role of antioxidants in fighting breast cancer explored

[Lani]

Researchers Say Mitochondrial Stress Fuels Cancer Growth, Provide Genetic Evidence That Antioxidants Can Help Treat It
[Sidney Kimmel Comprehensive Cancer Center]

Researchers from Jefferson's Kimmel Cancer Center have genetic evidence suggesting the antioxidant drugs currently used to treat lung disease, malaria and even the common cold can also help prevent and treat cancers because they fight against mitochondrial oxidative stress—a culprit in driving tumor growth.

For the first time, the researchers show that loss of the tumor suppressor protein Caveolin-1 (Cav-1) induces mitochondrial oxidative stress in the stromal micro-environment, a process that fuels cancer cells in most common types of breast cancer.

"Now we have genetic proof that mitochondrial oxidative stress is important for driving tumor growth," said lead researcher Michael P. Lisanti, M.D., Ph.D., professor of cancer biology at Jefferson Medical College of Thomas Jefferson University and member of the Kimmel Cancer Center at Jefferson. "This means we need to make anti-cancer drugs that specially target this type of oxidative stress. And there are already antioxidant drugs out there on the market as dietary supplements, like N-acetyl cysteine."

These findings were published in the online February 15 issue of Cancer Biology & Therapy.

Lisanti's lab previously discovered Cav-1 as a biomarker that functions as a tumor suppressor and is the single strongest predictor of breast cancer patient outcome. For example, if a woman has triple negative breast cancer and is Cav-1 positive in the stroma,

her survival is greater than 75 percent at 12 years, versus less than 10 percent at 5 years if she doesn't have the Cav-1 protein, according to Dr. Lisanti.

The researchers also established Cav-1's role in oxidative stress and tumor growth; however, where that stress originates and its mechanism(s) were unclear.

To determine this, Jefferson researchers applied a genetically tractable model for human cancer associated fibroblasts in this study using a targeted sh-RNA knock-down approach. Without the Cav-1 protein, researchers found that oxidative stress in cancer associated fibroblasts leads to mitochondrial dysfunction in stromal fibroblasts. In this context, oxidative stress and the resulting autophagy (producton of recycled nutrients) in the tumor-microenvironment function as metabolic energy or "food" to "fuel" tumor growth.

The researchers report that the loss of Cav-1 increases mitochondrial oxidative stress in the tumor stroma, increasing both tumor mass and tumor volume by four-fold, without any increase in tumor angiogenesis.

"Antioxidants have been associated with cancer reducing effects—beta carotene, for example—but the mechanisms, the genetic evidence, has been lacking," Dr. Lisanti said. "This study provides the necessary genetic evidence that reducing oxidative stress in the body will decrease tumor growth."

Currently, anti-cancer drugs targeting oxidative stress are not used because is it commonly thought they will reduce the effectiveness of certain chemotherapies, which increase oxidative stress.

"We are not taking advantage of the available drugs that reduce oxidative stress and autophagy, including metformin, chloroquine and N-acetyl cysteine," Dr. Lisanti said. "Now that we have genetic proof that oxidative stress and resulting autophagy are important for driving tumor growth, we should re-consider using antioxidants and autophagy inhibitors as anti-cancer agents."

The diabetic drug metformin and chloroquine, which is used for the prevention and treatment of malaria, prevent a loss of Cav-1 in cancer associated fibroblasts (which is due to oxidative stress), functionally cutting off the fuel supply to cancer cells.

This research also has important implications for understanding the pathogenesis of triple negative and tamoxifen-resistance in ER-positive breast caner patients, as well as other epithelial cancers, such as prostate cancers.

"Undoubtedly, this new genetically tractable system for cancer associated fibroblasts will help identify other key genetic 'factors' that can block tumor growth," Dr. Lisanti said.

ABSTRACT: Caveolin-1 and mitochondrial SOD2 (MnSOD) function as tumor suppressors in the stromal microenvironment: A new genetically tractable model for human cancer associated fibroblasts
[Cancer Biology & Therapy]
We have recently proposed a new model for understanding tumor metabolism, termed: "The Autophagic Tumor Stroma Model of Cancer Metabolism". In this new paradigm, catabolism (autophagy) in the tumor stroma fuels the anabolic growth of aggressive cancer cells. Mechanistically, tumor cells induce autophagy in adjacent cancer-associated fibroblasts via the loss of caveolin-1 (Cav-1), which is sufficient to promote oxidative stress in stromal fibroblasts. To further test this hypothesis, here we created human Cav-1 deficient immortalized fibroblasts using a targeted sh-RNA knock-down approach. Relative to control fibroblasts, Cav-1 deficient fibroblasts dramatically promoted tumor growth in xenograft assays employing an aggressive human breast cancer cell line, namely MDA-MB-231 cells. Co-injection of Cav-1 deficient fibroblasts, with MDA-MB-231 cells, increased both tumor mass and tumor volume by ~4-fold. Immuno-staining with CD31 indicated that this paracrine tumor promoting effect was clearly independent of angiogenesis. Mechanistically, proteomic analysis of these human Cav-1 deficient fibroblasts identified > 40 protein biomarkers that were upregulated, most of which were associated with i) myofibroblast differentiation, or ii) oxidative stress/hypoxia. In direct support of these findings, the tumor promoting effects of Cav-1 deficient fibroblasts could be functionally suppressed (nearly 2-fold) by the recombinant over-expression of SOD2 (superoxide dismutase 2), a known mitochondrial enzyme that de-activates superoxide, thereby reducing mitochondrial oxidative stress. In contrast, cytoplasmic soluble SOD1 had no effect, further highlighting a specific role for mitochondrial oxidative stress in this process. In summary, here we provide new evidence directly supporting a key role for a loss of stromal Cav-1 expression and oxidative stress in cancer-associated fibroblasts, in promoting tumor growth, which is consistent with "The Autophagic Tumor Stroma Model of Cancer". The human Cav-1 deficient fibroblasts that we have generated are a new genetically tractable model system for identifying other suppressors of the cancer-associated fibroblast phenotype, via a genetic "complementation" approach. This has important implications for understanding the pathogenesis of triple negative and basal breasts cancers, as well as tamoxifen-resistance in ER+ breast cancers, which are all associated with a Cav-1 deficient "lethal" tumor micro-environment, driving poor clinical outcome.