Tumour cells have long been known to have an increased metabolic rate, a property that is clinically exploitable. But how crucial is this for the maintenance of the tumour in vivo?

Normal cells produce their ATP in the mitochondria through oxidative phosphorylation, unless oxygen is limiting, in which case glucose is converted to lactate to produce ATP. Many tumour cells opt for the second pathway even in the presence of oxygen — known as the 'Warburg effect'. Changes in the mitochondria are also evident in tumour cells (such as an increased mitochondrial membrane potential), so Valeria Fantin and colleagues investigated the growth of tumour cells and examined the function of the mitochondria when lactate production is compromised.

One of the enzymes involved in lactate production is lactate dehydrogenase A (LDHA). Most of the mouse tumour cell lines that the authors examined were reliant on lactate production for their survival. However, two mouse mammary cell lines that express the oncogene Neu (also known as Erbb2) did not undergo apoptosis on treatment with Ldha short hairpin RNAs, and so were used to produce stable cell lines with reduced LDHA expression. These cells proliferated less than the parental cell lines under normoxic conditions, and this difference was exacerbated in hypoxic conditions. The LDHA-deficient cells were reliant on oxidative phosphorylation, and so produced much less ATP than the parental cells, possibly explaining their reduced proliferation in vitro. In addition, the Neu-expressing LDHA-deficient cells had a reduced mitochondrial membrane potential compared with the parental cells, and were less sensitive to a small molecule, F16, that is toxic to carcinoma cells with higher than normal mitochondrial membrane potential. Therefore, there is a link between mitochondrial membrane potential and the use of lactate to produce ATP.

So, does the reliance of Neu-expressing LDHA-deficient cells on oxidative phosphorylation compromise their growth in vivo? The Neu-expressing parental cell lines and the LDHA-deficient cells were transplanted into the mammary gland fat pads of syngeneic mice. The survival of mice with the parental cell lines was 58 days on average, whereas mice transplanted with LDHA-deficient cells survived for 162 days on average. So, cells without LDHA were able to survive and grow in vivo, but their growth was severely compromised.

Humans can survive in the absence of LDHA with relatively minor clinical effects, so targeting LDHA in tumour cells looks to be a promising avenue in cells that rely heavily on the Warburg effect for tumour survival.