Understanding the "lethal" drivers of tumor-stroma co-evolution: emerging role(s) for hypoxia, oxidative stress and autophagy/mitophagy in the tumor micro-environment - PubMed (original) (raw)

Review

Understanding the "lethal" drivers of tumor-stroma co-evolution: emerging role(s) for hypoxia, oxidative stress and autophagy/mitophagy in the tumor micro-environment

Michael P Lisanti et al. Cancer Biol Ther. 2010.

Abstract

We 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.

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Figures

Figure 1

Deciphering tumor-stroma co-evolution: the autophagic tumor stroma model of cancer cell metabolism. Cancer cells induce oxidative stress in adjacent stromal fibroblasts. Then, the resulting oxidative stress in cancer-associated fibroblasts helps drive tumor-stroma co-evolution, by randomly mutagenizing cancer cells, while protecting them against apoptosis and providing them with abundant recycled nutrients and chemical building blocks via autophagy. This results in a net energy transfer from the autophagic tumor stroma to the anabolic “hungry” cancer cells. Thus, stromal oxidative stress and autophagy function(s) as a “battery” to drive tumor-stroma co-evolution and “fuel” oxidative mitochondrial metabolism in cancer cells. A+ (positive), increased autophagy/mitophagy in cancer associated fibroblasts; A− (negative), decreased autophagy/mitophagy in epithelial cancer cells. AR (resistant), denotes the successful evolution of autophagy-resistant cancer cells, due to genetic silencing or deletion of required autophagy genes, such as Beclin1.

Figure 2

Acute knock-down of Cav-1 in human stromal fibroblasts increases ros production and negatively affects mitochondrial activity. (Upper) Cav-1 knock-down induces ROS production. CM-H2DCFDA staining (green) was performed on hTER T-fibroblasts treated with Cav-1 siRNA (right) or control siRNA (left). Cells were counterstained with Hoechst nuclear stain (blue). Samples were then immediately imaged using a 488 nm excitation wavelength. Note that Cav-1 knock-down greatly promotes ROS generation. Importantly, images were acquired using identical exposure settings. Original magnification, 20x. (Lower) Cav-1 knock-down decreases mitochondrial activity. hTERT-fibroblasts were treated with Cav-1 siRNA (right) or control siRNA (left). Then, functional mitochondria with active membrane potential were visualized using MitoTracker staining (red). DAPI was used to stain nuclei (blue). Note that transient Cav-1 knock-down greatly decreases mitochondrial activity. Importantly, paired images were acquired using identical exposure settings. Original magnification, 63x. Images were reproduced from references, and with permission.

Figure 3

Acute knock-down of Cav-1 in human stromal fibroblasts activates autophagy and mitophagy: implications for human breast cancer. (A) Acute loss of Cav-1 increases the expression of autophagic markers. hTER T-fibroblasts were treated with Cav-1 siRNA or control (CTR) siRNA. Cells were fixed and immuno-stained with antibodies against Beclin1, BNIP3 and BNIP3L. DAPI was used to visualize nuclei (blue). Importantly, paired images were acquired using identical exposure settings. Original magnification, 40x. Note that acute Cav-1 knockdown is sufficient to greatly increase the expression levels of all the autophagy/mitophagy markers we examined. (B) BNIP3L is highly increased in the stroma of human breast cancers that lack stromal Cav-1. Paraffin-embedded sections of human breast cancer samples lacking stromal Cav-1 were immuno-stained with antibodies directed against BNIP3L. Slides were then counter-stained with hematoxylin. Note that BNIP3L is highly expressed in the stromal compartment of human breast cancers that lack stromal Cav-1. Original magnification, 20x and 40x, as indicated. Images were reproduced from the references and , with permission.

References

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Understanding the "lethal" drivers of tumor-stroma co-evolution: emerging role(s) for hypoxia, oxidative stress and autophagy/mitophagy in the tumor micro-environment - PubMed (original) (raw)