Table 5 CAF-directed therapeutic resistance

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

Therapy	Cancer type	Key molecule from CAFs	Molecular mechanism in cancer cell	Refs.
Chemotherapeutics
5-FU	GC	Paracrine low SPARC	Activates AKT/mTOR and MEK/ERK pathway	¹⁴⁸
Adriamycin	PRAD	Paracrine IL-6 and exosomal miR-423	Activates JAK/STAT and TGF-β pathway, and upregulates glutathione and GREM2	^419,451,567
Paclitaxel	PRAD	Paracrine IL-6 and exosomal miR-423		^419,451,567
Adriamycin	BC	Paracrine CXCL12/HMGB1	Downregulates H2AX phosphorylation	^568,569
Adriamycin	SC	Paracrine Nodal	Activates Nodal/Samd/AKT pathway	¹³⁹
Cisplatin	ESCA	Paracrine PAI-1/IL-6	Activates AKT and ERK1/2 and CXCR7 pathway	^218,523,570
Cisplatin	LC	Paracrine SDF-1/ANXA3/IL-6	Activates NF-κB/Bcl-2 and JNK pathway, and upregulates p53	^{219,312,399,571}
Cisplatin	HNSCC	Exosomal miR-196a	Upregulates CDKN1B, ING5 LC3-II, and Beclin-1	^435,572
Cisplatin	OC	Paracrine POSTN/CXCL12 and exosomal miR-98	Activates STAT3, PI3K/AKT, and /Wnt/β-catenin pathway and downregulates CDKN1A	^{440,467,525,573}
Cisplatin	LUAD	Paracrine IL-11/COX-2	Activates IL-11/STAT3 pathway and downregulates TNFSF4	^461,529,574
Cisplatin	HCC	Paracrine HGF	Activates c-Met and Mec-ERK1/2 pathway	⁴⁸⁷
Cisplatin	VSCC	Exosomal lncRNA UCA1	Activates miR-103a/WEE1 pathway	⁵⁷⁵
Docetaxel	BC	Paracrine IL-8	Upregulates CXCL2, MMP1, IL-8, RARRES1, FGF1, and CXCR7	^362,576
Ebimycin	BC	Paracrine pyruvate and lactate	Upregulates mitochondrial activity	⁵⁷⁷
Gemcitabine	PDAC	Paracrine LAMA1/Survivin/IL-6/SDF-1/MMP3/MMP9/PDGF/and CCL-7 and exosomal Snail/miR-146a/miR-106b	Activates protein kinase, AKT, and SDF-1/CXCR4/SATB-1 pathway, and upregulates Snail and TP53INP1	^{70,309,351,433,478,565,577}
Oxaliplatin	HNSCC	Paracrine IL-6 and IL-8	Activates autophagy pathway	³⁵⁸
Oxaliplatin	CRC	Paracrine CM from CAFs	Activates STAT3 and p38 pathway	⁵⁷⁸
5-FU	CRC	Paracrine CM from CAFs	Activates STAT3 and p38 pathway	⁵⁷⁸
Paclitaxel	BC	Paracrine MMP1 and collagen IV	Activates TGF-β pathway	³⁵²
Paclitaxel	LUAD	Paracrine HGF	Activates c-Met/PI3K/AKT pathway	⁵⁷⁹
Paclitaxel	OC	Paracrine CM from CAFs	Upregulates LPP	⁵⁸⁰
Targeted therapeutic
Cetuximab	CRC	Paracrine EGF	Activates MAPK pathway	²⁵³
Cetuximab	HNSCC	Paracrine-soluble factors	Upregulates MMP1	^319,581
Lenzclutamiad	PRAD	Paracrine CM from CAFs	Activates PI3K/AKT pathway and upregulates E-cadherin and vimentin	⁵⁸²
EGFR-TKI	LUAD	Paracrine HGF	ND	²⁵⁵
Gefitinib	LC	Paracrine CM from CAFs	Activates AKT and ERK, ANXA2/EMT, and hedgehog pathway	^489,583,584
Erlotinib	LC	Paracrine CM from CAFs	Activates AKT and ERK, ANXA2/EMT, and hedgehog pathway	^489,583,584
Trastuzumab	BC	Paracrine IL-6/FGF-5	Activates NF-κB, JAK/STAT3, AKT, and c-SRC/HER2 pathway	^585,586
Trastuzumab	BC	Paracrine pyruvate/lactate/ fibronectin	Activates integrin-β1 pathway and promote mitochondrial activity	^577,586,587
Tamoxifen	BC	Paracrine pyruvate/lactate/ fibronectin		^577,586,587
Sorafenib	PRAD	Paracrine CM from CAFs	Activates autophagy pathway and upregulate AKT phosphorylation and Bcl-xL	⁵⁸⁸
Sorafenib	HCC	Paracrine HGF	Activates c-Met and Mec-ERK1/2 pathway	⁴⁸⁷
Radiotherapy therapy (RT)
RT	LC	Paracrine FGF/IGF-2	Activates autophagy pathway	^369,589
RT	PDAC	Paracrine-soluble factors	Activates protein kinase and AKT pathways	⁵⁹⁰
RT	CESC	Paracrine IGF-2, EGF, FGF-4, IGFBPs, and GM-CSF	Activates p38 pathway	⁵⁹¹
RT	LUAD	Paracrine CXCL12	Activates CXCL12/CXCR4 pathway	⁵⁹¹
RT	ESCA	Paracrine PDGFβ	Activates PDGFβ/PDGFβR/FOXO1 pathway and upregulates lncRNA DNM3OS	⁵⁹²
RT	CRC	Exosomal TGF-β/IGF-1	Activates TGF-β and IGF-1/IGF1R pathway	^368,421,490

ANXA3 annexin A3, AKT protein kinase B, B-ALL B cell acute lymphoblastic leukemia. BC breast cancer, CESC cervical and endocervical cancer, CM conditioned medium, COX-2 cyclooxygenase, CRC colorectal cancer, EGF epidermal growth factor, ERK extracellular signal-related kinase, ESCA esophageal carcinoma, FGF fibroblast growth factor, GC gastric cancer, HCC hepatocellular carcinoma, HGF hepatocyte growth factor, HMGB1 high-mobility group box 1, HNSCC head and neck squamous cell carcinoma, IGF insulin-like growth factor, IL interleukin, JAK Janus kinase, LAMA1 laminin subunit alpha 1, LC lung cancer, LUAD lung adenocarcinoma, MMP matrix metalloproteinases, mTOR mammalian target of rapamycin, ND not determined, NF-κB nuclear factor kappa-B, OC ovarian cancer, PDAC pancreatic ductal adenocarcinoma, PAI-1 plasminogen activator inhibitor 1, PDGF platelet-derived growth factor, PI3K phosphatidylinositol-3-kinase, POSTN periostin, PRAD prostate adenocarcinoma, RCC renal cell carcinoma, SC stomach cancer, SPARC secreted protein acidic and rich in cysteine, STAT signal transducer and activator of transcription, TGF transforming growth factor, TSCC tongue squamous cell carcinoma.

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Table 5 CAF-directed therapeutic resistance

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