David Kirkpatrick

March 8, 2010

Cancer killing nanotech assassins

Nanotechnology is proving to have many medical applications, and the bulk of those apps are in cancer research. Here’s the latest from Cornell.

The release:

Like little golden assassins, ‘smart’ nanoparticles identify, target and kill cancer cells

ITHACA, N.Y. – Another weapon in the arsenal against cancer: Nanoparticles that identify, target and kill specific cancer cells while leaving healthy cells alone.

Led by Carl Batt, the Liberty Hyde Bailey Professor of Food Science, the researchers synthesized nanoparticles – shaped something like a dumbbell – made of gold sandwiched between two pieces of iron oxide. They then attached antibodies, which target a molecule found only in colorectal cancer cells, to the particles. Once bound, the nanoparticles are engulfed by the cancer cells.

To kill the cells, the researchers use a near-infrared laser, which is a wavelength that doesn’t harm normal tissue at the levels used, but the radiation is absorbed by the gold in the nanoparticles. This causes the cancer cells to heat up and die.

“This is a so-called ‘smart’ therapy,” Batt said. “To be a smart therapy, it should be targeted, and it should have some ability to be activated only when it’s there and then kills just the cancer cells.”

The goal, said lead author and biomedical graduate student Dickson Kirui, is to improve the technology and make it suitable for testing in a human clinical trial. The researchers are now working on a similar experiment targeting prostate cancer cells.

“If, down the line, you could clinically just target the cancer cells, you could then spare the health surrounding cells from being harmed – that is the critical thing,” Kirui said.

Gold has potential as a material key to fighting cancer in future smart therapies. It is biocompatible, inert and relatively easy to tweak chemically. By changing the size and shape of the gold particle, Kirui and colleagues can tune them to respond to different wavelengths of energy.

Once taken up by the researchers’ gold particles, the cancer cells are destroyed by heat – just a few degrees above normal body temperature – while the surrounding tissue is left unharmed. Such a low-power laser does not have any effect on surrounding cells because that particular wavelength does not heat up cells if they are not loaded up with nanoparticles, the researchers explained.

Using iron oxide – which is basically rust – as the other parts of the particles might one day allow scientists to also track the progress of cancer treatments using magnetic resonance imaging, Kirui said, by taking advantage of the particles’ magnetic properties.

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The research was funded by the Sloan Foundation and the Ludwig Institute for Cancer Research, which has been a partner with Cornell since 1999 to bring laboratory work to clinical testing. The research is reported in the Feb. 15 online edition of the journal Nanotechnology.

Text by Anne Ju, Cornell Chronicle

December 5, 2008

News on dormant adult stem cells

The release:

Dormant stem cells for emergencies

Many specialized cells, such as in the skin, intestinal mucosa or blood, have a lifespan of only a few days. For these tissues to function, a steady replenishment of specialized cells is indispensable. This is the task of so-called “adult” stem cells also known as tissue stem cells.

Stem cells have two main characteristics: First, they are able to differentiate into all the different cell types that make up their respective tissue – a property called pluripotency. Second, they need to renew themselves in order to be able to supply new specialized tissue cells throughout life. These processes have best been studied in mouse bone marrow.

Up to now, scientists have assumed that adult stem cells have a low division rate. According to theory, they thus protect their DNA from mutations, which happen particularly during cell division and can lead to transformation into tumor stem cells. However, the actual number of divisions of a blood stem cell throughout an organism’s lifespan has remained unknown.

Professor Dr. Andreas Trumpp and Dr. Anne Wilson have now discovered a group of stem cells in mouse bone marrow that remain in a kind of dormancy almost throughout life. Trumpp, who has been head of the Cell Biology Division at DKFZ since summer 2008, had carried out these studies at the Ecole Polytechnique Fédérale in Lausanne, Switzerland, jointly with colleagues at the Ludwig Institute for Cancer Research located in the same city.

The scientists labeled the genetic material of all mouse blood cells and subsequently investigated how long this label is retained. With each division, the genetic material is apportioned to the daughter cells and, thus, the labeling dilutes. During these studies, the investigators discovered the dormant stem cells which divide only about five times throughout the life of a mouse. Translated to humans, this would correspond to only one cell division in 18 years. Most of the time, these cells, which constitute no more than about 15 percent of the whole stem cell population, remain in a kind of dormancy with very low metabolism. In contrast, stem cells of the larger group, the “active” stem cells, divide continuously about once a month.

However, in an emergency such as an injury of the bone marrow or if the messenger substance G-CSF is released, the dormant cell population awakes. Once awakened, it shows the highest potential for self-renewal ever to be observed in stem cells. If transplanted into irradiated mice, these cells replace the destroyed bone marrow and restore the whole hematopoietic system. It is possible to isolate new dormant stem cells from the transplanted animals and these cells are able to replace bone marrow again – this can be done several times in a row. The situation is different with “active” stem cells, where bone marrow replacement can successfully be carried out only once.

“We believe that the sleeping stem cells play almost no role in a healthy organism,” Trumpp explains. “The body keeps its most potent stem cells as a secret reserve for emergencies and hides them in caves in the bone marrow, also called niches. If the bone marrow is damaged, they immediately start dividing daily, because new blood cells are needed quickly.” Once the original cell count is restored and the bone marrow is repaired, these stem cells go back to deep sleep. The larger population of “active” stem cells, however, keeps up the physiological balance of blood cells in the normal healthy state.

Andreas Trumpp expects that these results may give valuable impetus to our understanding of cancer stem cells: “Cancer stem cells, too, probably remain in a dormant state most of the time – we think that this is one of the reasons why they are resistant to many kinds of chemotherapy that target rapidly growing cells. If we were able to wake up these sleepers before a patient receives treatment, it might be possible to also eliminate cancer stem cells for the first time and, thus, to treat the disease much more effectively by destroying the supply basis.”

In a second article*, Dr. Elisa Laurenti from Trumpp’s team shows that the two cancer genes c-Myc and N-Myc play a vital role in the functioning of stem cells. The two genes provide the blueprints for what are called transcription factors, which in turn regulate the activity of other genes and are overactive particularly in cancer cells. If both c-Myc and N-Myc are switched off at the same time in mice, the animals quickly start suffering from a general lack of blood cells and quickly die.

The two genes are not only responsible for survival of nearly all blood cells, but they also jointly control the two prime characteristics of stem cells – the capability of self-renewal and the potential to produce differentiated blood cells. This result is not only relevant for our understanding of stem cells, but it also explains the damage that can be caused by overactive Myc genes. Trumpp explains: “In tumors, too, c-Myc and N-Myc are presumably responsible for the self-renewal of cancer stem cells and, thus, for uncontrolled growth.”

 

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Anne Wilson; Gabriela Oser; Richard van der Wath; William Blanco; Elisa Laurenti; Maike Jaworski; Cyrille Durant; Leonid Eshkind; Ernesto Bockamp; Pietro Lio; Robson MacDonald, and Andreas Trumpp: Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair. CELL 2008, DOI 10.1016/j.cell.2008.10.048

*Elisa Laurenti, Barbara Varnum-Finney, Anne Wilson, Isabel Ferrero, William E. Blanco-Bose, Armin Ehninger, Paul S. Knoepfler, Pei-Feng Cheng, H. Robson MacDonald, Robert N. Eisenman, Irwin D. Bernstein, and Andreas Trumpp: Hematopoietic Stem Cell Function and Survival Depend on c-Myc and N-Myc Activity. CELL Stem Cell 2008, DOI 10.1016/j.stem.2008.09.005

The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) is the largest biomedical research institute in Germany and is a member of the Helmholtz Association of National Research Centers. More than 2,000 staff members, including 850 scientists, are investigating the mechanisms of cancer and are working to identify cancer risk factors. They provide the foundations for developing novel approaches in the prevention, diagnosis , and treatment of cancer. In addition, the staff of the Cancer Information Service (KID) offers information about the widespread disease of cancer for patients, their families, and the general public. The Center is funded by the German Federal Ministry of Education and Research (90%) and the State of Baden-Württemberg (10%).