Study helps explain fundamental process of tumor growth

Nearly 80 years ago, scientist Otto Warburg observed that cancer cells perform energy metabolism in a way that is different from normal adult cells. Many decades later, this observation was exploited by clinicians to better visualize tumors using PET (positron emission technology) imaging. But it has not been known exactly how tumor cells perform this alternate metabolic feat, nor was it known if this process was essential for tumor growth.

Now, two papers appearing in the March 13 issue of the journal Nature help answer these questions. Led by researchers at Beth Israel Deaconess Medical Center (BIDMC) and Harvard Medical School, the papers find that the metabolic process that has come to be known as the Warburg effect is essential for tumors’ rapid growth, and identifies the M2 form of pyruvate kinase (PKM2), an enzyme involved in sugar metabolism, as an important mechanism behind this process. This discovery could provide a target for the development of future cancer therapies.

“With this study we have answered a fundamental question regarding the ability of tumor cells to rapidly grow and proliferate,” explains senior author Lewis Cantley, PhD, Director of the Cancer Center at BIDMC and Professor of Systems Biology at Harvard Medical School.

Metabolic regulation in rapidly growing tissues, such as fetal tissue or tumors, is different from that of normal adult tissue, Cantley explains. “Through aerobic glycolysis, or the Warburg effect, cancer cells produce energy by taking up glucose at much higher rates than other cells while, at the same time, using a smaller fraction of the glucose for energy production. This allows cancer cells to function more like fetal cells, promoting extremely rapid growth.” This unique metabolic property of cancer cells has led to the success of PET imaging as a means of cancer detection; because radioactive glucose injected into patients prior to the imaging exam is preferentially taken up by glucose-hungry tumor cells, the areas of high glucose uptake are displayed dramatically on the PET scan.

Using a novel proteomic screen to identify new phosphotyrosine binding proteins, Cantley and his colleagues first determined that PKM2 can bind to phosphotyrosine-containing peptides. “We observed that in contrast to the forms of pyruvate kinase found in most normal adult tissues, only PKM2, which is found in fetal cells, interacted with phosphotyrosine,” explains Cantley. “This finding was particularly interesting because previous reports had shown that this M2 form was the pyruvate kinase form used by all cancer cells.”

In order to understand the implications of this discovery, Cantley and his coauthors next embarked upon experiments to evaluate the importance of PKM2 to cancer cells. Reasoning that tumor tissue switches pyruvate kinase expression from an adult M1 isoform to the embryonic M2 isoform, they performed immunoblotting and immunohistochemistry analysis of numerous cancer cell lines, breast cancer models and human colon cancer, confirming that PKM2 was the only form of pyruvate kinase found in cancerous tissue.

The authors then knocked down PKM2 expression in human cancer cell lines and expressed the adult M1 form instead. This switch from the fetal M2 form to the adult M1 isoform led to reduced lactate production and increased oxygen consumption – a reversal of the Warburg effect.

“We were able to show that only cells which express the M2 form of pyruvate kinase – and metabolize glucose in the way described by Otto Warburg 80 years ago – had the ability to form tumors in mice,” notes Cantley. In addition, the investigators demonstrated that it is the ability of PKM2 to interact with phosphotyrosine that enables this form of pyruvate kinase to promote the unique glucose metabolism seen in cancer cells, thereby allowing these cells to make tumors in vivo.

The findings are consistent with the idea that tumor cells preferentially use glucose for purposes other than making adenosine triphosphate (ATP), the energy currency used by normal cells. “We suspect that this mechanism evolved to ensure that fetal tissues only use glucose for growth when they are activated by appropriate growth factor receptor protein-tyrosine kinases,” adds Cantley. “By re-expressing PKM2, cancer cells acquire the ability to use glucose for anabolic processes.

“Because PKM2 is found in all of the cancer cells that we have examined, because it is not found in most normal adult tissues, and because it is critical for tumor formation, this form of pyruvate kinase is a possible target for cancer therapy,” he adds.

Source: Beth Israel Deaconess Medical Center

Related stories:

Breast cancer: How tumor cells break free and form metastases
When tumor cells acquire the capacity to move around and invade other tissues, there is a risk of metastases and cancer treatment becomes more difficult. At the Institut Curie, CNRS Director of Research Philippe Chavrier and his group have just discovered how breast cancer cells break the bonds that tether them to the tumor.
Researchers identify promising cancer drug target in prostate tumors
Scientists at Dana-Farber Cancer Institute report they have blocked the development of prostate tumors in cancer-prone mice by knocking out a molecular unit they describe as a "powerhouse" that drives runaway cell growth.
One step closer to green chemistry and improved pharmaceuticals
Proteins are the workhorses of our cells. They help to digest our food, are at the core of our immune system, and literally shape our body from top to toe. Proteins also play an important role in biotechnology in the form of enzymes, which are important in the creation of anything from pharmaceuticals to bread, washing powder and much more. Their possibilities are virtually without limit.
Crucial factors in lymphoma development and survival discovered
Experiments with new mouse model suggest therapeutic targets
Researchers at National Jewish Medical and Research Center have discovered an important factor in the development of B-cell lymphomas, one of the fastest growing forms of cancer. The B-cell receptor on the surface of B cells can cooperate with the MYC oncogene to accelerate the development of lymphomas. The research team, led by Yosef Refaeli, PhD, Assistant Professor of Pediatrics at National Jewish Medical and Research Center , also showed that disruption of signals from the B-cell receptor can inhibit growth of the tumors. The research is being published in the June 24 issue of the journal, PLos Biology.
Certain anticancer agents could be harmful to patients with heart disease
A set of promising new anticancer agents could have unforeseen risks in individuals with heart disease, suggests research at Washington University School of Medicine in St. Louis. The anticancer drugs — which go by the strange name of hedgehog antagonists — interfere with a biochemical process that promotes growth in some cancer cells. But the researchers showed that interfering with this biochemical process in mice with heart disease led to further deterioration of cardiac function and ultimately death.
Understanding the migration of cancer cells
Activity of regulatory proteins for the growth of filopodia and lamelopodia clarified
Lamellipodia are veil-shaped protrusions of the plasma membrane, that can turn into upward-curled ruffles if they fail to adhere to the substrate. A dendritic meshwork of short and highly branched actin filaments might constitute their main structural component. The other type of protrusion, the filopodia, are finger-like and consist of parallel, long and unbranched actin filaments. Interestingly, fast-crawling cells mainly form lamellipodia/ruffles while poorly migrating or non-motile cells often show the coexistence of both lamellipodial and filopodial protrusions. These observations suggest that the lamellipodia-to-filopodia selection might regulate cell migration. Moreover, the pivotal contribution of lamellipodial and filopodial protrusions to important developmental and homeostatic processes certainly requires tight regulatory mechanisms.
Mayo researchers discover how measles virus spreads
Textbooks will require revisions, researchers say
Measles, one of the most common contagious diseases, has been thought to enter the body through the surface of airways and lungs, like many other major viruses. Now, Mayo Clinic researchers and their collaborators say that's not the case, and some medical texts will have to be revised. The findings are reported in today's online edition of The Journal of Clinical Investigation .
Could new discovery about a shape-shifting protein lead to a mighty 'morpheein' bacteria fighter?
A small molecule that locks an essential enzyme in an inactive form could one day form the basis of a new class of unbeatable, species-specific antibiotics, according to researchers at Fox Chase Cancer Center.

News discussion:

Medicine & Health news