Growth stimuli in cancer growth resemble those exhibited in wound healing. However, the process of nemosis is absent in cancer-associated fibroblasts (CAFs), which remain constitutively active. CAFs are present in almost all solid tumors but are most abundant in breast, prostate and pancreatic cancers. TGF-β1, TGF-β2, PDGF, IL-6, bFGF, reactive oxide species and protein kinase C are considered the key players in tumor-induced transdifferentiation of surrounding fibroblasts. Full-extent transdifferentiation was obtained only when the medium contained TGF-β1 or TGF-β2 (with or without other factors), whereas PDGF, bFGF or IL-6 (each alone) induced only partial transdifferentiation. Recent evidence suggests that the fibroblasts associated with primary cancers differ from those associated with metastases. The metastases-associated fibroblasts are converted by a metastasis-specific spectrum of factors. A large portion of paracrine tumor signaling is mediated by cancer cell-derived vesicles termed exosomes and microvesicles. The cancer cell-derived exosomes contain abundant and diverse proteomes and a number of signaling factors (TGF-ß1, TGF-ß2, IL-6, MMP2 and MMP9), particularly under hypoxic conditions. In contrast to the traditional view, the clonal expansion and selection of neoplastic cells should not be viewed outside the host body context. It is vital for a neoplastic cell to achieve the ability to re-program host body cells into CAFs and by this influence to modulate its microenvironment and receive positive feedback for growth and drug resistance. Neoplastic cells, which fail to develop such capacity, do not pass critical barriers in tumorigenesis and remain dormant and benign.

Charles University Prague 3rd Faculty of Medicine Ruská 87 CZ 100 00 Prague Czech Republic

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