Cancer-associated fibroblasts enact field cancerization by promoting extratumoral oxidative stress

Abstract

Histological inspection of visually normal tissue adjacent to neoplastic lesions often reveals multiple foci of cellular abnormalities. This suggests the presence of a regional carcinogenic signal that spreads oncogenic transformation and field cancerization. We observed an abundance of mutagenic reactive oxygen species in the stroma of cryosectioned patient tumor biopsies, indicative of extratumoral oxidative stress. Diffusible hydrogen peroxide (H2O2) was elevated in the conditioned medium of cultured skin epithelia at various stages of oncogenic transformation, and H2O2 production increased with greater tumor-forming and metastatic capacity of the studied cell lines. Explanted cancer-associated fibroblasts (CAFs) also had higher levels of H2O2 secretion compared with normal fibroblasts (FIBs). These results suggest that extracellular H2O2 acts as a field effect carcinogen. Indeed, H2O2-treated keratinocytes displayed decreased phosphatase and tensin homolog (PTEN) and increased Src activities because of oxidative modification. Furthermore, treating FIBs with CAF-conditioned medium or exogenous H2O2 resulted in the acquisition of an oxidative, CAF-like state. In vivo, the proliferative potential and invasiveness of composite tumor xenografts comprising cancerous or non-tumor-forming epithelia with CAFs and FIBs could be attenuated by the presence of catalase. Importantly, we showed that oxidatively transformed FIBs isolated from composite tumor xenografts retained their ability to promote tumor growth and aggressiveness when adoptively transferred into new xenografts. Higher H2O2 production by CAFs was contingent on impaired TGFβ signaling leading to the suppression of the antioxidant enzyme glutathione peroxidase 1 (GPX1). Finally, we detected a reduction in Smad3, TAK1 and TGFβRII expression in a cohort of 197 clinical squamous cell carcinoma (SCC) CAFs, suggesting that impaired stromal TGFβ signaling may be a clinical feature of SCC. Our study indicated that CAFs and cancer cells engage redox signaling circuitries and mitogenic signaling to reinforce their reciprocal relationship, suggesting that future anticancer approaches should simultaneously target ligand receptor and redox-mediated pathways.

Genetic Ancestry–dependent Differences in Breast Cancer–induced Field Defects in the Tumor-adjacent Normal Breast

“…Recent studies have shown cancer-induced field defects influencing gene expression patterns in histologically normal tissues surrounding cancer (3,34,35). These observations raise a concern, as well as provide an opportunity for further investigation.…”

Concise Review: Prostate Cancer Stem Cells: Current Understanding

“…CAFs are one of the major components of tumor stroma which not only directly influence tumor cells but also influences other types of cells in form of stimulation (e.g., recruitment of endothelial cells) or inhibition (e.g., exclusion of T-cells) leading to the establishment of a tumor-permissive microenvironment [107]. An activated CAF phenotype is associated with elevated microenvironmental oxidative stress that might, in turn, stimulate genetic changes in the epithelial cells and normal stromal fibroblasts and their cancer transformation [116]. Based on the heterogeneity of expressed markers, CAFs have been suggested to derive from different cellular origins, for example, activation of resident fibroblasts, recruitment of bone marrow derived progenitor cells to the tumor site, and trans-differentiation through the endothelial-mesenchymal or epithelial-mesenchymal transition as reviewed recently by Levesque and Nelson [107].…”

Antioxidants Maintain Cellular Redox Homeostasis by Elimination of Reactive Oxygen Species

“…Moreover, ROS can activate the MAPK pathways which the activation of ERK, JNK, and p38 MAPK signaling proteins were involved in apoptosis via ROS generation. Studies have demonstrated the MAPK pathways, plays a pivotal role in cell survival and the enhanced protection of cancer cells from apoptosis during tumorigenesis [150]. Modulation of MAPK by Antioxidant is also involved in the therapy such as heart failure model [151].…”