Jefferson researchers provide genetic evidence that antioxidants can help treat cancer

Jefferson Researchers Say Stress Fuels Cancer Growth, Provide Genetic Evidence That Antioxidants Can Help Treat It. Researchers from the Kimmel Cancer Center at Jefferson 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. All researchers from Thomas Jefferson University are affiliated with the Kimmel Cancer Center and declare no conflicts of interest. Prof. Michael Phillip Lisanti Professor of Cancer Biology.Professor of Medical Oncology. Professor of Biochemistry and Molecular Biology.Leader, Program in Molecular Biology and Genetics of Cancer Kimmel Cancer Center. Expertise and Research Interests; Caveolin-1 in Signaling, Cancer, and

Stem Cell Biology. The focus of my laboratory is to understand, at the molecular and cellular level, the role of caveolin-1 (Cav-1) in i) normal signaling and ii) pathogenic signaling during the development of human cancers. Our work over the last decade directly demonstrates that Cav-1 functions as a brake during signal transduction, akin to the behavior of other tumor suppressor genes. At the molecular level, Cav-1 contains a 20-amino acid region that we have termed the caveolin-scaffolding domain (CSD). This region functions as a modular protein domain that recognizes a well-defined caveolin-binding motif (CBM) present in many classes of signaling molecules, especially protein kinases. Thus, we have proposed that Cav-1, via its scaffolding domain, functions as a broad-spectrum kinase inhibitor. This explains Cav-1”s ability to act as a natural endogenous inhibitor of the p42/44-MAP kinase cascade, as well as other mitogenic signaling pathways, and initiate cell cycle arrest in the Go/G1 phase of the cell cycle. We are currently assessing the activity of a variety of caveolin-mimetic peptides that can be used as potential therapeutics. At the cellular level, we have recently focused on the mammary epithelial cell. We have shown that sporadic Cav-1 mutations occur at high frequency in human breast cancers (about one-third of estrogen-receptor positive patients harbor a dominant-negative Cav-1 mutation). Thus, we have used Cav-1 (-/-) mice (generated in my laboratory) as a model system to study the effect of loss-of-caveolin-function on the behavior of the mammary gland, both in vivo and ex vivo. Our results show that loss of Cav-1 in vivo results in mammary epithelial cell hyperplasia, a pre-malignant mammary lesion, and increased susceptibility towards mammary tumorigenesis. Ex vivo, our studies with primary cultures of Cav-1 (-/-) mammary epithelia show many

interesting phenotypes, such as increased proliferation, defects in 3D-lumen formation, growth-factor independence, as well as increased cell invasiveness and epithelial branching. At the molecular level, these phenotypes are due to the constitutive activation of key signaling pathways normally repressed by Cav-1, involving ERK-1/2, Smad-2/3, and Stat5a hyper-activation, as well as increased expression of estrogen receptor (ER-alpha), Cyclin D1, and MMP-2/9. Thus, loss-of-Cav-1 function provides a novel initiating mechanism for human cancers, as Cav-1 normally suppresses a plethora of pro-proliferative signaling pathways. We have also observed the Cav-1 (-/-) mice show hyper-proliferation in other epithelial compartments, such as the basal keratinocyte layer of the skin and in the crypts of the small intestine.Given that Cav-1 is highly expressed in terminally differentiated cells, its absence may lead to an increase in adult epithelial stem cell populations. This could explain some of the tumor suppressor effects of Cav-1, as it functions to maintain cells in a differentiated non-proliferative state. In direct support of this hypothesis, we have recently shown that Cav-1 (-/-) mice have increased levels of both mammary stem cells and intestinal crypt stem cells. These studies provide direct support for the idea that cancer stem cells should be targeted for caveolin-replacement therapy. News from: Thomas Jefferson University and Thomas Jefferson University Hospitals

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