Impact of STAT-signaling pathway on cancer-associated fibroblasts in colorectal cancer and its role in immunosuppression

Table 1 Phenotypic and functional heterogeneity of subtypes of cancer-associated fibroblasts in solid tumors

Cancer type	Subtype of CAF	Markers	Functions
CRC	CAF-A	MMP2, DCN, αFAP, and COL1A2	ECM remodeling
	CAF-B	α-SMA, ACTA2, TAGLN, and PDGFA	Not reported
	CAF-A	α-SMA low, TAGLN low and FAP+	ECM remodeling
Colon cancer	CAF-B	α-SMA high, TAGLN high, and FAP-	Not reported
PDAC	myCAFs (pCAFs)	α-SMA high, CTGF, TNC, TAGLN, MYL9, TPM1, TPM2, POSTN, and MMP11	Tumor proliferation, migration, invasion, and ECM remodeling
	iCAFs (pCAFs)	α-SMA low, PDGFRα high, HAS1, HAS2, IL-6, IL-8, IL-11, CXCL1, CXCL2, CCL2, CXCL12, C3 and Ly6C high	Immune suppression, cachexia and chemoresistance
	apCAFs (pCAFs)	MHC class II, H2-Aa, H2-Ab1, and CD74	Antigen-present, immune modulation
	CAF-A	POSTN	Tumor proliferation, invasion, metastasis
	CAF-B	MYH11	Lymph-node metastasis, poor prognostic factor
	CAF-C	PDPN	Immune promotion, favorable prognostic factor
	FB1 (overlaps with iCAFs)	α-SMA low, CXCL12, PDGFRα high, and IL-6 I	Immunosuppressive/tumor promoting
	FB3 (overlaps with myCAFs)	α-SMA high, TAGLN and CTGF	Not reported
	C8 (overlaps with iCAFs)	α-SMA low, Ly6C high, and IL-6	Immunosuppressive
	C2 (overlaps with myCAFs)	α-SMA high, TAGLN, and LRCC15	ECM producing/immunosupresive
Lung cancer	myCAF	α-SMA high/EMT signature	Angiogenesis; myogenesis/ECM producing
PDAC/oral/colon/bladder/intestinal cancers	rCAFs	Meflin, BMP-4, Hedgehog, and IKKβ	Antitumoral effect
Breast cancer	CAF-S1	CD29, FAP high, α-SMA, PDGFRβ, FSP1, IL-6, and CXCL12	Tumor proliferation, migration, lymph-nodes metastasis, immune suppression and EMT initiation
	CAF-S2	Negative for all markers	Contractile signature
	CAF-S3	α-SMA low, CD29, FSP1 and PDGFRβ	Not reported
	CAF-S4	CD29 high, FSP1, PDGFRβ and α-SMA	Tumor invasion, migration, lymph-nodes metastasis
	myCAFs	α-SMA, ACTA2, TAGLN, MYL9, IGFBP-3, and TNC	Tumor proliferation, migration, invasion, angiogenesis, and EMT
	iCAFs	Ly6c1, CLEC3B, HAS1, DPT, and COL14A1	Tumor proliferation, metastasis, angiogenesis, immune evasion and chemoresistance
	apCAFs	CD74, H2-Aa, H2-Ab1, H2-Eb1, KRT18, and FSP1	Antigen-present, immune modulation
	vCAFs/cCAF	Notch3, EPAS1, COL18A1 and NR2F2 (perivascular cells)	Angiogenesis
	mCAFs	Fibulin-1, PDGFRα, and CXCL14 (resident fibroblasts)	Immune regulation
	CD10+GPR77+	CD10 and GPR77	Chemoresistance
HGSOC	CAF-S1	CD29, FAP, αSMA, FSP1, PDGFRβ, and CXCL12β	Tumor proliferation, immune suppression
	CAF-S2 (non-activated)	Not reported	Not reported
	CAF-S3 (non-activated)	CD29, FSP1, and PDGFRβ	Not reported
	CAF-S4	CD29, αSMA, FSP1, and PDGFRβ	Tumor proliferation
OSCC	CAF-N	HA, MMPs	Tumor invasion, immunosuppression
	CAF-D	TGF-β	Tumor migration
Head and neck cancer	Myofibroblasts/activated CAFs	α-SMA low, MYL9, MYLK/PDGFRα high	Contractile signature/ECM producing

CRC: Colorectal cancer; PDAC: Pancreatic ductal adenocarcinoma; HGSOC: High-grade serous ovarian cancer; OSCC: Oral squamous cell carcinoma; myCAFs: Myofibroblastic cancer-associated fibroblasts; iCAFs: Inflammatory cancer-associated fibroblasts; apCAFs: Antigen presenting cancer-associated fibroblasts; pCAFs: Cancer-promoting cancer-associated fibroblasts; rCAFs: Cancer-restraining cancer-associated fibroblasts; vCAFs: Cancer-vascular cancer-associated fibroblasts; cCAFs: Cancer cycling cancer-associated fibroblasts; mCAFs: Cancer-matrix cancer-associated fibroblasts; MMP2: Matrix metalloproteinase 2; DCN: Decorin; FAP: Fibroblast activation protein; COL1A2: Collagen type 1 Alpha 2; α-SMA: Alpha smooth muscle actin; ACTA2: Actin alpha 2;TAGLN: Transgelin; PDGFA: Platelet derived growth factor A; CTGF: Connective tissue growth factor; TNC: Tenascin-C; MYL9: Myosin light chain 9; TPM1: Tropomyosin 1; TPM2: Tropomyosin 2; POSTN: Periostin; MMP11: Matrix metalloproteinase 11; PDGFRα: Platelet-derived growth factor receptor; HAS1: Hyaluronan synthase 1; HAS2: Hyaluronan synthase 2; IL-6: Interleukin-6; IL-8: Interleukin-8; IL-11: Interleukin-11; CXCL1: C-X-C chemokine ligand 1; CXCL2: C-X-C chemokine ligand 2; CCL2: C–C chemokine ligand 2; CXCL12: C-X-C chemokine ligand 12; C3: Complement 3; Ly6c1: Lymphocyte antigen 6 complex; MHC class II: Major histocompatibility complex class I; H2-Aa: Histocompatibility 2 class II antigen A alpha; H2-Ab1: Histocompatibility 2 class II antigen A beta 1; CD74: Cluster of differentiation 74; ECM: Extracellular matrix; MYH11: Myosin-11; PDPN: Podoplanin; LRCC15: Leucine rich repeat containing 15; BMP-4: Bone morphogenetic protein 4; IKKβ: Inhibitor kappa B kinase beta; CD29: Cluster of differentiation 29; PDGFRβ: Platelet-derived growth factor receptor β; FSP1: Fibroblast-specific protein 1; MYL9: Myosin light chain 9; IGFBP-3: IGF-binding protein 3; CLEC3B: C-type lectin domain family 3 member B; DPT: Dermatopontin; COL14A1: Collagen type XIV alpha 1; H2-Eb1: Histocompatibility 2 class II antigen E beta 1; KRT18: Keratin 18; EPAS1: Endothelial PAS domain protein 1; COL18A1: Collagen type XVIII alpha 1; NR2F2: Nuclear receptor subfamily 2 group F member 2; Fibulin-1; CXCL14: C-X-C chemokine ligand 14; SCRG1: Scrapie responsive gene 1; CD10: Cluster of differentiation 10; GPR77: G protein-coupled receptor 77; HA: Hyaluronan; MMPs: Matrix metalloproteinases; TGF-β: Transforming growth factor beta; MYLK: Myosin light chain kinase.

Table 2 The intestinal mesenchymal sub-populations in homeostasis of intestinal tissue

Cell	Functions	Markers
Mesenchymal stem cells	Stem cell properties, differentiation potential into osteoblasts, adipocytes, and chondroblasts, and maintain hematopoiesis	Vimentin+, CD90+, PDGFRα+, PDGFRβ+, ΙCAM1+, VCAM1+, CD73+, CD105+, CD29+, CD44+, and SMM-
Intestinal subepithelial myofibroblasts	Mechanical support, immune regulation, angiogenesis regulation, vascular function, stem cell niche maintenance, epithelial homeostasis, and extracellular matrix maintenance	αSMA+, vimentin+, CD90+, Desmin-, ER-TR7+. PDGFRβ+, VCAM1-, MHC class I, II+, CD80+, CD86+, collagen I +, NG2+, AOC3+, NKX2-3-, SHOX2-, SMM-, and FAP+
Smooth muscle cells	Mechanical support and smooth muscle contraction	αSMA+, vimentin-, CD90-, Desmin+, FSP1-, PDGFRα+, VCAM1-, NG2+, AOC3+, NKX2-3+, SHOX2-, and SMM+
Pericytes	Angiogenesis regulation, vascular function, cell trafficking, and stem cell properties	αSMA+, vimentin+, Desmin+, PDGFRα+, PDGFRβ+, VCAM1+, MHC class I, II+, CD80+, CD86+, NG2+, and SMM-
Lamina propria fibroblasts	Mechanical support, immune regulation, angiogenesis regulation, vascular function, stem cell niche maintenance epithelial homeostasis, extracellular matrix maintenance	αSMA-, vimentin+, CD90+, Desmin-, FSP1+, PDGFRα+, PDGFRβ-, VCAM1-, AOC3-, NKX2-3-, SHOX2+, and SMM-

CD90: Cluster of differentiation 90; PDGFRα: Platelet-derived growth factor receptor alpha; PDGFRβ: Platelet-derived growth factor receptor beta; ICAM1: Intercellular adhesion molecule 1; VCAM1: Vascular cell adhesion protein 1; CD73: Cluster of differentiation 73; CD105: Cluster of differentiation 105; CD29: Cluster of differentiation 29; CD44: Cluster of differentiation 44; SMM: Smooth muscle myosin; α-SMA: Alpha smooth muscle actin; ER-TR7: Fibroblasts monoclonal antibody; MHC class I: Major histocompatibility complex class I; MHC class II: Major histocompatibility complex class II; CD80: Cluster of differentiation 80; CD86: Cluster of differentiation 86; NG2: Neuron-glial antigen 2; AOC3: Amine oxidase copper containing 3; NKX2-3: NK2 Homeobox 3; SHOX2: Short stature homeobox 2; FAP: Fibroblast activating protein; FSP1: Fibroblast-specific protein 1.