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Metabolite that promotes cancer cell transformation and colorectal cancer spread identified

December 1, 2016
Osaka University
The metabolite D-2-hydroxyglurate (D-2HG) promotes epithelial–mesenchymal transition of colorectal cancer cells, leading them to develop features of lower adherence to neighboring cells, increased invasiveness, and greater likelihood of metastatic spread. This finding highlights the value of targeting D-2HG to establish new therapeutic approaches against colorectal cancer.

The production of oncometabolite (D-2HG) from glutamine results in invasion of cancer cells into the blood stream and spread to distant organs.
Credit: Image courtesy of Osaka University

Cancer cells exhibit a range of properties that diverge from those of their normal healthy counterparts, including levels of various metabolites. However, it has been difficult to determine whether such altered levels is a cause or a consequence of the cancerous growth.

In a breakthrough that offers hope for improved treatment of colorectal cancer, Osaka University researchers have identified a metabolite that causes cancer cells to develop more dangerous properties and increases the likelihood that cancer will spread in colorectal cancer patients.

The team examined different varieties of cancer cells and cells from normal tissues and revealed high levels of D-2-hydroxyglutarate (D-2HG) in colorectal cancer cells. They then administered either D-2HG into cancer cells and found it induced the cells to undergo transformation. This transformation involved the cells adhering less strongly to each other and migrating more easily. These properties in the body are associated with cancer progression and spread.

"When we grew the cells with D-2HG on plates and measured their movement, they migrated further than untreated cells" lead author Hugh Colvin says. "Using a Matrigel assay that models the ability of cancer cells to enter local tissue, the D-2HG treated cells were also more invasive."

The researchers showed that D-2HG acts by increasing the expression of a gene called ZEB1, which promotes this cell transformation. They also obtained specimens from 28 human colorectal cancer patients and divided them into two groups with low or high levels of D-2HG. The patients' records showed that the high group had more often suffered cancer spread to distant organs, which suggested the importance of D-2HG in patient prognosis.

"When cancer cells initially emerge, it can be difficult for them to survive and multiply because of the local conditions," coauthor Hideshi Ishii says. "D-2HG makes cancer cell survival more likely by causing them to transform from epithelial to mesenchymal cells, meaning that they can invade local tissue, enter the blood, and be transported elsewhere to establish a new tumor."

With the importance of this molecule in cancer progression and prognosis revealed, it can be focused on as a promising target for colorectal cancer treatments.

Story Source:

Materials provided by Osaka University. Note: Content may be edited for style and length.

Journal Reference:

  1. Hugh Colvin, Naohiro Nishida, Masamitsu Konno, Naotsugu Haraguchi, Hidekazu Takahashi, Junichi Nishimura, Taishi Hata, Koichi Kawamoto, Ayumu Asai, Kenta Tsunekuni, Jun Koseki, Tsunekazu Mizushima, Taroh Satoh, Yuichiro Doki, Masaki Mori, Hideshi Ishii. Oncometabolite D-2-Hydroxyglurate Directly Induces Epithelial-Mesenchymal Transition and is Associated with Distant Metastasis in Colorectal Cancer. Scientific Reports, 2016; 6: 36289 DOI: 10.1038/srep36289

Cite This Page:

Osaka University. "Metabolite that promotes cancer cell transformation and colorectal cancer spread identified." ScienceDaily. ScienceDaily, 1 December 2016. <>.
Osaka University. (2016, December 1). Metabolite that promotes cancer cell transformation and colorectal cancer spread identified. ScienceDaily. Retrieved May 26, 2017 from
Osaka University. "Metabolite that promotes cancer cell transformation and colorectal cancer spread identified." ScienceDaily. (accessed May 26, 2017).