Oxidative stress in cancer associated fibroblasts drives tumor-stroma co-evolution

• DOI: 10.4161/cc.9.16.12553
• Publication Date: 2010-08-16T16:18:08Z
• Authors: Ubaldo E. Martine...; Renee M. Balliet; Dayana Rivadeneira; Barbara Chiavarina; Stephanos Pavlides; Chenguang Wang; Diana Whitaker-Me...; Kristin Daumer; Zhao Lin; Agnieszka Witkiewicz; Neal Flomenberg; Anthony Howell; Richard Pestell; Erik Knudsen; Federica Sotgia; Michael P. Lisanti
• Keywords: Genomic instability; 0301 basic medicine; Nitric oxide (NO); The "field effect"; Nitric Oxide Synthase Type III; Caveolin 1; Down-Regulation; Breast Neoplasms; Nitric Oxide; In cancer biology; Genomic Instability; Cell Line; Histones; 03 medical and health sciences; Caveolin-1; Autophagy; Humans; Lactic Acid; RNA, Small Interfering; Reactive oxygen species (ROS); Fibroblasts; Aneuploidy; Biological Evolution; Cancer associated fibroblasts; Coculture Techniques; Mitochondria; 3. Good health; Oxidative Stress; Oxidative stress; DNA damage; Female; RNA Interference; Mitochondrial dysfunction; Anti-oxidant cancer therapy; DNA Damage

Loss of stromal fibroblast caveolin-1 (Cav-1) is a powerful single independent predictor of poor prognosis in human breast cancer patients, and is associated with early tumor recurrence, lymph node metastasis and tamoxifen-resistance. We developed a novel co-culture system to understand the mechanism(s) by which a loss of stromal fibroblast Cav-1 induces a "lethal tumor micro-environment." Here, we propose a new paradigm to explain the powerful prognostic value of stromal Cav-1. In this model, cancer cells induce oxidative stress in cancer-associated fibroblasts, which then acts as a "metabolic" and "mutagenic" motor to drive tumor-stroma co-evolution, DNA damage and aneuploidy in cancer cells. More specifically, we show that an acute loss of Cav-1 expression leads to mitochondrial dysfunction, oxidative stress and aerobic glycolysis in cancer associated fibroblasts. Also, we propose that defective mitochondria are removed from cancer-associated fibroblasts by autophagy/mitophagy that is induced by oxidative stress. As a consequence, cancer associated fibroblasts provide nutrients (such as lactate) to stimulate mitochondrial biogenesis and oxidative metabolism in adjacent cancer cells (the "Reverse Warburg Effect"). We provide evidence that oxidative stress in cancer-associated fibroblasts is sufficient to induce genomic instability in adjacent cancer cells, via a bystander effect, potentially increasing their aggressive behavior. Finally, we directly demonstrate that nitric oxide (NO) over-production, secondary to Cav-1 loss, is the root cause for mitochondrial dysfunction in cancer associated fibroblasts. In support of this notion, treatment with anti-oxidants (such as N-acetyl-cysteine, metformin and quercetin) or NO inhibitors (L-NAME) was sufficient to reverse many of the cancer-associated fibroblast phenotypes that we describe. Thus, cancer cells use "oxidative stress" in adjacent fibroblasts (i) as an "engine" to fuel their own survival via the stromal production of nutrients and (ii) to drive their own mutagenic evolution towards a more aggressive phenotype, by promoting genomic instability. We also present evidence that the "field effect" in cancer biology could also be related to the stromal production of ROS and NO species. eNOS-expressing fibroblasts have the ability to downregulate Cav-1 and induce mitochondrial dysfunction in adjacent fibroblasts that do not express eNOS. As such, the effects of stromal oxidative stress can be laterally propagated, amplified and are effectively "contagious"--spread from cell-to-cell like a virus--creating an "oncogenic/mutagenic" field promoting widespread DNA damage.