How the interplay among the tumor microenvironment and the gut microbiota influences the stemness of colorectal cancer cells

Table 1 Tumor microenvironment factors associated with stemness in colorectal cancer

TME factor	Action	Ref.
Growth/inducible factors
Epidermal growth factor	Regulates and promotes CCSC growth	[50]
Insulin-like growth factor	Regulates and promotes CCSC growth	[50]
TGF-β	Participates in the initiation of the EMT, invasion, metastasis and initiation of angiogenesis associated to CCSC	[13,29,50]
Bone mophogenetic protein 4	Induces differentiation and decreases the tumorigenic potential of CCSC	[16,60,63]
Bone mophogenic protein 2	Stimulates the differentiation of CCSC inducting autophagic degradation of β-catenin	[44,63]
Hepatocyte growth factor	Activates Wnt signaling and the clonogenicity from CCSC	[53,54]
Macrophage migration inhibitory factor	Increases CCSC properties	[49]
Vascular endothelial growth factor	Promotes growth, epithelial to mesenchymal transition and stemness	[50,51]
Platelet derived growth factor	Promotes growth, epithelial to mesenchymal transition and stemness	[50]
Osteopontin	Regulates EMT and participates in the activation of the Wnt/β-catenin signaling pathway, promoting stemness	[4,156]
HIF-1A	Activates Wnt/β-catenin pathway inducing self-renewal of CCSC. Promotes survival and maintenance of CCSC	[40,157]
Citokines/immune associated proteins
IL-1β	Modulates the expression of CCSC markers	[158]
IL-4	Facilitates the communication of CCSC with stromal cell, maintains their properties and evades the immune system	[5,44]
IL-6	Promotes the expression of the CCSC markers, ALDH1 and LGR5	[1,47]
IL-8	Induces stemness and EMT	[50,159]
IL-17A	Promotes invasiveness and self-renewal and increases CCSC properties	[12]
IL-22	Promotes invasiveness and self-renewal and increases CCSC properties	[12]
IL-33	Induces the expression of core stem cell genes in CRC-derived cells	[160]
Chemokine (C-C motif) ligand 2	Promotes CCSC properties	[4,49]
Tumor necrosis factor- α	Modulates CCSC features and induces cell death	[158,161]
Parathyroid hormone related-protein	Activates Wnt/β-catenin pathway and promotes events related to stemness	[162-164]
Non-coding RNA
miR-135 a/b and miR-17	Promote stemness through the activation of Wnt/β-catenin signaling	[157]
miR-34 and miR-93	Inhibit stemness	[157]
miR-92a-3p	Promotes 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/b	Repress TGF-β activity and stemness	[157]
miR-146 and Let-7	Affect stem cell fate or proliferation, activation of several stemness markers in a colon cancer cell line	[157]
miR-221/222 and miR-21	Induce the development and maintenance of CCSC	[157]
miR-21	Promotes the activation of the Wnt/β-catenin signaling pathway and increases the population of CCSC	[157]
miR-145	Represses miR-21 and its expression inversely correlates with that of CCSC markers	[157,166]
miR-137	Suppresses CCSC tumorigenicity	[167]
miR-147	Decreases the expression of CCSC markers
miR-200, miR-203, miR-141 and miR-429	Regulate CCSC through negative modulation of EMT and self-renewal	[157]
lncRNA H19	Promotes CCSC phenotype and drug resistance	[168]
Signaling pathway ligands
Wnt ligands	Increase CCSC characteristics and enhances tumor-initiating potential	[5,157]
Delta like canonical Notch ligand 4	Participates on CSC maintenance	[44]
Jagged1	Participates on CSC maintenance	[66]
SHH	Promotes CCSC survival, self-renewal and drug resistance	[67,68]
Enzymes
Phospholipase D2	Promotes CRC stemness	[4,49]
Extra-cellular matrix components
Tenascin, fibronectin, collagen type I, secreted protein acidic and rich in cysteine, galectin	Contribute to stemness and CCSC activities	[1]

EMT: Epithelial to mesenchymal transition; CCSC: Colorectal cancer stem cells; CRC: Colorectal cancer; lncRNA: Long non-coding ribonucleic acid; miR: Micro ribonucleic acid; SHH: Sonic Hedgehog protein; TGF-β: Transforming growth factor beta; IL: Interleukin.

Table 2 Consensus molecular subtypes of colorectal cancer

	CMS1-immune (14%)	CMS2-canonical (37%)	CMS3-metabolic (13%)	CMS4-mesenchymal (23%)	Unclassified (13%)
General features	Hypermutated	Epithelial	Epithelial	TGF-β activation. Angiogenesis	Mixed phenotype of multiple CMS
	Microsatellite unstable	WNT and MYC signaling activation	Metabolic dysregulation	Upregulation of EMT
Mutations	BRAF, MSH6, RNF43, ATM, TGFBr2, PTEN	APC, KRAS, TP53, PIK3CA	APC, KRAS, TP53, PIK3CA	APC, KRAS, TP53, PIK3CA
TME	Decrease of CAFs	Decrease of CAFs	Decrease of CAFs	Increase of CAFs; Immunosuppressive signature
	High immune and inflammatory signature	Low immune and inflammatory signature	Low immune and inflammatory signature

This Table is based on Islas et al[1], 2022; Fidelle et al[79], 2020; Trinh et al[169], 2018; Becht et al[78], 2016; Guinney et al[77], 2015. APC: Adenomatous polyposis coli gene; ATM: Ataxia telangiectasia mutated gene; BRAF: Serine/threonine-protein kinase B-raf gene; CAFs: Cancer associated fibroblasts; CMS: Consensus molecular subtype; EMT, Epithelial to mesenchymal transition; KRAS: Ki-ras2 kirsten rat sarcoma viral oncogene homolog gene; MSH6: MutS homolog 6 gene; PIK3CA: Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene; PTEN: Phosphatase and tensin homolog gene; RNF43: Ring finger protein 43 gene; TGF-β: Transforming growth factor beta; TGFBr2: Transforming growth factor beta receptor 2 gene; TME: Tumor microenvironment; TP53: Transformation-related protein 53 gene.

Table 3 Microorganisms present in the intestinal mucosa associated with stemness in colorectal cancer

Microorganism	Action	Ref.
Bacterioides dorei, Bacterioides vulgatum, Parabacterioides distasonis, Lachnoclostridium sp., and Mordavella sp	Inhibit the action of factors related to CCSC phenotype. Inhibit CRC development and progression	[59,114]
Bacterioides fragilis	Releases an enterotoxin that promotes immune TME cells activation with secretion of factors related to CCSC	[118]
Citrobacter rodentium	Protects the inflammatory CCSC niche	[121]
Clostridium septicum	Contributes to CRC development and to the activation of signaling pathways associated with CCSC	[59]
Enterococcus faecalis	Induces 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 coli	Upregulates the expression of CCSC-associated genes. Releases genotoxin colibactin which induces the production of growth factors related to CCSC	[112,117,79]
Fusobacterium nucleatum	Stimulates the secretion of immune factors related to CCSC	[79]
Helicobacter pylori	Promotes the expression of markers associated with stemness	[101,102]
Lactobacillus acidophilus	Promotes proliferation or death in CCSC depending on dose	[104]
Porphyromonas gingivalis	Promotes the expression of markers associated with stemness	[101,102]
Shigella, and Citrobacter	Upregulate the expression of CCSC-associated genes	[112]

CCSC: Colorectal cancer stem cells; CRC: Colorectal cancer; TGF-β: Transforming growth factor beta; TME: Tumor microenvironment.