Table 5.
CAF-directed therapeutic resistance
| 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 | ||||
| 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 | ||||
| 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 | ||||
| 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 | ||||
| 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.