Differentiation of tumour-promoting stromal myofibroblasts by cancer exosomes.
Activation of myofibroblast rich stroma is a rate-limiting step essential for cancer progression. The responsible factors are not fully understood, but TGFβ1 is probably critical. A proportion of TGFβ1 is associated with extracellular nano-vesicles termed exosomes, secreted by carcinoma cells, and the relative importance of soluble and vesicular TGFβ in stromal activation is presented. Prostate cancer exosomes triggered TGFβ1-dependent fibroblast differentiation, to a distinctive myofibroblast phenotype resembling stromal cells isolated from cancerous prostate tissue; supporting angiogenesis in vitro and accelerating tumour growth in vivo. Myofibroblasts generated using soluble TGFβ1 were not pro-angiogenic or tumour-promoting. Cleaving heparan sulphate side chains from the exosome surface had no impact on TGFβ levels yet attenuated SMAD-dependent signalling and myofibroblastic differentiation. Eliminating exosomes from the cancer cell secretome, targeting Rab27a, abolished differentiation and lead to failure in stroma-assisted tumour growth in vivo. Exosomal TGFβ1 is therefore required for the formation of tumour-promoting stroma.
Section of Oncology, Institute of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK.
J P
JP
Webber
Section of Oncology, Institute of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK.
L K
LK
Spary
Section of Surgery, Institute of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK.
A J
AJ
Sanders
Section of Oncology, Institute of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK.
R
R
Chowdhury
Section of Surgery, Institute of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK.
W G
WG
Jiang
Section of Nephrology, Institute of Molecular and Experimental Medicine, Cardiff University School of Medicine, Cardiff, UK.
R
R
Steadman
Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff, UK.
J
J
Wymant
Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff, UK.
A T
AT
Jones
Section of Surgery, Institute of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK.
H
H
Kynaston
Section of Oncology, Institute of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK.
M D
MD
Mason
Section of Oncology, Institute of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK.
Z
Z
Tabi
Section of Oncology, Institute of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK.
A
A
Clayton
D000818:Animals; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D055354:Exosomes / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006497:Heparan Sulfate / Q000378:metabolism / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008819:Mice, Nude; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism / Q000494:pharmacology; D014183:Transplantation, Heterologous; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000075745:rab27 GTP-Binding Proteins
D006497:Heparan Sulfate; D036341:Intercellular Signaling Peptides and Proteins; D053773:Transforming Growth Factor beta1; D020691:rab GTP-Binding Proteins; D000075745:rab27 GTP-Binding Proteins; C066694:RAB27A protein, human