Tumor microenvironment involvement in colorectal cancer progression via Wnt/β-catenin pathway: Providing understanding of the complex mechanisms of chemoresistance

Table 1 Factors secreted by the tumor microenvironment and their role in colorectal cancer progression

Released/secreted components	Source, TME cell	Known effects in CRC	Ref.
Growth factors
TGF-β	CAFs; TIICs1; MSCs1	Proliferation on tumor and stromal cells in late stages of tumorigenesis. EMT program and CSC-like traits. Metastasis, vasculogenesis and angiogenesis	[5,21,136]
BMPs	CAFs	Anti-tumor activity. Or pro-tumor activity, induce CSCs phenotype, EMT program and chemoresistance. Differentiation of colon CSCs	[5,137,138]
HGF	CAFs; TIICs; MSCs1	Invasion, metastasis and stemness	[21,54,139,140]
VEGF	ECs; CAFs; TIICs	Angiogenesis, invasiveness, metastasis	[104,140,141]
FGF	CAFs; MSCs	CAFs profiles. Tumor growth and metastasis	[142,143]
PDGF	CAFs	Tumor growth and metastasis	[144]
TNF-α	TIICs	Proliferation. Growth arrest and cancer cell death, angiogenesis and metastasis	[141,145]
Cytokines
IL-1	TIICs	Angiogenesis and metastasis	[141,146]
IL-2	TIICs	Anti-tumor activity	[1,147]
IL-6	TIICs; MSCs; CAFs	Proliferation, angiogenesis and metastasis	[1,141]
IL-8	TIICs; MSCs	Tumor growth, angiogenesis and chemoresistance	[1,148]
IL-17	CAFs; TIICs	Anti-tumor or pro-tumor activity. Invasion and self-renewal of CSCs	[1,104,149]
IL-18	TIICs	Anti-tumor activity	[150]
IL-22	TIICs	Proliferation, invasion and stemness	[1,104]
IL-33	ECs; TIICs	Anti-tumor activity Suppresses tumorigenesis. Or pro-tumor activity. Angiogenesis and metastasis. Tumor growth through immunosuppressive microenvironment favoring	[1,104,151]
CCL2	TIICs; MCS	Tumor progression	[152]
CCL5	TIICs	Tumor progression. Acts on tumor cells and TAMs	[153]
CCL7	CAFs	Proliferation, invasion, and migration	[154]
CXCL12	CAFs; MSCs	Proliferation and invasion	[142,155]
PTHrP	Undefined TME cells	Proliferation, invasion, angiogenesis, migration and chemoresistance	[34,35,66,156,157]
Osteopontin	TIICs	Metastasis, stemness and chemoresistance	[85]
Prostaglandins
PGs (like PGE2)	CAFs; TIICs; MSCs	Resistance to apoptosis, increased proliferation, angiogenesis and metastasis	[21,32]
Signaling pathways ligands
NOTCH ligands (Jagged-1; Jagged-2; DLL4)	ECs	CSCs phenotype, EMT program and metastasis	[104,158]
WNT ligands (Wnt2, Wnt5)	CAFs	Invasion, metastasis and angiogenesis	[44,45,54]
Enzymes
Serine proteinases (like MMPs)	TAMs; TANs	Invasion and angiogenesis	[140,145]
Immunosuppressive enzymes (like iNOS)	TIICs	Tumor progression. Inhibitory effect on the immune system, apoptosis of immune cells	[39]
Receptors
TLRs	CAFs, ECs	Inflammatory-mediated tumorigenesis	[41,43]
RNA molecules
miR-92a-3p	CAFs	CSCs phenotype, EMT program and chemoresistance	[24]
lncRNA H19	CAFs	Stemness and chemoresistance	[25]
miR-155	MSCs1	Migration	[21,159]
miR-375	MSCs1	Chemoresistance	[21,160]
cRNA	CAFs	Tumor progression or anti-tumor activity	[26,27]

¹Factor's actions demonstrated for colorectal cancer (CRC). Their source from the tumor microenvironment (TME) has been identified for other types of cancer, but not for CRC. BMP: Bone morphogenetic CAFs: Cancer-associated fibroblasts; CCL: C-C motif chemokine ligand; cRNA: Circular RNA; CSCs: Cancer stem cells; CXCL: C-X-C motif chemokine ligand; ECs: Endothelial cells; EMT: Epithelial to mesenchymal transition; FGF: Fibroblast growth factor; HGF: Hepatocyte growth factor; IL: Interleukin; iNOS: Inducible nitric oxide synthase; lncRNA: Long non-coding RNA; miR: MicroRNA; MMPs: Matrix metalloproteinases; MSCs: Mesenchymal stem cells; PDGF: Platelet-derived growth factor; PGs: Prostaglandins; PTHrP: Parathyroid Hormone-related Peptide; TAMs: Tumor-associated macrophages; TANs: Tumor-associated neutrophils; TGF-β: Transforming growth factor-β; TIICs: Tumor-infiltrating immune cells; TLRs: Toll-like receptors; TNF-α: Tumor necrosis factor-α; VEGF: Vascular endothelial growth factor.