Wednesday, 28 June 2017

Trashes of Dead Cancer Cells May Spark Cancer To Spread: Study

Cell-free chromatin from dying cancer cells may be the fundamental means by which cancer spreads locally and metastasizes systemically.

By Ratneshwar Thakur   Published in The Hawk

(Tannistha Saha; Prof. Indraneel Mittra ; Sahid Chaudhary)

Across the world, researchers have been trying to develop therapeutics, especially to kill the cancer cells. However, in a recent study it has been shown that left over of dead cancer cells also have potential to spread the cancers, which makes the therapeutic scenario nastiest because most of the available treatments involve killing of cancer cells by various means.

Several hundred billion to a trillion cells die in the body every day and a similar number is regenerated to maintain homeostasis. A considerable amount of fragmented nucleic acids (DNA) from the dying cells enter into the extracellular compartment. Although the liver clears out the nucleic acid debris, however, it has been reported that when tumour cells die, especially after therapeutic interventions, their fragmented chromatin have been detected in circulation. There is much current interest in using the presence of circulating DNA for therapy-response predictions in cancer.

“The motivations for this study came from our earlier findings that circulating nucleic acids, especially circulating chromatin fragments, can get integrated into healthy cell genomes and induce DNA damage and apoptotic responses,” says Prof. Indraneel Mittra, Tata Memorial Centre, Advanced Centre for Treatment, Research & Education in Cancer (ACTREC).

Although the presence of chromatin (DNA) in circulation has been known for a long time, Prof. Mittra’s group were the first to demonstrate that these fragmented particles are biologically active molecules.

In this study, Chromatin isolated from serum of cancer patients and healthy volunteers were shown to readily enter into healthy cells in culture, integrate into their genomes to induce DNA damage and apoptotic response in the recipient cells. Intravenous injection of human cell-free chromatin into mice resulted in the genomic integration of human DNA in vital organs of mice. “Throughout our studies, we found cell-free chromatin from cancer patients to be more active than that from healthy volunteers,” said Prof. Mittra. This study was published in the journal “Cell Death Discovery.”

Prof. Mittra and his team believe that release of cell-free chromatin from dying cancer cells could integrate into surrounding healthy cells and damage their DNA and induce an inflammatory response. DNA damage and inflammation are potent drivers of oncogenic transformation leading us to hypothesize that cell-free chromatin from dying cancer cells may be the fundamental means by which cancer spreads locally and metastasizes systemically.

This new study challenges the entrenched theory of cancer metastasis that living circulating tumour cells lodge in distant organs and grow to form secondary tumours. “This study is the culmination of over 15-years of research which opens up an entirely new form of biology i.e., that of “DNA outside the cell – a new paradigm in biomedical research,” said the Investigators. 

“Our study suggests about re-thinking of the way we treat cancer which is to “kill” cancer cells at any cost. The result may be that the more we kill, the more we may be spreading cancer. Therefore, future research should be focused on destroying/degrading the chromatin fragments that emerge from dead cancer cells thereby preventing further spread,” Prof. Mittra explained about the future perspectives of his finding.

Tuesday, 13 June 2017

Scientists Shed Light On How Cancer Stem Cells Override Apoptotic Cell Death

Indian origin Researchers from The University of Texas MD Anderson Cancer Center demonstrated the dual role of VHL in apoptotic cancer stem cells that determine life and death decisions through the blebbishield emergency program.

 Ratneshwar Thakur Published in The Hawk

(Image Credit: Dr. Goodwin G. Jinesh)

In our body, somatic cells are born by mitosis and almost all will die by apoptosis. Apoptosis is a physiological process in our body where the death of cells occurs as a normal and controlled part of an organism's growth or development. Researchers have been trying to develop the therapy to promote the death of cancer cells without causing damage to normal cells. Understanding of how cancer cells actually manage to escape apoptosis could be an answer to selectively kill these cancer cells.

Indian origin researchers Dr. Goodwin G. Jinesh, PhD., and Prof. Ashish M. Kamat, MD, MBBS, FACS, from Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA have demonstrated that cancer stem cells override apoptotic death after commencement of apoptosis by blebbishield emergency program. The study was published in the journal “Cell Death Discovery”.

Blebbishield emergency program constructs blebbishields from apoptotic bodies by stimulating robust dynamin-dependent endocytosis to drive cellular transformation. “The role of VHL in endocytosis and metastasis sparked the idea that VHL could be involved in blebbishield emergency program, despite it is a well-known tumor suppressor in renal cell carcinoma,” said the Investigators.

VHL is a well-known tumor suppressor and it often behaves like oncogene and the reasons behind such contradictory functions were not clearly demonstrated to date. The investigators have shown for the first time that the isoform length matters i.e., the short p19-VHL isoform acts as an oncogene by interacting specifically with RalBP1 during blebbishield formation, whereas the expression of long isoform p30-VHL correlates with inhibition of blebbishield emergency program. The researchers also tracked the VHL target genes that are differentially expressed during blebbishield emergency program and find that an oxidative stress management gene network is in action to execute blebbishield emergency program.

The Recent study suggests that improved understanding of the endocytosis regulators acting during the blebbishield emergency program is necessary to shed light on human tumorigenesis and develop therapeutics to block blebbishield emergency program.

VHL is a gene that is disabled in renal cell carcinoma. In the age of CRISPR/Cas9 human gene-editing, the recent study sheds light on the fact that which isoform one should opt for CRISPR/Cas9 editing and which isoform shouldn't be opted. The researchers are positive that, this will be useful in multiple cancer types including bladder cancer.

Since VHL is demonstrated as both tumor suppressor gene and oncogene promoting metastasis in an isoform-dependent manner, the isoform length gains wide medical and scientific interest to aid the development of cancer therapies.

Saturday, 3 June 2017

Methylene Blue: A Promising Anti-Aging Agent for Human skin

Experiments with human skin cells and the simulated skin tissues suggest that Methylene Blue has a great potential for skin care.

By Ratneshwar Thakur Published in The Hawk

  (These cross-section images show three-dimensional human skin models made of living skin cells. Untreated model skin (left panel) shows a thinner dermis layer (black arrow) compared with model skin treated with the antioxidant methylene blue (right panel).

The researchers, from the University of Maryland (UMD), have demonstrated that the chemical—an antioxidant called methylene blue (MB) — has a great potential for skin care and it could slow or reverse several well-known signs of aging. The study was published in the journal “Scientific Reports” on May 30, 2017. 

Oxidative stress is the major cause of skin aging that includes wrinkles, pigmentation, and weakened wound healing ability. Application of antioxidants in skin care is well accepted as an effective approach to delay the skin aging process. Oxidative stress is basically an imbalance between the production of free radicals and the ability of the body to counteract or detoxify their harmful effects through neutralization by antioxidants. 

“Our work suggests that methylene blue could be a powerful antioxidant for use in skin care products,” said Dr. Kan Cao, Associate Professor of Cell Biology and Molecular Genetics at UMD. “The effects we are seeing are not temporary. Methylene blue appears to make fundamental, long-term changes to skin cells.”

In this study, MB was tested on skin cells, from healthy middle-aged donors, as well as those diagnosed with progeria—a rare genetic condition that causes a person to age prematurely. The researchers have also compared three other known antioxidants N-Acetyl-L-Cysteine (NAC), MitoQ and MitoTEMPO (mTEM) along with Methylene Blue. Interestingly, MB was the most effective in improving several age-related symptoms.

The investigators speculate that MB exerts its potent antioxidant effects through multiple pathways like blocking oxidant production and boosting antioxidant defense. MB possesses unique properties, including a wide solubility in both water and organic solvents. These properties allow MB to enter easily through bilayer membranes of skin cells and reach different cellular compartments.

“I was encouraged and excited to see skin fibroblasts, derived from individuals more than 80 years old, grow much better in methylene blue-containing medium with reduced cellular senescence markers,” said Dr. Zheng-Mei Xiong, lead author of the study and an Assistant Professor of Cell Biology and Molecular Genetics at UMD. 

One of the most important functions of the skin is to provide a barrier to protect the body against environmental insults and to prevent excess water evaporation.

Next, UMD Investigators have performed several experiments on the simulated skin (a system developed by Cao and Xiong)—a three-dimensional model made of living skin cells—includes all the major layers and structures of skin tissue, with the exception of hair follicles and sweat glands. “This system allowed us to test a range of aging symptoms that we can’t replicate in cultured cells alone,” Dr. Cao said. “Most surprisingly, we saw that model skin treated with methylene blue retained more water and increased in thickness—both of which are features typical of younger skin.”

“We have already begun formulating cosmetics that contain methylene blue. Now we are looking to translate this into marketable products,” Dr. Cao said. “We are also very excited to develop the three-dimensional skin model system. Perhaps down the road, we can customize the system with bio-printing, such that we might be able to use a patient’s own cells to provide a tailor-made testing platform specific to their needs.”