Cancer Associated Fibroblasts Exploit Reactive Oxygen Species Through a Proinflammatory Signature Leading to Epithelial Mesenchymal Transition and Stemness

Abstract

Cancer-associated fibroblasts (CAFs) are key determinants in the malignant progression of cancer, supporting tumorigenesis and metastasis. CAFs also mediate epithelial mesenchymal transition (EMT) of tumor cells and their achievement of stem cell traits. We demonstrate that CAFs induce EMT and stemness through a proinflammatory signature, which exploits reactive oxygen species to drive a migratory and aggressive phenotype of prostate carcinoma cells. CAFs exert their propelling role for EMT in strict dependence on cycloxygenase-2 (COX-2), nuclear factor-jB, and hypoxia-inducible factor-1. CAF-secreted metalloproteases elicit in carcinoma cells a Rac1b/COX-2-mediated release of reactive oxygen species, which is mandatory for EMT, stemness, and dissemination of metastatic cells. Tumor growth is abolished, and metastasis formation is severely impaired by RNA interfering-mediated targeting of the proinflammatory signature, thereby supporting the therapeutic targeting of the circuitry COX-2/nuclear factor-jB /hypoxia-inducible factor-1 as a valuable antimetastatic tool affecting cancer cell malignancy.

Anoikis: an emerging hallmark in health and diseases

“…Stemness is indeed a device to survive in a hostile microenvironment, once the primary cancer has grown. So the acquisition of stem cell features, linked to both EMT [107,108] and ROS production [109], may contribute to the survival and subsequent proliferation of cancer cells.…”

The Inflammatory Tumor Microenvironment, Epithelial Mesenchymal Transition and Lung Carcinogenesis

“…For example, CAFs have been shown to induce EMT and stemness through pro-inflammatory signaling which elicits COX-2/ Rac1b-mediated release of reactive oxygen species (ROS) that ultimately drive a migratory and aggressive phenotype of prostate carcinoma cells [148]. This ROS-mediated induction of EMT and stemness by hypoxia is dependent on both NF-κB and HIF-1.…”

Frequent Gene Products and Molecular Pathways Altered in Prostate Cancer- and Metastasis-Initiating Cells and Their Progenies and Novel Promising Multitargeted Therapies

“…The truncated ERG oncoprotein can cooperate with the PTEN (phosphatase tensin homolog deleted on chromosome 10) downregulation-induced phosphatidylinositol 3-kinase (PI3K)/Akt activation and induce the PC cell invasion and angiogenesis-like wild-type oncogenic ERG transcription factor (33,(35)(36)(37)(38)(39)(40)(41). In addition, the changes in the tumor reactive stroma, including the release of different growth factors by activated myofibroblasts, typically take place during PC progression under normoxic and hypoxic conditions and may promote the malignant transformation of PC cells and neoangiogenesis (5,11,13,(43)(44)(45)(46)(47).…”