TUMORS MIGHT GROW FASTER AT NIGHT

They emerge at night, while we sleep unaware, growing and spreading out as quickly as they can. And they are deadly. In a surprise finding that was recently published in Nature Communications, Weizmann Institute of Science researchers showed that nighttime is the right time for cancer to grow and spread in the body. Their findings suggest that administering certain treatments in time with the body's day-night cycle could boost their efficiency.

This finding arose out of an investigation into the relationships between different receptors in the cell -- a complex network that we still do not completely understand. The receptors -- protein molecules on the cell's surface or within cells -- take in biochemical messages secreted by other cells and pass them on into the cell's interior. The scientists, led by Dr. Mattia Lauriola, a postdoctoral fellow in the research group of Prof. Yosef Yarden of the Weizmann Institute's Biological Regulation Department, working together with Prof. Eytan Domany of the Physics of Complex Systems Department, focused on two particular receptors. The first, the epidermal growth factor receptor, EGFR, promotes the growth and migration of cells, including cancer cells. The second binds to a steroid hormone called a glucocorticoid (GC). Glucocorticoids play a role in maintaining the body's energy levels during the day, as well as the metabolic exchange of materials. It is often called the stress hormone because its levels rise in stressful situations, rapidly bringing the body to a state of full alert.

With multiple receptors, the cell receives all sorts of messages at once, and some of these messages can take precedence over others. In the experiment, Lauriola and Yarden found that cell migration -- the activity promoted by the EGF receptor -- is suppressed when the GC receptor is bound to its steroid messenger.

Since the steroid levels peak during waking hours and drop off during sleep, the scientists asked how this might affect the second receptor -- EGFR. Checking the levels of this activity in mice, they found that there was a significant difference: This receptor is much more active during sleep and quiescent during waking hours.

How relevant are these findings for cancers, particularly those which use the EGF receptors to grow and spread? To find out, the scientists gave Lapatinib -- one of the new generation of cancer drugs -- to mouse models of cancer. This drug, used to treat breast cancer, is designed to inhibit EGFR, and thus to prevent the growth and migration of the cancer cells. In the experiment, they gave the mice the drug at different times of day. The results revealed significant differences between the sizes of tumors in the different groups of mice, depending on whether they had been given the drug during sleep or waking hours. The experimental findings suggest that it is indeed the rise and fall in the levels of the GC steroids over the course of 24 hours that hinder or enable the growth of the cancer.

The conclusion, say the scientists, is that it could be more efficient to administer certain anticancer drugs at night.

"It seems to be an issue of timing," says Yarden. "Cancer treatments are often administered in the daytime, just when the patient's body is suppressing the spread of the cancer on its own. What we propose is not a new treatment, but rather a new treatment schedule for some of the current drugs."

REPROGRAMMED CELLS GROW IN TO NEW BLOOD VESSELS

By transforming human scar cells into blood vessel cells, scientists at Houston Methodist may have discovered a new way to repair damaged tissue. The method, described in an upcoming issue of Circulation, appeared to improve blood flow, oxygenation, and nutrition to areas in need

Cardiovascular scientists at Houston Methodist, with colleagues at Stanford University and Cincinnati Children's Hospital, learned that fibroblasts -- cells that causes scarring and are plentiful throughout the human body -- can be coaxed into becoming endothelium, an entirely different type of adult cell that forms the lining of blood vessels.

"To our knowledge, this is the first time that trans-differentiation to a therapeutic cell type has been accomplished with a small molecules and proteins," said Houston Methodist Research Institute Department of Cardiovascular Sciences Chair John Cooke, M.D., Ph.D., the study's principal investigator. "In this particular case, we've found a way to turn fibroblasts into 'shapeshifters' nearly on command."

Cooke said the regenerative medicine approach provides proof-of-concept for a small molecule therapy that could one day be used to improve the healing of cardiovascular damage or other injuries.

Other research groups have managed to generate endothelial cells cells using infectious virus particles specially engineered to deliver gene-manipulating DNA to cells. The DNA encodes proteins called transcription factors to alter gene expression patterns in such a way that cells behave more like endothelial cells.

"There are problems with using viruses to transfer genes into cells," Cooke said. "This gene therapy approach is more complicated, and using viral vectors means the possibility of causing damage to the patient's chromosomes. We believe a small-molecule approach to transforming the cells will be far more feasible and safer for clinical therapies."

The new method described by Cooke and his coauthors starts with exposing fibroblasts to poly I:C (polyinosinic:polycytidylic acid), a small segment of double-stranded RNA that binds to the host cell receptor TLR3 (toll-like receptor 3), tricking the cells into reacting as if attacked by a virus. Cooke and coauthors reported to Cell in 2012 that fibroblasts' response to a viral attack -- or, in this case, a fake viral attack -- appears to be a vital step in diverting fibroblasts toward a new cell fate. After treatment with poly I:C, the researchers observed a reorganization of nuclear chromatin, allowing previously blocked-off genes to be expressed. The fibroblasts were then treated with factors, such as VEGF, that are known to compel less differentiated cells into becoming endothelial cells.

Cooke and his colleagues reported to Circulation that about 2 percent of the fibroblasts were transformed from fibroblasts into endothelial cells, a rate comparable to what other research groups have accomplished using viruses and gene therapy. But Cooke said preliminary, as-yet-unpublished work by his group suggests they may be able to achieve transformation rates as high as 15 percent.

"That's about where we think the yield of transformed cells needs to be," Cooke said. "You don't want all of the fibroblasts to be transformed -- fibroblasts perform a number of important functions, including making proteins that hold tissue together. Our approach will transform some of the scar cells into blood vessel cells that will provide blood flow to heal the injury."

In a second part of the study, the scientists introduced the transformed human cells into immune-deficient mice that had poor blood flow to their hind limbs. The human blood vessel cells increased the number of vessels in the mouse limb, improving circulation.

"The cells spontaneously form new blood vessels -- they self assemble," Cooke said. "Our transformed cells appear to form capillaries in vivo that join with the existing vessels in the animal, as we saw mouse red blood cells inside the vessels composed of human cells."

Cooke, who is also the director of the Houston Methodist Center for Cardiovascular Regeneration, said that figuring out how to manipulate adult cells of one type into becoming a completely different type of cell will be an important part of the development of regenerative medicine as a scientific and clinical field. Humans are generally unable to regenerate heavily damaged tissue, whereas other animals, such as some newts and flat worms, can regenerate entire lost limbs -- even entire heads.

"It is likely that modifications of this small molecule approach may be used to generate other body cells of therapeutic interest," Cooke said. "What we are seeing is evidence of the fluidity of cell fate with the proper stimulation. If we can understand the underlying pathways and how to manipulate them, we may very well learn how reawaken primordial mechanisms for regeneration that are active in lower vertebrates such as newts."

Cooke said more animal model studies are needed before his group begins clinical trials.

"One of the next steps will be to see if we can rescue an animal from an injury," Cooke said. "We want to know if the therapy enhances healing by increasing blood flow to tissues that may have been damaged by a loss of blood because of ischemia."

Surrender to the Roots and grow anew

She lay her troubled breath at the feet of the towering tree

Surrendering to the roots' thirst she releases her tears

Pouring over into the clay she spills her lost hope

letting her bones melt into the cups of mother earth

her flesh becomes dirt

her blood becomes water

her hardened pain becomes crystal

Turning in time all the mothers before her

listen, and let go

an avalanche of old wounds

and as they fell they carved spectacular

sculptures in the mountainside

transforming history into magnificence.