
115.
VilàP, ViñasL, ViciénG, et al.OS-026-YI Functional role of CD44+ cancer stem cells in intrahepatic cholangiocarcinoma. J Hepatol, 2024; 80:S24; doi: 10.1016/S0168-8278(24)00467-7
116.
ZiranuP, PrettaA, AimolaV, et al.CD44: A new prognostic marker in colorectal cancer? Cancers (Basel), 2024; 16(8):1569; doi: 10.3390/cancers16081569
117.
WangZ, TangY, XieL, et al.The prognostic and clinical value of CD44 in colorectal cancer: A meta-analysis. Front Oncol, 2019; 9:309; doi: 10.3389/fonc.2019.00309
118.
GabrAG, AbdallahA, ShabanSH, et al.CD44 as a prognostic marker in early colorectal cancer: Single center experience “South Egypt cancer institute”, Egypt. Alexandria Journal of Medicine, 2023; 59(1):68–74; doi: 10.1080/20905068.2023.2240112
119.
DingK, JiangX, NiJ, et al.JWA inhibits nicotine-induced lung cancer stemness and progression through CHRNA5/AKT-mediated JWA/SP1/CD44 axis. Ecotoxicol Environ Saf, 2023; 259:115043; doi: 10.1016/j.ecoenv.2023.115043
120.
RyooI-G, ChoiB-h, KuS-K, et al.High CD44 expression mediates p62-associated NFE2L2/NRF2 activation in breast cancer stem cell-like cells: Implications for cancer stem cell resistance. Redox Biol, 2018; 17:246–258; doi: 10.1016/j.redox.2018.04.015
121.
KesharwaniP, ChadarR, SheikhA, et al.CD44-targeted Nanocarrier for cancer therapy. Front Pharmacol, 2021; 12:800481; doi: 10.3389/fphar.2021.800481
122.
SubhanMA, YalamartySSK, FilipczakN, et al.Recent advances in tumor targeting via EPR effect for cancer treatment. J Pers Med, 2021; 11(6):571; doi: 10.3390/jpm11060571
123.
MattheolabakisG, MilaneL, SinghA, et al.Hyaluronic acid targeting of CD44 for cancer therapy: From receptor biology to nanomedicine. J Drug Target, 2015; 23(7–8):605–618; doi: 10.3109/1061186x.2015.1052072
124.
CirilloN. The Hyaluronan/CD44 axis: A double-edged sword in cancer. Int J Mol Sci, 2023; 24(21):15812.
125.
BatesRC, EdwardsNS, BurnsGF, et al.A CD44 survival pathway triggers chemoresistance via lyn kinase and phosphoinositide 3-kinase/Akt in colon carcinoma cells. Cancer Res, 2001; 61(13):5275–5283.
126.
HengWS, PoreM, MeijerC, et al.A unique small cell lung carcinoma disease progression model shows progressive accumulation of cancer stem cell properties and CD44 as a potential diagnostic marker. Lung Cancer, 2021; 154:13–22; doi: 10.1016/j.lungcan.2021.02.002
127.
YuX, Munoz-SagredoL, StreuleK, et al.CD44 loss of function sensitizes AML cells to the BCL-2 inhibitor venetoclax by decreasing CXCL12-driven survival cues. Blood, 2021; 138(12):1067–1080; doi: 10.1182/blood.2020006343
128.
KlankRL, Decker GrunkeSA, BangasserBL, et al.Biphasic dependence of glioma survival and cell migration on CD44 expression level. Cell Rep, 2017; 18(1):23–31; doi: 10.1016/j.celrep.2016.12.024
129.
GhatakS, HascallVC, KaramanosN, et al.Interplay between chemotherapy-activated cancer associated fibroblasts and cancer initiating cells expressing CD44v6 promotes colon cancer resistance. Front Oncol, 2022; 12:906415; doi: 10.3389/fonc.2022.906415
130.
CalveteJ, LarrinagaG, ErrarteP, et al.The coexpression of fibroblast activation protein (FAP) and basal-type markers (CK 5/6 and CD44) predicts prognosis in high-grade invasive urothelial carcinoma of the bladder. Hum Pathol, 2019; 91:61–68; doi: 10.1016/j.humpath.2019.07.002
131.
LodaA, SemeraroF, ParoliniS, et al.Cancer stem-like cells in uveal melanoma: Novel insights and therapeutic implications. Biochim Biophys Acta Rev Cancer, 2024; 1879(3):189104; doi: 10.1016/j.bbcan.2024.189104
132.
LiuS, LiuZ, ShangA, et al.CD44 is a potential immunotherapeutic target and affects macrophage infiltration leading to poor prognosis. Sci Rep, 2023; 13(1):9657; doi: 10.1038/s41598-023-33915-4
133.
GotoN, SuzukiH, TanakaT, et al.Development of a novel Anti−CD44 monoclonal antibody for multiple applications against esophageal squamous cell carcinomas. Int J Mol Sci, 2022; 23(10):5535.
134.
JangMK, MashimaT, SeimiyaH. Tankyrase inhibitors target colorectal cancer stem cells via AXIN-Dependent downregulation of c-KIT tyrosine kinase. Mol Cancer Ther, 2020; 19(3):765–776; doi: 10.1158/1535-7163.Mct-19-0668
135.
ForsterS, RadpourR. Molecular immunotherapy: Promising approach to treat metastatic colorectal cancer by targeting resistant cancer cells or cancer stem cells. Front Oncol, 2020; 10:569017; doi: 10.3389/fonc.2020.569017
136.
Arroyo-OlarteR, Mejía-MuñozA, León-CabreraS. Expanded alternatives of CRISPR-Cas9 applications in immunotherapy of colorectal cancer. Mol Diagn Ther, 2024; 28(1):69–86; doi: 10.1007/s40291-023-00680-z
137.
XiaoX, ChenH, YangL, et al.Concise review: Cancer cell reprogramming and therapeutic implications. Transl Oncol, 2022; 24:101503; doi: 10.1016/j.tranon.2022.101503
138.
BomanBM, ViswanathanV, FaceyCOB, et al.The v8-10 variant isoform of CD44 is selectively expressed in the normal human colonic stem cell niche and frequently is overexpressed in colon carcinomas during tumor development. Cancer Biol Ther, 2023; 24(1):2195363; doi: 10.1080/15384047.2023.2195363
139.
ChenLS, WangAX, DongB, et al.A new prospect in cancer therapy: Targeting cancer stem cells to eradicate cancer. Chin J Cancer, 2012; 31(12):564–572; doi: 10.5732/cjc.011.10444
140.
FiranM, DhillonS, EstessP, et al.Suppressor activity and potency among regulatory T cells is discriminated by functionally active CD44. Blood, 2006; 107(2):619–627; doi: 10.1182/blood-2005-06-2277
141.
SoJY, WahlerJ, Das GuptaS, et al.HES1-mediated inhibition of Notch1 signaling by a Gemini vitamin D analog leads to decreased CD44+/CD24−/low tumor-initiating subpopulation in basal-like breast cancer. J Steroid Biochem Mol Biol, 2015; 148:111–121; doi: 10.1016/j.jsbmb.2014.12.013
142.
ChandraJ, MoluguluN, AnnaduraiS, et al.Hyaluronic acid-functionalized lipoplexes and polyplexes as emerging nanocarriers for receptor-targeted cancer therapy. Environ Res, 2023; 233:116506; doi: 10.1016/j.envres.2023.116506
143.
TawaraM, SuzukiH, GotoN, et al.A novel Anti-CD44 variant 9 monoclonal antibody C(44)Mab-1 was developed for Immunohistochemical analyses against colorectal cancers. Curr Issues Mol Biol, 2023; 45(4):3658–3673; doi: 10.3390/cimb45040238
144.
ShenYA, WangCY, ChuangHY, et al.CD44 and CD24 coordinate the reprogramming of nasopharyngeal carcinoma cells towards a cancer stem cell phenotype through STAT3 activation. Oncotarget, 2016; 7(36):58351–58366; doi: 10.18632/oncotarget.11113
145.
ZiranuP, AimolaV, PrettaA, et al.New horizons in metastatic colorectal cancer: Prognostic role of CD44 expression. Cancers (Basel), 2023; 15(4):1212.
146.
FailmezgerH, HesselH, KapilA, et al.Spatial heterogeneity of cancer associated protein expression in immunohistochemically stained images as an improved prognostic biomarker. Front Oncol, 2022; 12:964716; doi: 10.3389/fonc.2022.964716
147.
ZolnikBS, González-FernándezA, SadriehN, et al.Minireview: Nanoparticles and the Immune System. Endocrinology, 2010; 151(2):458–465; doi: 10.1210/en.2009-1082%J
148.
JadhavV, RoyA, KaurK, et al.Recent advances in nanomaterial-based drug delivery systems. Nano-Structures & Nano-Objects, 2024; 37:101103; doi: 10.1016/j.nanoso.2024.101103
149.
MaityAR, StepenskyD. Pharmacokinetics and Pharmacodynamics of Nano-Drug Delivery Systems. In: Intracellular Delivery III: Market Entry Barriers of Nanomedicines. (ProkopA, WeissigV. eds.) Springer International Publishing: Cham; 2016; pp. 341–362.
150.
HemalathaD, SuneethaM, KimH, et al.CD-44 active cystamine-bridged hyaluronic acid-polydopamine nanoparticles for chemo-photothermal cancer therapy. Colloids and Surfaces A: Physicochemical and Engineering Aspects, 2024; 682:132879; doi: 10.1016/j.colsurfa.2023.132879
151.
HongL, LiW, LiY, et al.Nanoparticle-based drug delivery systems targeting cancer cell surfaces. RSC Adv, 2023; 13(31):21365–21382; doi: 10.1039/d3ra02969g
152.
SiddiquiL, HasanN, MishraPK, et al.CD44 mediated colon cancer targeting mutlifaceted lignin nanoparticles: Synthesis, in vitro characterization and in vivo efficacy studies. Int J Pharm, 2023; 643:123270; doi: 10.1016/j.ijpharm.2023.123270
153.
PanC, ZhangT, LiS, et al.Hybrid nanoparticles modified by hyaluronic acid loading an HSP90 inhibitor as a novel delivery system for subcutaneous and orthotopic colon cancer therapy. Int J Nanomedicine, 2021; 16:1743–1755; doi: 10.2147/ijn.S275805
154.
ChiangY-F, HuangK-C, ChenH-Y, et al.Hinokitiol Inhibits Breast Cancer Cells In Vitro Stemness-Progression and Self-Renewal with Apoptosis and Autophagy Modulation via the CD44/Nanog/SOX2/Oct4 Pathway. 2024.
155.
ZhuY, FuF, WangZ, et al.Polyphyllin VII is a potential drug targeting CD44 positive colon cancer cells. Curr Cancer Drug Targets, 2022; 22(5):426–435; doi: 10.2174/1568009622666220304110222
156.
HenkeE, NandigamaR, ErgünS. Extracellular matrix in the tumor microenvironment and its impact on cancer therapy. Front Mol Biosci, 2019; 6:160; doi: 10.3389/fmolb.2019.00160
157.
FarrugiaBL, MelroseJ. The glycosaminoglycan side chains and modular core proteins of Heparan Sulphate proteoglycans and the varied ways they provide tissue protection by regulating physiological processes and cellular behaviour. Int J Mol Sci, 2023; 24(18):14101.
158.
WuQ, HuY, YuB, et al.Polysaccharide-based tumor microenvironment-responsive drug delivery systems for cancer therapy. J Control Release, 2023; 362:19–43; doi: 10.1016/j.jconrel.2023.08.019
159.
TrapassoS, AllegraE. Role of CD44 as a marker of cancer stem cells in head and neck cancer. Biologics, 2012; 6:379–383; doi: 10.2147/btt.S37906
160.
WilliamsK, MotianiK, Vummidi GiridharP, et al.CD44 integrates signaling in normal stem cell, cancer stem cell and (pre)metastatic niches. Exp Biol Med (Maywood), 2013; 238(3):324–338; doi: 10.1177/1535370213480714
161.
MaL, DongL, ChangP. CD44v6 engages in colorectal cancer progression. Cell Death Dis, 2019; 10(1):30; doi: 10.1038/s41419-018-1265-7
162.
GrassilliE, CerritoMG. Emerging actionable targets to treat therapy-resistant colorectal cancers. Cancer Drug Resistance (Alhambra, Calif), 2022; 5(1):36–63; doi: 10.20517/cdr.2021.96
163.
EjimaR, SuzukiH, TanakaT, et al.Development of a novel Anti-CD44 Variant 6 monoclonal antibody C(44)Mab-9 for multiple applications against colorectal carcinomas. Int J Mol Sci, 2023; 24(4):4007; doi: 10.3390/ijms24044007
164.
QiaoQ, LiJ, TaoC, et al.Camptothecin-loaded chondroitin sulfate-celecoxib reduction-sensitive micelles for enhanced colon cancer treatment. Int J Biol Macromol, 2025; 315(Pt 1):144489; doi: 10.1016/j.ijbiomac.2025.144489
165.
WuF, AnX, LiS, et al.Enhancing chemoimmunotherapy for colorectal cancer with paclitaxel and alantolactone via CD44-Targeted nanoparticles: A STAT3 signaling pathway modulation approach. Asian J Pharm Sci, 2025; 20(1):100993; doi: 10.1016/j.ajps.2024.100993
