Table 4 CAF-mediated anticancer therapies

From: Signaling pathways in cancer-associated fibroblasts and targeted therapy for cancer

Target	Cancer cell origin	Study type (sample size)	Anticancer therapies (NCT number)	Anticancer mechanisms	Refs.
Inhibiting transformation from normal fibroblasts to CAF
NOX4	Head, neck, colorectum	Preclinical	GKT137831	Delays transdifferentiation of fibroblast to CAF	⁵³⁰
TGF-β	Breast, ovary	Preclinical	HA-PTX/MATT HNPs; LY2157299	Blocks the fibroblast activation by downregulating the TGF-β expression	^531,532
Promoting transformation from CAF to normal fibroblasts
CAF	Solid tumors	Preclinical	sTRAIL LPD	Induces fibroblast reprogramming	⁵³³
TGF-β	Breast	Preclinical	Artemisinin derivatives	Inactivates CAF and inhibits metastasis	⁵³⁴
VDR	Pancreas	Preclinical	Calcipotriol	Reprises the quiescent state of CAF	⁵³⁵
Vitamin A	Pancreas	Preclinical	ATRA	Induces quiescence of stellate cells	⁵³⁶
Inhibiting tumor development and progression
CAF	Esophagus, stomach	Preclinical	Bortezomib + panobinostat	Reduces the viability of CAF through inducing caspase-3-mediated apoptosis	⁵³⁷
CAF	Lung	Preclinical	5-Fluorouracil	Eliminates CAF recruited by tumors	⁵³⁸
CAF	Stomach	Preclinical	Losartan + others	Reduces CAF activity and collagen fiber	⁵³⁹
CSF1R + CXCR2	Lung, breast, colon, others	Preclinical	JNJ-40346527 + SB225002	Blocks protumor PMN-MDSC recruitment and reduces tumor growth	³³⁸
FAP	Esophagus, breast, lung, colon, rectum	Preclinical; phase I (43)	PIT; ¹³¹I-mAbF19 PDT; Sibrotuzumab; αFAP-PE38	Depletes CAF specifically or inhibits function of CAF to suppress tumor progression	^{382,540,541,542,543,544,545}
FAP + DPPIV	Lung	Preclinical	FAP deletion; PT630	Increases collagen level, decreases CAF content and blood vessel density in tumor	⁵⁴⁶
Integrin αvβ3	Breast	Preclinical	ProAgio	Reduces intratumoral collagen and decreases growth factors from CAF	⁵⁴⁷
MMP	Breast, solid tumors	Preclinical; phase I (32)	HA-PTX/MATT HNPs; S-3304	Suppresses angiogenesis, degradation of extracellular matrix, and metastasis	^531,548
MiR-214 + miR-301a	Stomach	Preclinical	Astragaloside IV	Reduces expression of oncogenic pluripotency factors SOX2 and NANOG	⁵⁴⁹
PDGFR signaling	Cervix uteri	Preclinical	Imatinib	Reduces epithelial cell growth factor and angiogenic factor by CAF	⁵⁵⁰
ROS/MAPK + ferroptosis pathways	Nasopharynx	Preclinical	Disulfiram/copper	Induces cytotoxic effects on CAF and tumor cells, promotes CAF apoptosis, and inactivates CAF	¹⁷⁹
TEM-1	Colorectum	Phase II (126)	MORAb-004 (NCT01507545)	Blocks specific TEM-1 receptor–ligand interactions	⁵⁵¹
Tenascin	Brain	Phase II (43)	¹³¹I-m81C6	Delays tumors growth and metastasis	⁵⁵²
TGF-β	Breast, liver	Preclinical	Pirfenidone; LY2109761	Induces CAF apoptosis and inhibits CAF proliferation	^90,553
VEGF	Pleura	Phase III (448)	Bevacizumab + others	Inhibits tumor angiogenesis	⁵⁵⁴
VDR/1RARβ	Skin	Preclinical	EB1089; LE135	Reduces cancer cell proliferation and/or increases apoptosis	³¹⁸
Activating immunity system
CAF	Liver	Preclinical	DC/CAF fusion	Activates cytotoxic T lymphocytes	⁵⁵⁵
CCR2 + IDO1 + NOX2	Lung	Preclinical	CCR2i + epacadostat + GSK-2795039	Reverses the interaction between CAF and monocytic myeloid cells	⁵⁵⁶
CXCR4	Pancreas	Preclinical	AMD3100 + others	Reverses tumor immune evasion	³³⁶
FAP	Colon, breast	Preclinical	DNA vaccine; PIT	Enhances cytotoxic T cell infiltration	^336,545
PD-L1 + TGF-β	Breast, colorectum	Preclinical	M7824	Activates innate and adaptive immune to suppress tumor growth and metastasis	⁵⁵⁷
Reversing tumor chemoresistance
AR	Pancreas	Phase II (49)	Losartan + others	Reduces collagen and hyaluronan level	⁵⁵⁸
ATRA	Pancreas	Preclinical	ATRA + gemcitabine	Targets multiple tumor–stromal pathways	⁵⁵⁹
Collagen I	Breast	Preclinical	Losartan-loaded C₁₆-N	Inhibits CAF and collagen synthesis	⁵⁶⁰
CTGF	Pancreas	Preclinical; phase I (50)	FG-3019 gemcitabin (NCT01181245)	Decreases X-linked inhibitor of apoptosis protein to kill tumor cell	⁵⁶¹
FAP-α	Prostate	Preclinical	Drug-loaded CAP-NPs	Disrupts stromal barrier to drug	⁵⁶²
GPR77	Breast	Preclinical	Anti-GPR77 antibody	Reduces the infiltration of CAF	⁵⁶³
Hedgehog pathway	Pancreas	Preclinical	IPI-926 + gemcitabine	Depletes CAF to increase intratumoral concentration of gemcitabine	³⁹⁵
Hyaluronan	Pancreas	Phase II (279)	PEGPH20 + others	Increases drug delivery	⁵⁶⁴
IL-6	Stomach	Preclinical	Tocilizumab	Renews chemotherapy-induced apoptosis	³⁸⁸
mTOR/4E-BP1 pathway	Pancreas	Preclinical	SOM230 + gemcitabine	Blocks insoluble or soluble proteins synthesis and secretion from CAF	⁵⁶⁵
Vimentin + SMA	Pancreas	Phase I (7)	PEGPH20 + Avelumab (NCT03481920)	Increases drug delivery and immune infiltration	⁵⁶⁶

4E-BP1 4E-binding protein 1, AR angiotensin receptor, ATRA all-trans retinoic acid, CAF cancer-associated fibroblast, CAP-NP cleavable amphiphilic peptide nanoparticles, CSF1R colony-stimulating factor-1 receptor, CTGF connective tissue growth factor, CXCR2 chemokine receptor 2, DC dendritic cells, DPPIV dipeptidyl peptidase IV, ECM extracellular matrix, FAP fibroblast activation protein, GPR77 G-protein-coupled receptor 77, HA-PTX/MATT hyaluronic acid-paclitaxel/marimastat, HNP hybrid nanoparticles, IL interleukin, LPD lipid-coated protamine DNA complexes, MAPK mitogen-activated protein kinase, MMP matrix metalloproteinases, mTOR mammalian target of rapamycin, NOX4 NAD(P)H oxidase-4, PEGPH20 pegvorhyaluronidase alfa, PDGFR platelet-derived growth factor receptor, PDT photodynamic therapy, PIT photoimmunotherapy, PMN-MDSC polymorphonuclear myeloid-derived suppressor cells, RAR retinoic acid receptor, ROS reactive oxygen species, SMA smooth muscle actin, sTRAIL secretable TNF-related apoptosis-inducing ligand, TGF transforming growth factor, TEM-1 tumor endothelial marker-1, VEGF vascular endothelial growth factor, VDR vitamin D receptor.

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Table 4 CAF-mediated anticancer therapies

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