Cancer

One way to tackle a tumor is to take aim at the metabolic reactions that fuel their growth. But a report in the February Cell Metabolism, a Cell Press Publication, shows that one metabolism-targeted cancer therapy will not fit all. That means that metabolic profiling will be essential for defining each cancer and choosing the best treatment accordingly, the researchers say.

The evidence comes from studies in mice showing that tumors' metabolic profiles vary based on the genes underlying a particular cancer and on the tissue of origin.

"Cancer research is dominated now by genomics and the hope that genetic fingerprints will allow us to guide therapy," said J. Michael Bishop of the University of California, San Francisco. "The issue is whether that is sufficient. We argue that it isn't because metabolic changes are complex and hard to predict. You may need to have the metabolome as well as the genome."

Just as a cancer genome refers to the complete set of genes, the metabolome refers to the complete set of metabolites in a given tumor.

The altered metabolism of tumors has been considered a target for anticancer therapy. For instance, tumors and cancer cell lines consume more glucose than normal cells do, a phenomenon known as the Warburg effect. There has often been the impression that such changes in metabolism are characteristic of cancers in general, but cancer is a genetically heterogeneous disease. The team led by Bishop and Mariia Yuneva wondered how metabolism might vary with the underlying genetic causes of cancer.

They found in mice that liver cancers driven by different cancer-causing genes (Myc versus Met) show differences in the metabolism of two major nutrients: glucose and glutamine. What's more, the metabolism of Myc-induced lung tumors is different from Myc-induced liver tumors.

"Our work shows that different tumors can have very different metabolisms," Yuneva said. "You can't generalize."

Bishop and Yuneva say their findings also highlight glutamine metabolism as a potential new target for therapy in some tumors, noting that the focus has been primarily on glucose metabolism. Interestingly, the data shows that a version of a glutaminase enzyme normally found in kidney cells turns up in cancerous liver cells. That means there might be a way to attack the metabolism of the cancer without damaging normal liver tissue.

"We shouldn't lose sight of the rather immediate therapeutic potential," Bishop said.

The researchers will continue to inventory metabolic variation in mouse models. Ultimately, they say it will be important to catalogue the metabolic variation in the much more complex, human setting

The future of disease diagnosis may lie in a "breathalyzer"-like technology currently under development at the University of Wisconsin-Madison.

New research published online in February in the peer-reviewed journal Metabolism demonstrates a simple but sensitive method that can distinguish normal and disease-state glucose metabolism by a quick assay of blood or exhaled air.

Many diseases, including diabetes, cancer, and infections, alter the body's metabolism in distinctive ways. The new work shows that these biochemical changes can be detected much sooner than typical symptoms would appear - even within a few hours - offering hope of early disease detection and diagnosis.

"With this methodology, we have advanced methods for tracing metabolic pathways that are perturbed in disease," says senior author Fariba Assadi-Porter, a UW-Madison biochemist and scientist at the Nuclear Magnetic Resonance Facility at Madison. "It's a cheaper, faster, and more sensitive method of diagnosis."

The researchers studied mice with metabolic symptoms similar to those seen in women with polycystic ovary syndrome (PCOS), an endocrine disorder that can cause a wide range of symptoms including infertility, ovarian cysts, and metabolic dysfunction. PCOS affects approximately 1 in 10 women but currently can only be diagnosed after puberty and by exclusion of all other likely diseases - a time-consuming and frustrating process for patients and doctors alike.

"The goal is to find a better way of diagnosing these women early on, before puberty, when the disease can be controlled by medication or exercise and diet, and to prevent these women from getting metabolic syndromes like diabetes, obesity, and associated problems like heart disease," Assadi-Porter says.

The researchers were able to detect distinct metabolic changes in the mice by measuring the isotopic signatures of carbon-containing metabolic byproducts in the blood or breath. They injected glucose containing a single atom of the heavier isotope carbon-13 to trace which metabolic pathways were most active in the sick or healthy mice. Within minutes, they could measure changes in the ratio of carbon-12 to carbon-13 in the carbon dioxide exhaled by the mice, says co-author Warren Porter, a UW-Madison professor of zoology.

One advantage of the approach is that it surveys the workings of the entire body with a single measure. In addition to simplifying diagnosis, it could also provide rapid feedback about the effectiveness of treatments.

"The pattern of these ratios in blood or breath is different for different diseases - for example cancer, diabetes, or obesity - which makes this applicable to a wide range of diseases," explains Assadi-Porter.

The technology relies on the fact that the body uses different sources to produce energy under different conditions. "Your body changes its fuel source. When we're healthy we use the food that we eat," Porter says. "When we get sick, the immune system takes over the body and starts tearing apart proteins to make antibodies and use them as an energy source."

That shift from sugars to proteins engages different biochemical pathways in the body, resulting in distinct changes in the carbon isotopes that show up in exhaled carbon dioxide. If detected quickly, these changes may signal the earliest stages of disease.

The researchers found similar patterns using two independent assays - nuclear magnetic resonance spectroscopy on blood serum and cavity ring-down spectroscopy on exhaled breath. The breath-based method is particularly exciting, they say, because it is non-invasive and even more sensitive than the blood-based assays.

In the mice, the techniques were sensitive enough to detect statistically significant differences between even very small populations of healthy and sick mice.

The current cavity ring-down spectroscopy analysis uses a machine about the size of a shoebox, but the researchers envision a small, hand-held "breathalyzer" that could easily be taken into rural or remote areas. They co-founded a company, Isomark, LLC, to develop the technology and its applications. They hope to explore the underlying biology of disease and better understand whether the distinctive biochemical changes they can observe are causative or side effects.

A University of Minnesota-led research team has proposed a mechanism for the control of whether embryonic stem cells continue to proliferate and stay stem cells, or differentiate into adult cells like brain, liver or skin.

The work has implications in two areas. In cancer treatment, it is desirable to inhibit cell proliferation. But to grow adult stem cells for transplantation to victims of injury or disease, it would be desirable to sustain proliferation until a sufficient number of cells have been produced to make a usable organ or tissue.

The study gives researchers a handle on how those two competing processes might be controlled. It was performed at the university's Hormel Institute in Austin, Minn., using mouse stem cells. The researchers, led by Hormel Institute Executive Director Zigang Dong and Associate Director Ann M. Bode, have published a report in the journal Nature: Structure and Molecular Biology.

"This is breakthrough research and provides the molecular basis for development of regenerative medicine," said Dong. "This research will aid in the development of the next generation of drugs that make repairs and regeneration within the body possible following damage by such factors as cancer, aging, heart disease, diabetes, or paralysis caused by traumatic injury."

The mechanism centers on a protein called Klf4, which is found in embryonic stem cells and whose activities include keeping those cells dividing and proliferating rather than differentiating. That is, Klf4 maintains the character of the stem cells; this process is called self-renewal. The researchers discovered that two enzymes, called ERK1 and ERK2, inactivate Klf; this allows the cells to begin differentiating into adult cells.

The two enzymes are part of a "bucket brigade" of signals that starts when a chemical messenger arrives from outside the embryonic stem cells. Chemical messages are passed to inside the cells, resulting in, among other things, the two enzymes swinging into action.

The researchers also discovered how the enzymes control Klf4. They attach a small molecule - phosphate, consisting of phosphorus and oxygen - to Klf4. This "tag" marks it for destruction by the cellular machinery that recycles proteins.

Further, they found that suppressing the activity of the two enzymes allows the stem cells to maintain their self-renewal and resist differentiation. Taken together, their findings paint a picture of the ERK1 and ERK2 enzymes as major players in deciding the future of embryonic stem cells--and potentially cancer cells, whose rapid growth mirrors the behavior of the stem cells.

Klf4 is one of several factors used to reprogram certain adult skin cells to become a form of stem cells called iPS (induced pluripotent stem) cells, which behave similarly to embryonic stem cells. Also, many studies have shown that Klf4 can either activate or repress the functioning of genes and, in certain contexts, act as either an oncogene (that promotes cancer) or a tumor suppressor. Given these and their own findings reported here, the Hormel Institute researchers suggest that the self-renewal program of cancer cells might resemble that of embryonic stem cells