Study helps explain fundamental process of tumor growth

March 12, 2008

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

Explore further: New strategy for unleashing cancer-fighting power of p53 gene

Related Stories

New strategy for unleashing cancer-fighting power of p53 gene

December 13, 2017
Tumor protein p53 is one of the most critical determinants of the fate of cancer cells, as it can determine whether a cell lives or dies in response to stress. In a new study published today in the journal Nature Communications, ...

Scientists develop new artificial ovary prototype

December 13, 2017
Belgian researchers have taken important steps towards creating transplantable artificial ovaries. Once successful, these could be of value to women struggling with infertility or cancer patients who cannot conceive after ...

Researchers identify epigenetic orchestrator of pancreatic cancer cells

December 11, 2017
Genentech researchers have identified an enzyme that shifts pancreatic cancer cells to a more aggressive, drug-resistant state by epigenetically modifying the cells' chromatin. The study, which will be published December ...

Drug suppresses spread of breast cancer caused by stem-like cells

December 12, 2017
Rare stem-like tumor cells play a critical role in the spread of breast cancer, but a vulnerability in the pathway that powers them offers a strategy to target these cells using existing drugs before metastatic disease occurs, ...

Liver cancer: Lipid synthesis promotes tumor formation

December 11, 2017
Lipids comprise an optimal energy source and an important cell component. Researchers from the Biozentrum of the University of Basel and from the University of Geneva have now discovered that the protein mTOR stimulates the ...

Cancer gene plays key role in cystic fibrosis lung infections

December 12, 2017
PTEN is best known as a tumor suppressor, a type of protein that protects cells from growing uncontrollably and becoming cancerous. But according to a new study from Columbia University Medical Center (CUMC), PTEN has a second, ...

Recommended for you

'Bet hedging' explains the efficacy of many combination cancer therapies

December 14, 2017
The efficacy of many FDA-approved cancer drug combinations is not due to synergistic interactions between drugs, but rather to a form of "bet hedging," according to a new study published by Harvard Medical School researchers ...

Scientists unlock structure of mTOR, a key cancer cell signaling protein

December 14, 2017
Researchers in the Sloan Kettering Institute have solved the structure of an important signaling molecule in cancer cells. They used a new technology called cryo-EM to visualize the structure in three dimensions. The detailed ...

Liquid biopsy results differed substantially between two providers

December 14, 2017
Two Johns Hopkins prostate cancer researchers found significant disparities when they submitted identical patient samples to two different commercial liquid biopsy providers. Liquid biopsy is a new and noninvasive alternative ...

Testing the accuracy of FDA-approved and lab-developed cancer genetics tests

December 14, 2017
Cancer molecular testing can drive clinical decision making and help a clinician determine if a patient is a good candidate for a targeted therapeutic drug. Clinical tests for common cancer causing-mutations in the genes ...

Newest data links inflammation to chemo-brain

December 14, 2017
Inflammation in the blood plays a key role in "chemo-brain," according to a published pilot study that provides evidence for what scientists have long believed.

One in five young colon cancer patients have genetic link

December 13, 2017
As doctors grapple with increasing rates of colorectal cancers in young people, new research from the University of Michigan may offer some insight into how the disease developed and how to prevent further cancers. Researchers ...

1 comment

Adjust slider to filter visible comments by rank

Display comments: newest first

E_L_Earnhardt
not rated yet Mar 13, 2008
Warburg was no fool! If we really want to cure cancer we will go back to his work!

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.