Table 1 Cancer-derived EV functions on CAF generation and property

Proteins

From

To

Integrins

Breast cancer Pancreatic cancer

Cancer cells

CAFs

Up-regulates S100 gene expressions and promote cell qrowth and migration

[7]

TGF-β

Bladder cancer

Generate CAFs by activating SMAD-dependent pathway

[72]

Integlin αv and β1

Breast cancer

Integrin αv and β1 are enriched in CD63-positive EVs and induce CAF-like phenotypes in the fibroblasts. Galectin-3 might regulate the loading integrin αv and β1 in EVs.

[176]

ITGB4

Breast cancer

Induces BCL2 interacting protein 3 like (BNIP3L)-dependent mitophagy and glycolysis.

[33]

Sphingosine 1

Breast cancer

Sphingosine 1 drived from cancer cells may stimulate ERK-1/2 signalling and DNA synthesis

[73]

Survivin

Breast cancer

Generate CAFs with myofibroblastic features through inducing SOD1 expression to promote tumour proliferation and metastasis

[74]

Wnt2B

Cervical cancer

Generate CAFs through activating Wnt/β-catenin signalling

[75]

HSPC111

Colorectal cancer

Reprogramming lipid metabolism in CAFs to promote cancer metastasis.

[180]

TIMP-1

Colorectal cancer

Cancer-derived EVs transfer TIMP-1 to induced ECM remodelling in the fibroblasts.

[178]

LMP1

Epstein-Barr virus (EBV)-associated Nasopharyngeal carcinoma

Generate CAFs through NF-κB signalling and change aerobic glycolysis and autophagy in CAFs

[76]

PKM2

Gastric cancer

Generate CAFs by PKM2 nuclear translocation inducing NF-κB signalling

[77]

TGF-β

Head and neck squamous cell carcinoma

Generate CAFs through activation canonical TGF-β signalling pathway

[32]

PKM2

Hypoxic resistant lung cancer cells

Induce metabolic reprogramming in CAFs

[78]

IGF2

Liver cancer

Fluid shear stress-induced cancer cell medium promoted the activation and proliferation of CAFs via activating PI3K/AKT signaling pathway.

[172]

α-SMA

Lung cancer

Cancer-derived EV transfer α-SMA in both lung cancer cell line and fibroblasts. These EVs also promote cell proliferation and inhibit apoptosis.

[79]

TGF-β

Malignant ascite from gastriccancer and ovarian cancer

TGF-β in EVs may induce CAF phenotypes in peritonieal mesothelial cells

[80]

HSP90 and p-IKKα/β complex

Melanoma

Promote the proangiogenic capacity via activating NF-κB signalling to induce CXCL1 expression in CAFs.

[173]

TGF-β

Mesothelioma Colorectal cancer Prostate cancer Bladder cancer

Triger the myofibroblast differen-tiation

[30]

FAP and EBV-encoded latent membrane protein 1 (LMP1)

Nasopharyngeal carcinoma

Generate CAFs via enhancing YAP1 signalling and increasing FAP expression.

[177]

COL6A1

Osteosarcoma

COL6A1-positive EVs generate CAFs expressing interleukins, α-SMA, and TGF-β

[81]

Gain-of-function p53

Ovarian cancer

Instigate CAF phenotypes in fibroblasts through the Nrf2-dependent pathway

[39]

Annexin A1

Pancreatic cancer

Induce myofibroblasts features in the fibroblasts and endothelial cells

[82]

Lin28B

Pancreatic cancer

Generate CAFs from pancreatic stellate cells through activating let-7/HMGA2/PDGFRβ axis.

[83]

Hyal1

Prostate cancer

Stimulate fibroblast chemotaxis by the increased adhesion and activating FAK signalling.

[84]

TGF-β

Prostate cancer

Triger the myofibroblast differen-tiation and promote cancer growth and angiogenesis

[31]

C-terminal Dsg2

Squamous cell carcinoma

Dsg2-positive EVs activate Erk1/2 signalling and promote cell proliferation in fibroblasts.

[85]

Coding RNAs

From

To

Inflammation-inducing mRNAs

Melanoma

Cancer cells

CAFs

Induce CAF subtype with inflammatory signatures in within metastatic niche

[47]

non-coding of transposable RNAs

From

To

miR-105

Breast cancer

Cancer cells

CAFs

Reprogram glucose and glutamine metabolism to fuel adjacent cancer cells

[34]

miR-105 and miR-204

Breast cancer

Cancer-derived EVs might transfer miR-105 and miR-204 and suppress RAGC expression in fibroblasts.

[175]

miR-122

Breast cancer

Down-regulates glucose consumption of fibroblasts

[63]

miR-125b

Breast cancer

Generates CAFs from resident fibroblasts through targeting TP53INP1 expression

[43]

miR-130b-3p

Breast cancer

Generate CAFs via targeting SPIN90 in fibroblasts and facilitate cancer progression.

[179]

miR-185-5p, miR-652-5p, and miR-1246

Breast cancer

Three miRNAs in cancer-derived EVs can be involved in the induction of CAF phenotypes in normal fibroblasts.

[171]

miR-370-3p

Breast cancer

Induce fibroblast activation through CYLD/NF-κB signalling and promote cancer progression

[86]

Decreased miR-34c

Cholangiocarcinoma

Enhancing Wnt1 expression in fibroblasts and generate CAFs. miR-34 directly target Wnt1 expression.

[87]

miR-146a

Chronic lyphocytic leukaemia

Generate CAFs by targeting USP16 expression in fibroblasts

[88]

miR-10a

Colorectal cancer (SW480 cell line)

Inhibit migration and expression of IL-6 and IL-8 expression in fibroblasts

[89]

miR-1249-5p, miR-6737-5p, and miR-6819-5p

Colorectal cancer

EVs derived from cancer cells with p53 shRNA genrate CAFs. miRNAs in EVs may contribute to induction of CAF phenotype in fibroblasts.

[44]

miR-146a-5p and miR-155-5p

Colorectal cancer

Generate CAFs via targeting SOCS1 and ZBTB2 to activate JAK2-STAT3/NF-κB signalling. CXCL12/CXCR7 is associated with these miRNA expressions in cancer cells.

[181]

miR-200 family

Colorectal cancer

CRC cells with an epithelial phenotype but not a mesenchymal phenotype secrete miR-200 family members via EVs to attenuate TGF-β-mediated CAF features by targeting ZEB1 in normal fibroblasts.

[45]

miR-4534

Colorectal cancer

Suppress autophagy to induce CAF phenotypes in fibroblasts. EV miR-4534 targets ATG2B expression.

[182]

miR-27a

Gastric cancer

Generate CAFs to support cancer migration and invasion.

[90]

Several miRNAs including miR-193b

Gastric cancer

Induce CAF subtype with inflammatory signatures

[46]

miR-192, miR-215

Head and neck squamous cell carcinoma

Generate CAFs through targeting CAV1 to induce TGF-β/SMAD signalling

[91]

miR-9-5p

Head and neck squamous cell carcinoma

HPV-positive head and neck squamous cell carcinoma cells secrete miR-9-5p via EVs. EV miR-9-5p suppresses NOX4 expression to inhibit the induction of TGF-β-mediated CAF phenotype in fibroblasts.

[174]

miR-21

Hepatocellular carcinoma

Generate CAFs from hepatocyte stellate cells through activating PDK1/Akt signalling

[92]

miR-1247-3p

Hepatocellular carcinoma

Generate CAFs expressing inflammatory genes through targeting B4GALT3 to activate β1 integlin/NF-κB signalling

[49]

miR-181d-5p

Hepatoma cell

May induce CAF state via targeting SOCS3 expression in bone-marrow stem cells (BMSCs)

[93]

miR-3473b

Lewis lung carcinoma

Generate inflammatory gene expressing CAFs through activationg NF-κB singnalling

[94]

miR-142-3p

Lung cancer

EVs derived from cancer cells with miR-142-3p over-expression generate CAFs via non-canonical TGF-β signalling

[96]

miR-210

Lung cancer

Generate CAFs expressing proangiogenic factors through activating JAK2/STAT3 signalling

[95]

lncRNA Gm26809

Melanoma

Generate CAF properties in NIH3T3 fibroblasts

[97]

miR-155

Melanoma

Generate CAFs expressing proangiogenic factors through inhibiting SOCS1 to activate JAK2/STAT3 signalling

[99]

miR-155 and miR-210

Melanoma

Increase aerobic glycolysis and decrease oxidative phosphorylation in fibroblasts.

[98]

miR-375

Merkel cell carcinoma

Generate CAFs through targeting RBPJ and p53 expression

[100]

miR-21

Mouse melanoma cell

Promote the invasion activity of fibroblasts through targeting TIMP-3 expression

[101]

lncRNA (LncRNA-CAF)

Oral squamous cell carcinoma

Stimulate IL-33 expression and CAF phenotypes in fibroblasts to influence CAF generation from other surrounding fibroblasts and promotes tumour growth

[102]

miR-630

Ovarian cancer

Generate CAFs through targeting KLF6 and activating NF-κB signalling pathway

[103]

miR-155

Pancreatic cancer

Induce cancer-associated fibroblast like phenotype through repressing TP53P1

[104]

Several miRNAs including miR-1246 and miR-1268

Rhabdomyosarcoma

Rhabdomyosarcoma-derived EVs promote cell growth and stimulate angiogenic capacities in fibroblasts

[105]

Others

From

To

Not investigated

Bladder cancer

Cancer cells

CAFs

Cancer-derived EVs induce inflammatory CAFs (iCAFs)

[48]

miR-1246, TGF-β, β-catenin, IL-6, p-STAT3

Colorectal cancer

Cancer-derived EVs generate CAFs. But the precise mechanism of how molecules in EVs induce CAF signatures in fibroblasts is not addressed.

[108]

Not investigated

Colorectal cancer

Stimulate migration capacity of CAFs via activating Rho-Fak signalling

[106]

Not investigated

Colorectal cancer

Cancer-derived EVs generate CAFs to acquire the capacity to invade matrix and to support cancer invasion.

[107]

Not investigated

Experimentally induced cancer stem cells (Piwil2-CSC)

Generate CAFs and enhance cell migration and invasion in CAFs.

[109]

Not investigated

Gastric cancer

Generate CAFs from pericytes through activating PI3K/AKT and MEK/ERK signalling pathways

[110]

Not investigated

Gastric cancer

Generate CAFs through canonical TGF-β signalling pathway

[111]

Not investigated

Lung cancer

Mediate immunomodulate effect via inducing PD-L1

[112]

Not investigated

Lung cancer

Cancer cells with TP53 mutation mediate the integrin trafficking in the fibroblasts via EVs and promote the deposition of invasive ECMs

[38]

Not investigated

Ovarian cancer

Cancer-derived EVs instigate cell adhesion and migration capacity in CAFs.

[67]

Not investigated

Prostate cancer

Cancer-derived EVs stimulate prometastatic factors including brain-derived neurotrophic factor and CXCL12.

[113]

Not investigated

Salivary adenoid cystic carcinoma

Induce the capacity to enhance cancer invasion and NGF expression in human periodontal ligament fibroblasts.

[114]