Study Shows How the Nanog Protein Promotes Growth of Head and Neck Cancer

A new study led by researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC–James) has identified a biochemical pathway in cancer stem cells that is essential for promoting head and neck cancer.

The study shows that a protein called Nanog, which is normally active in embryonic stem cells, promotes the growth of cancer stem cells in head and neck cancer. The findings provide information essential for designing novel targeted drugs that might improve the treatment of head and neck cancer.

Normally, Nanog helps healthy embryonic stem cells maintain their undifferentiated, uncommitted (i.e., pluripotent) state. But recent evidence suggests that Nanog promotes tumor growth by stimulating the proliferation of cancer stem cells.

“This study defines a signaling axis that is essential for head and neck cancer progression, and our findings show that this axis may be disrupted at three key steps,” says principal investigator Quintin Pan, PhD, associate professor of otolaryngology at the OSUCCC – James. “Targeted drugs that are designed to inhibit any or all of these three steps might greatly improve the treatment of head and neck cancer.”

The findings were published in a recent issue of the journal Oncogene.

Specifically, the study shows that an enzyme called “protein kinase C-epsilon” (PKCepsilon) adds energy-packing phosphate groups to the Nanog molecule. This phosphorylation of Nanog stabilizes and activates the molecule.

It also triggers a series of events: Two Nanog molecules bind together, and these are joined by a third “co-activating” molecule called p300. This molecular complex then binds to the promoter region of a gene called Bmi1, an event that increases the expression of the gene. This, in turn, stimulates proliferation of cancer stem cells.

“Our work shows that the PKCepsilon/Nanog/Bmi1 signaling axis is essential to promote head and neck cancer,” Pan says. “And it provides initial evidence that the development of inhibitors that block critical points in this axis might yield a potent collection of targeted anti-cancer therapeutics that could be valuable for the treatment of head and neck cancer.”

(Image: Gray’s Anatomy of the Human Body)

What are stem cells?

In a paper published in Cell yesterday, scientists from the US and Thailand have, for the first time, successfully produced embryonic stem cells from human skin cells.

That sounds interesting, but what are stem cells and where do they come from?

If you take a limb from a rose tree, and put it in soil, it will grow into a thriving bush.

But you might say: “Plants are special. This won’t work with animals.” Or will it? If you cut off a lizard’s tail, a new tail may grow. A lobster can grow back a lost claw.

There is a special type of flatworm that can be cut in half, again and again hundreds of times, and each half grows back into a full worm.

Similarly, if you cut out half a human liver, it will grow back. The story of Prometheus, whose liver was eaten away by eagles and regrew each day, suggests that the Greeks of ancient times knew about regeneration of organs.

This sort of regeneration is attributed to special cells called “stem cells”.

Reprogramming the workers

Most of our cells are like many professional workers – they are hardened in their ways and can’t manage career changes.

Blood cells carry oxygen or fight disease, muscle cells expand and contract to move us around, nerve cells carry signals, skin cells form a protective layer over our bodies, and structures made up of kidney cells filter our blood.

The cells of most organs or tissues are referred to as “terminally differentiated” cells. They have specialised, and many won’t divide again. If they are damaged or die they will disappear. This is very important.

Although we feel like we grow a lot after we are born, we really only double in size two or three times and most of our cells don’t divide much.

If they did we would be at great risk from cancer – the uncontrolled doubling of cells at the wrong time.

We have a lot of cells and it is important that none of them run out of control.

But some cells can double to renew themselves and can also differentiate and give rise to specialised progeny.

These are the stem cells. We need them to produce new skin to replace damaged skin cells. Similarly, we need them in our guts to replace damaged cells on the surface of our intestines.

Our blood cells also get worn out as they race around our bodies so we have blood stem cells that divide and replace themselves. They also differentiate to form the different types of white and red blood cells we need.

Australian researchers identified stem cells in the breast that can proliferate and form a complete functioning breast. There are also stem cells in the brain and in the heart.

While stem cells tend to be very rare, they exist in many of our organs.

Types of stem cells

The ultimate stem cells are embryonic stem cells.

These cells are found in the inner cell mass of the early embryo and are referred to as “totipotent” since they have the ability to form every cell that is needed in the growing embryo.

They can be extracted from the early embryo and grown in culture dishes.

They can also be genetically modified by the addition of DNA, then injected back into other embryos or into adult animals where find their way into localities that suit them and replace themselves by duplication or differentiate into other cell types that may be needed. For a long time this type of work had been done primarily in laboratory mice.

The techniques in yesterday’s Cell paper involved injecting the nucleus from a human skin cell into a human egg (the nucleus of which has been destroyed) then growing the resulting embryo until the inner cell mass cells could be harvested.

The method may still be controversial because it uses unfertilised eggs, but many people will regard it as preferable to using human embryos. And there are other interesting methods for making stem cells.

Somatic cells to stem cells

It is also possible to convert skin cells, and indeed many different terminally differentiated cells, back into what are called “induced pluripotent stem cells” or iPS cells.

One uses the “magic four” or “OKSM” set of DNA-binding proteins that govern normal stem cell biology:

• Octamer-binding transcription factor 4 (OCT4)
• Kruppel-like factor 4 (KLF4)
• SRY (sex determining region Y)-box 2 (SOX2)
• cellular myelocytomatosis virus-like gene (MYC)

In 2012 Shinya Yamanaka won the Nobel Prize for discovering how to convert normal cells into iPS cells using the OKSM regulators to turn on and off the right genes and convert skin cells into stem cells.

Researchers are continuing to investigate whether iPS cells have the same therapeutic potential as embryo derived stem cells.

It is hoped that stem cells may provide therapies for people suffering from degenerative diseases.

Skin cells could be taken from a patient, converted to stem cells, and then these could be injected back into the damaged organ.

Ideally, they would repopulate the damaged organ with new cells.

So why doesn’t this happen in normal biology? Why aren’t our own heart stem cells busy trying to repair broken hearts?

They may be but our natural supply of stem cells is limited and presumably insufficient to tackle severe disease.

So why don’t we just have more stem cells in our bodies?

The down side of having too many stem cells may be cancer.

Stem cells share a number of features with cancer cells – both are able to self-renew and double without limit.

One theory about cancer holds that the disease most often originates not from terminally differentiated cells but from one of the small number of stem cells in the relevant tissues.

The obvious concern about using stem cells for therapy is that injecting too many could increase the chances that some of these cells would proliferate beyond control, and ultimately give rise to cancer.

Stem cell therapy for regenerative medicine is an exciting idea.

Every day we are learning more about stem cells – how to purify or make them, and how to grow them in culture and direct them down particular pathways to repopulate different organs.

Future research will assess the risks and how effective they can be in experimental systems and ultimately in human patients.

Temple scientists find cancer-causing virus in the brain, potential connection to epilepsy

Researchers at Shriner’s Hospital Pediatric Research Center at the Temple University School of Medicine, and the University of Pennsylvania have evidence linking the human papillomavirus 16 (HPV16) – the most common cause of cervical cancer – to a common form of childhood epilepsy. They have shown for the first time that HPV16 may be present in the human brain, and found that when they added a viral protein to the brains of fetal mice, the mice all demonstrated the same developmental problems in the cerebral cortex associated with this type of epilepsy, called focal cortical dysplasia type IIB (FCDIIB). The findings suggest that the virus could play a role in the development of epilepsy.

The results also mean that doctors may have to re-think their approach to treating this type of epilepsy, and perhaps consider other therapeutic options related to HPV, an infectious disease.

"This is a novel mechanism, and it fills a gap in our understanding about the development of congenital brain malformations," said Peter Crino, MD, PhD, Professor of Neurology at Temple University School of Medicine, and a member of Shriner’s Hospital Pediatric Research Center, and the senior author of a recent report in the Annals of Neurology.

"If our data are correct, future treatment of cortical dysplasia could include targeted therapy against HPV16 infection, with the goal of halting seizures. Identifying an infectious agent as part of the pathogenesis of brain malformations could open up an array of new therapeutic approaches against various forms of epilepsy."

(Image: ASME.org)

New findings on mortality of individuals with schizophrenia

A new study from Lund University in Sweden shows that the average life expectancy of men and women with schizophrenia is 15 years and 12 years shorter respectively than for those who do not suffer from the disease. The study has been carried out in collaboration with Stanford University in the US.

The reasons why people with schizophrenia have a shorter life expectancy have previously been unknown, but have been much discussed in recent years. The research report that has now been published shows that individuals with schizophrenia are more likely to die of two major diseases.

The study followed over six million individuals from 2003 to 2009, of whom 8,277 had schizophrenia, by analysing the Swedish population and health registers.

The results show that people with schizophrenia had contact with the health service over twice as often as people without the condition, but they were no more likely to be diagnosed with cardiovascular disease or cancer.

“Yet we saw an opposing pattern of death from these diseases. It is clear that the health service is failing to diagnose cardiovascular disease and cancer in these patients”, says Jan Sundquist, general practitioner and professor at the Centre for Primary Health Care Research at Lund University.

Women with schizophrenia were 3.3 times more likely to die of cardiovascular disease and men 2.2 times more likely. Women with schizophrenia were 1.7 times more likely to die of cancer while men were 1.4 times more likely, compared with those without schizophrenia. Only 26.3% of the men with schizophrenia who died of cardiovascular disease had been diagnosed before their deaths, compared with 43.7% of the men who did not have schizophrenia.

“It is unacceptable that such a vulnerable group of people, who also have extensive documented contact with the health service, should die prematurely of conditions such as cardiovascular disease and cancer – diseases that should be preventable”, says Professor Sundquist. “A much greater degree of diagnostic and preventive measures could be put in place for this vulnerable group in our society.”

Four-stranded ‘quadruple helix’ DNA structure proven to exist in human cells

In 1953, Cambridge researchers Watson and Crick published a paper describing the interweaving ‘double helix’ DNA structure – the chemical code for all life.

Now, in the year of that scientific landmark’s 60^th Anniversary, Cambridge researchers have published a paper proving that four-stranded ‘quadruple helix’ DNA structures – known as G-quadruplexes – also exist within the human genome. They form in regions of DNA that are rich in the building block guanine, usually abbreviated to ‘G’.

The findings mark the culmination of over 10 years investigation by scientists to show these complex structures in vivo – in living human cells – working from the hypothetical, through computational modelling to synthetic lab experiments and finally the identification in human cancer cells using fluorescent biomarkers.

The research, published in Nature Chemistry and funded by Cancer Research UK, goes on to show clear links between concentrations of four-stranded quadruplexes and the process of DNA replication, which is pivotal to cell division and production.

New immune therapy successfully treats brain tumors in mice

Using an artificial protein that stimulates the body’s natural immune system to fight cancer, a research team at Duke Medicine has engineered a lethal weapon that kills brain tumors in mice while sparing other tissue. If it can be shown to work in humans, it would overcome a major obstacle that has hampered the effectiveness of immune-based therapies.

The protein is manufactured with two arms – one that exclusively binds to tumor cells and another that snags the body’s fighter T-cells, spurring an attack on the tumor. In six out of eight mice with brain tumors, the treatment resulted in cures, according to findings published Dec. 17, 2012, in the Proceedings of the National Academy of Sciences.

"This work represents a revival of a somewhat old concept that targeting cancer with tumor-specific antigens may well be the most effective way to treat cancer without toxicity," said senior author John H. Sampson, M.D., PhD, a neurosurgeon at The Preston Robert Tisch Brain Tumor Center at Duke. "But there have been problems with that approach, especially for brain tumors. Our therapeutic agent is exciting, because it acts like Velcro to bind T-cells to tumor cells and induces them to kill without any negative effects on surrounding normal tissues."

Sampson and colleagues focused on the immune approach in brain tumors, which are notoriously difficult to treat. Despite surgery, radiation and chemotherapy, glioblastomas are universally fatal, with a median survival of 15 months.

Immunotherapies, in which the body’s B-cells and T-cells are triggered to attack tumors, have shown promise in treating brain and other cancers, but have been problematic in clinical use. Treatments have been difficult to administer at therapeutic doses, or have spurred side effects in which the immune system also attacks healthy tissue and organs.

Working to overcome those pitfalls, the Duke-led researchers designed a kind of connector - an artificial protein called a bispecific T-cell engager, or BiTE – that tethers the tumor to its killer. Their newly engineered protein includes fractions of two separate antibodies, one that recruits and engages the body’s fighter T-cells and one that expressly homes in on an antigen known as EGFRvIII, which only occurs in cancers.

Once connected via the new bispecific antibody, the T-cells recognize the tumor as an invader, and mount an attack. Normal tissue, which does not carry the tumor antigen, is left unscathed.

New form of cell division found

Researchers at the University of Wisconsin Carbone Cancer Center have discovered a new form of cell division in human cells.

They believe it serves as a natural back-up mechanism during faulty cell division, preventing some cells from going down a path that can lead to cancer.

"If we could promote this new form of cell division, which we call klerokinesis, we may be able to prevent some cancers from developing," says lead researcher Dr. Mark Burkard, an assistant professor of hematology-oncology in the department of medicine at the UW School of Medicine and Public Health.

Burkard presented the finding on Monday, Dec. 17 at the annual meeting of the American Society for Cell Biology in San Francisco.

(View a short video of the process here)

Metabolic Protein Launches Sugar Feast That Nurtures Brain Tumors

Researchers at The University of Texas MD Anderson Cancer Center have tracked down a cancer-promoting protein’s pathway into the cell nucleus and discovered how, once there, it fires up a glucose metabolism pathway on which brain tumors thrive.

They also found a vital spot along the protein’s journey that can be attacked with a type of drug not yet deployed against glioblastoma multiforme, the most common and lethal form of brain cancer. Published online by Nature Cell Biology, the paper further illuminates the importance of pyruvate kinase M2 (PKM2) in cancer development and progression.

"PKM2 is very active during infancy, when you want rapid cell growth, and eventually it turns off. Tumor cells turn PKM2 back on - it’s overexpressed in many types of cancer," said Zhimin Lu, M.D., Ph.D., the paper’s senior author and an associate professor in MD Anderson’s Department of Neuro-Oncology.

Lu and colleagues showed earlier this year that PKM2 in the nucleus also activates a variety of genes involved in cell division. The latest paper shows how it triggers aerobic glycolysis, processing glucose into energy, also known as the Warburg effect, upon which many types of solid tumors rely to survive and grow.

"PKM2 must get to the nucleus to activate genes involved in cell proliferation and the Warburg effect," Lu said. "If we can keep it out of the nucleus, we can block both of those cancer-promoting pathways. PKM2 could be an Achilles’ heel for cancer."

By pinpointing the complicated steps necessary for PKM2 to penetrate the nucleus, Lu and colleagues found a potentially druggable target that could keep the protein locked in the cell’s cytoplasm.

(Image Credit: Wikimedia Commons)