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.