From bench to bedside: Stem cell applications in gastric cancer therapy and their emerging clinical relevance

Table 1 Clinical relevance of gastric cancer stem cells key markers and their significance

Gene/marker	Clinical significance
CD44	Common GCSC marker; associated with self-renewal, metastasis, and poor prognosis
CD133	Identifies chemoresistant GCSCs; linked with tumor initiation and relapse
ALDH1A1	Enzyme marker of stemness; correlates with advanced disease and survival
EpCAM	Cell adhesion molecule; supports tumor-initiating capacity
SOX2, NANOG, OCT4	Pluripotency transcription factors; sustain stem-like properties and correlate with aggressive phenotypes
LGR5	Stem cell receptor; marks progenitor-like GCSCs with poor clinical outcomes

CD: Cluster of differentiation; GCSC: Gastric cancer stem cell.

Table 2 Regulatory mechanisms of gastric cancer stem cells genes and pathways

Gene/pathway	Role in stemness regulation
Wnt/β-catenin	Promotes self-renewal, EMT, and therapy resistance
Notch/Hedgehog/TGF-β	Maintain stemness programs, regulate cell fate and differentiation
FOXO4, TET1	Tumor suppressors; their loss enhances stemness and predicts poor prognosis
SOX9	Promotes symmetric division and expansion of GCSC pool; linked with recurrence
E2F1, PRDM1, AR, STMN1, c-Myc	Oncogenic drivers; upregulate stemness markers, proliferation, and resistance
ncRNAs (LINC00520, HCP5, circUBA2, miR-378a-3p, miR-15a-5p)	Regulate signaling pathways (Wnt, Hedgehog, Hippo) to promote or suppress stemness traits

ncRNA: Noncoding RNA; TGF: Transforming growth factor; EMT: Epithelial-mesenchymal transition; GCSC: Gastric cancer stem cell.

Table 3 Therapy resistance mediated by gastric cancer stem cells gene-level insights

Gene/marker	Contribution to therapy resistance
CD133, CD44	Enriched after chemotherapy (cisplatin/oxaliplatin); mediate chemoresistance and tumor regrowth
GPX4, OTUD5, POLQ, DHODH	Protect GCSCs from ferroptosis; therapeutic vulnerability for drug development
PD-L1	Enhances immune evasion and CSC survival; predicts poor response to immunotherapy
TAP1 (low expression)	Impairs antigen presentation, promoting immune escape
AQP5, beclin-1, ULK1	Autophagy regulators that sustain stemness under stress and confer resistance
CYB5R1	Links redox balance to stemness and chemoresistance; high expression predicts poor survival

CD: Cluster of differentiation; DHODH: Dihydroorotate dehydrogenase; PD-L1: Programmed death-ligand 1; GCSC: Gastric cancer stem cell; CSC: Cancer stem cell.

Table 4 Key stemness-associated markers and clinical implications in gastric cancer

Marker/signature	Type	Clinical association	Prognostic/predictive implication	Ref.
TET1, FOXO4	Tumor suppressors	Progressive loss from primary to metastasis	Low expression poor survival; FOXO4 = independent adverse factor	Qi et al[48]
SOX9	Transcription factor	High in tumors; linked to recurrence (especially liver)	High SOX9 worse survival, chemo resistance; low SOX9 better response to adjuvant chemo	Chen et al[49]
E2F1, PRDM1, STMN1, TMEM206, SYT11, WTAP, c-Myc, TAK1	Oncogenic drivers	Associated with stemness programs	High expression poor survival; validated as independent adverse markers	Wang et al[8]; Fu et al[20]; Qin et al[22]; Liu and Da[26]; Kim et al[30]; Wei et al[50]; Zhang et al[71]; Yang et al[83]
RORβ, CDK5RAP3, BATF2, ATOH1, TRIM28, METTL14	Tumor suppressors	Restrain stemness/EMT pathways	High expression better prognosis and/or improved chemo sensitivity	Wen et al[5]; Zhong et al[24]; Zhang et al[25]; Cao et al[53]; Lin et al[54]; Ning et al[72]
LINC00520, HCP5, circUBA2, circFAM73A, circ 0051246	Oncogenic ncRNAs	Promote stemness, EMT, aggressive phenotype	High expression worse survival, adverse clinicopathologic features	Xia et al[27]; Liu et al[55]; Yu et al[56]; Deng et al[58]; Li et al[73]
miR-148/152, miR-378a-3p, miR-375, miR-144-3p	Tumor-suppressive microRNAs	Inhibit stemness pathways	Higher levels improved prognosis, reduced stemness/chemoresistance	Xia et al[27]; Xu et al[61]; Shen et al[62]; Lu et al[63]; Li et al[73]
CD44/miR-21-5p/TGF-β2 axis	Stemness/chemoresistance axis	Linked to strong chemoresistance	Activation poor treatment response	Nie et al[59]; Li et al[73]
IL-17B/IL-17RB	Cytokine axis	Elevated serum and tumor expression	Potential circulating marker of CSC activity; associated with adverse features	Bie et al[89]
MSC- and CAF-derived signatures	Stromal signatures	Reflect TME remodeling, immune suppression	High scores poor survival; nomograms outperform TNM for 1-, 3-, 5-year OS	Mak et al[11]; Shen et al[12]
cGCSCs (CD24+ CD44+ EpCAM+ CD54-)	Circulating CSCs	Detected in GC patients only	High diagnostic accuracy (AUC = 0.911); support liquid biopsy monitoring	Becerril-Rico et al[7]
Exosomal Wnt5a	Exosomal marker	Linked to lymph node metastasis	Indicates pro-metastatic, stemness-supporting signaling	Wang et al[14]
Exosomal lncFERO	Exosomal ncRNA	Associated with ferroptosis resistance	High levels poor prognosis; marker of chemotoxicity-induced stemness	Zhang et al[91]

CD: Cluster of differentiation; ncRNA: Noncoding RNA; TGF: Transforming growth factor; IL: Interleukin; MSC: Mesenchymal stem cells; CAF: Cancer-associated fibroblast; cGCSCs: Circulating gastric cancer stem cells; lncFERO: Ferroptosis-related long noncoding RNA; CSC: Cancer stem cell; EMT: Epithelial-mesenchymal transition; TME: Tumor microenvironment; GC: Gastric cancer; TNM: Tumor node metastasis; OS: Overall survival; AUC: Area under the curve.