Understanding the "lethal" drivers of tumor-stroma co-evolution: Emerging role(s) for hypoxia, oxidative stress and autophagy/mitophagy in the tumor micro-environment.
AuthorsLisanti, Michael P
Martinez-Outschoorn, U E
AffiliationThe Jefferson Stem Cell Biology and Regenerative Medicine Center, Department of Medical Oncology and Departments of Stem Cell Biology & Regenerative Medicine and Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA; Manchester Breast Centre & Breakthrough Breast Cancer Research Unit, Paterson Institute for Cancer Research, School of Cancer, Enabling Sciences and Technology, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK. firstname.lastname@example.org.
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AbstractWe have recently proposed a new model for understanding how tumors evolve. To achieve successful "Tumor-Stroma Co-Evolution", cancer cells induce oxidative stress in adjacent fibroblasts and possibly other stromal cells. Oxidative stress in the tumor stroma mimics the effects of hypoxia, under aerobic conditions, resulting in an excess production of reactive oxygen species (ROS). Excess stromal production of ROS drives the onset of an anti-oxidant defense in adjacent cancer cells, protecting them from apoptosis. Moreover, excess stromal ROS production has a "Bystander-Effect", leading to DNA damage and aneuploidy in adjacent cancer cells, both hallmarks of genomic instability. Finally, ROS-driven oxidative stress induces autophagy and mitophagy in the tumor micro-environment, leading to the stromal over-production of recycled nutrients (including energy-rich metabolites, such as ketones and L-lactate). These recycled nutrients or chemical building blocks then help drive mitochondrial biogenesis in cancer cells, thereby promoting the anabolic growth of cancer cells (via an energy imbalance). We also show that ketones and lactate help "fuel" tumor growth and cancer cell metastasis and can act as chemo-attractants for cancer cells. We have termed this new paradigm for accelerating tumor-stroma co-evolution, "The Autophagic Tumor Stroma Model of Cancer Cell Metabolism". Heterotypic signaling in cancer-associated fibroblasts activates the transcription factors HIF1alpha and NFκB, potentiating the onset of hypoxic and inflammatory response(s), which further upregulates the autophagic program in the stromal compartment. Via stromal autophagy, this hypoxic/inflammatory response may provide a new escape mechanism for cancer cells during anti-angiogenic therapy, further exacerbating tumor recurrence and metastasis.
CitationUnderstanding the "lethal" drivers of tumor-stroma co-evolution: Emerging role(s) for hypoxia, oxidative stress and autophagy/mitophagy in the tumor micro-environment. 2010, 10 (6): Cancer Biol Ther
JournalCancer Biology & Therapy
- Autophagy in cancer associated fibroblasts promotes tumor cell survival: Role of hypoxia, HIF1 induction and NFκB activation in the tumor stromal microenvironment.
- Authors: Martinez-Outschoorn UE, Trimmer C, Lin Z, Whitaker-Menezes D, Chiavarina B, Zhou J, Wang C, Pavlides S, Martinez-Cantarin MP, Capozza F, Witkiewicz AK, Flomenberg N, Howell A, Pestell RG, Caro J, Lisanti MP, Sotgia F
- Issue date: 2010 Sep 1
- Oxidative stress in cancer associated fibroblasts drives tumor-stroma co-evolution: A new paradigm for understanding tumor metabolism, the field effect and genomic instability in cancer cells.
- Authors: Martinez-Outschoorn UE, Balliet RM, Rivadeneira DB, Chiavarina B, Pavlides S, Wang C, Whitaker-Menezes D, Daumer KM, Lin Z, Witkiewicz AK, Flomenberg N, Howell A, Pestell RG, Knudsen ES, Sotgia F, Lisanti MP
- Issue date: 2010 Aug 15
- Stromal-epithelial metabolic coupling in cancer: integrating autophagy and metabolism in the tumor microenvironment.
- Authors: Martinez-Outschoorn UE, Pavlides S, Howell A, Pestell RG, Tanowitz HB, Sotgia F, Lisanti MP
- Issue date: 2011 Jul
- The autophagic tumor stroma model of cancer or "battery-operated tumor growth": A simple solution to the autophagy paradox.
- Authors: Martinez-Outschoorn UE, Whitaker-Menezes D, Pavlides S, Chiavarina B, Bonuccelli G, Casey T, Tsirigos A, Migneco G, Witkiewicz A, Balliet R, Mercier I, Wang C, Flomenberg N, Howell A, Lin Z, Caro J, Pestell RG, Sotgia F, Lisanti MP
- Issue date: 2010 Nov 1
- The autophagic tumor stroma model of cancer: Role of oxidative stress and ketone production in fueling tumor cell metabolism.
- Authors: Pavlides S, Tsirigos A, Migneco G, Whitaker-Menezes D, Chiavarina B, Flomenberg N, Frank PG, Casimiro MC, Wang C, Pestell RG, Martinez-Outschoorn UE, Howell A, Sotgia F, Lisanti MP
- Issue date: 2010 Sep 1