Copyright ©The Author(s) 2023.
World J Stem Cells. May 26, 2023; 15(5): 281-301
Published online May 26, 2023. doi: 10.4252/wjsc.v15.i5.281
Table 1 Tumor microenvironment factors associated with stemness in colorectal cancer
TME factor
Growth/inducible factors
Epidermal growth factorRegulates and promotes CCSC growth[50]
Insulin-like growth factorRegulates and promotes CCSC growth[50]
TGF-βParticipates in the initiation of the EMT, invasion, metastasis and initiation of angiogenesis associated to CCSC[13,29,50]
Bone mophogenetic protein 4Induces differentiation and decreases the tumorigenic potential of CCSC[16,60,63]
Bone mophogenic protein 2Stimulates the differentiation of CCSC inducting autophagic degradation of β-catenin[44,63]
Hepatocyte growth factorActivates Wnt signaling and the clonogenicity from CCSC[53,54]
Macrophage migration inhibitory factorIncreases CCSC properties[49]
Vascular endothelial growth factorPromotes growth, epithelial to mesenchymal transition and stemness[50,51]
Platelet derived growth factorPromotes growth, epithelial to mesenchymal transition and stemness[50]
OsteopontinRegulates EMT and participates in the activation of the Wnt/β-catenin signaling pathway, promoting stemness[4,156]
HIF-1AActivates Wnt/β-catenin pathway inducing self-renewal of CCSC. Promotes survival and maintenance of CCSC[40,157]
Citokines/immune associated proteins
IL-1βModulates the expression of CCSC markers[158]
IL-4Facilitates the communication of CCSC with stromal cell, maintains their properties and evades the immune system[5,44]
IL-6Promotes the expression of the CCSC markers, ALDH1 and LGR5[1,47]
IL-8Induces stemness and EMT[50,159]
IL-17APromotes invasiveness and self-renewal and increases CCSC properties[12]
IL-22Promotes invasiveness and self-renewal and increases CCSC properties[12]
IL-33Induces the expression of core stem cell genes in CRC-derived cells[160]
Chemokine (C-C motif) ligand 2Promotes CCSC properties[4,49]
Tumor necrosis factor- αModulates CCSC features and induces cell death[158,161]
Parathyroid hormone related-proteinActivates Wnt/β-catenin pathway and promotes events related to stemness[162-164]
Non-coding RNA
miR-135 a/b and miR-17Promote stemness through the activation of Wnt/β-catenin signaling[157]
miR-34 and miR-93Inhibit stemness[157]
miR-92a-3pPromotes Wnt signaling activation and consequently the expression of β-catenin target genes related to stemness, the EMT program, and chemoresistance[165]
miR-20a and miR-106 a/bRepress TGF-β activity and stemness[157]
miR-146 and Let-7Affect stem cell fate or proliferation, activation of several stemness markers in a colon cancer cell line[157]
miR-221/222 and miR-21Induce the development and maintenance of CCSC[157]
miR-21Promotes the activation of the Wnt/β-catenin signaling pathway and increases the population of CCSC[157]
miR-145Represses miR-21 and its expression inversely correlates with that of CCSC markers[157,166]
miR-137Suppresses CCSC tumorigenicity[167]
miR-147Decreases the expression of CCSC markers
miR-200, miR-203, miR-141 and miR-429Regulate CCSC through negative modulation of EMT and self-renewal[157]
lncRNA H19Promotes CCSC phenotype and drug resistance[168]
Signaling pathway ligands
Wnt ligandsIncrease CCSC characteristics and enhances tumor-initiating potential[5,157]
Delta like canonical Notch ligand 4Participates on CSC maintenance[44]
Jagged1Participates on CSC maintenance[66]
SHH Promotes CCSC survival, self-renewal and drug resistance[67,68]
Phospholipase D2Promotes CRC stemness[4,49]
Extra-cellular matrix components
Tenascin, fibronectin, collagen type I, secreted protein acidic and rich in cysteine, galectinContribute to stemness and CCSC activities[1]
Table 2 Consensus molecular subtypes of colorectal cancer

CMS1-immune (14%)
CMS2-canonical (37%)
CMS3-metabolic (13%)
CMS4-mesenchymal (23%)
Unclassified (13%)
General featuresHypermutatedEpithelialEpithelialTGF-β activation. AngiogenesisMixed phenotype of multiple CMS
Microsatellite unstableWNT and MYC signaling activationMetabolic dysregulationUpregulation of EMT
TMEDecrease of CAFsDecrease of CAFsDecrease of CAFsIncrease of CAFs; Immunosuppressive signature
High immune and inflammatory signatureLow immune and inflammatory signatureLow immune and inflammatory signature
Table 3 Microorganisms present in the intestinal mucosa associated with stemness in colorectal cancer
Bacterioides dorei, Bacterioides vulgatum, Parabacterioides distasonis, Lachnoclostridium sp., and Mordavella spInhibit the action of factors related to CCSC phenotype. Inhibit CRC development and progression[59,114]
Bacterioides fragilisReleases an enterotoxin that promotes immune TME cells activation with secretion of factors related to CCSC[118]
Citrobacter rodentiumProtects the inflammatory CCSC niche[121]
Clostridium septicumContributes to CRC development and to the activation of signaling pathways associated with CCSC[59]
Enterococcus faecalisInduces the expression of TGF-β, thereby activating signaling pathways associated with CCSC. Activates Wnt/β-catenin signaling and pluripotent transcription factors associated with CCSC[113,115]
Escherichia coliUpregulates the expression of CCSC-associated genes. Releases genotoxin colibactin which induces the production of growth factors related to CCSC[112,117,79]
Fusobacterium nucleatumStimulates the secretion of immune factors related to CCSC[79]
Helicobacter pyloriPromotes the expression of markers associated with stemness[101,102]
Lactobacillus acidophilusPromotes proliferation or death in CCSC depending on dose[104]
Porphyromonas gingivalisPromotes the expression of markers associated with stemness[101,102]
Shigella, and CitrobacterUpregulate the expression of CCSC-associated genes[112]