Researchers from the Vlaams Instituut voor Biotechnologie-Katholieke Universiteit (VIB-KU) Leuven Center for Cancer Biology discovered that the nutrient pyruvate is necessary to create favorable conditions for metastasis in cancer cells' extracellular matrix.
In order for cancer cells to metastasize, they must create a metastatic niche. First, cancer cells must activate the enzyme collagen prolyl-4-hydroxylase (p4HA) to start forming the environment around them. Enzymatic reactions that occur in cancer cells are controlled by what type of nutrient is available. The researchers discovered that collagen p4HA is dictated by the nutrient pyruvate. In addition, they discovered that pyruvate uptake induces the production of a-ketoglutarate, a metabolite used in the Krebs cycle, which is a crucial process cells undergo to generate energy.
Once produced, a-ketoglutarate increases the activity of the enzyme p4HA, which then activates collagen hydroxylation. When the researchers inhibited pyruvate metabolism, collagen hydroxylation was hindered, thereby reducing growth of lung metastasis from breast cancer in mouse models. However, because pyruvate is used by healthy cells, it will be a difficult cancer drug target, since inhibiting it would harm healthy cells.
When another study at VIB-KU Leuven Lab of Clinical and Experimental Endocrinology was conducted on how healthy bone cells use p4HA, the researchers discovered that bone cells also required a-ketoglutarate to regulate p4HA activity; however, the metabolite created a healthy environment for the bone cells. Although cancer cells need pyruvate to metastasize, healthy bone cells do not rely on pyruvate; instead, they rely on the nutrient glutamine.
Together, both studies provide insight into what nutrients are necessary for healthy and cancerous cells. Hopefully with this information, scientists will be able to develop a drug that targets nutrients used by cancer cells without harming healthy cells.
For More Information
Elia I, Rossi M, Stegen S, et al (2019). Breast cancer cells rely on environmental pyruvate to shape the metastatic niche. Nature. [Epub ahead of print] DOI:10.1038/s41586-019-0977-x
Stegen S, van Gastel N, Eelen G, et al (2016). HIF-1a promote glutamine-mediated redox homeostatis and glycogen-dependent bioenergetics to support postimplantation bone cell survival. Cell Metab, 23(2):265-279. DOI:10.1016/j.cmet.2016.01.002
Image Courtesy of Ed Uthman