The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth

Many tumour cells have elevated rates of glucose uptake but reduced rates of oxidative phosphorylation. This persistence of high lactate production by tumours in the presence of oxygen, known as aerobic glycolysis, was first noted by Otto Warburg more than 75 yr ago. How tumour cells establish this altered metabolic phenotype and whether it is essential for tumorigenesis is as yet unknown. Here we show that a single switch in a splice isoform of the glycolytic enzyme pyruvate kinase is necessary for the shift in cellular metabolism to aerobic glycolysis and that this promotes tumorigenesis. Tumour cells have been shown to express exclusively the embryonic M2 isoform of pyruvate kinase. Here we use short hairpin RNA to knockdown pyruvate kinase M2 expression in human cancer cell lines and replace it with pyruvate kinase M1. Switching pyruvate kinase expression to the M1 (adult) isoform leads to reversal of the Warburg effect, as judged by reduced lactate production and increased oxygen consumption, and this correlates with a reduced ability to form tumours in nude mouse xenografts. These results demonstrate that M2 expression is necessary for aerobic glycolysis and that this metabolic phenotype provides a selective growth advantage for tumour cells in vivo.     

Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling

Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin's lymphoma, is clinically heterogeneous: 40% of patients respond well to current therapy and have prolonged survival, whereas the remainder succumb to the disease. We proposed that this variability in natural history reflects unrecognized molecular heterogeneity in the tumours. Using DNA microarrays, we have conducted a systematic characterization of gene expression in B-cell malignancies. Here we show that there is diversity in gene expression among the tumours of DLBCL patients, apparently reflecting the variation in tumour proliferation rate, host response and differentiation state of the tumour. We identified two molecularly distinct forms of DLBCL which had gene expression patterns indicative of different stages of B-cell differentiation. One type expressed genes characteristic of germinal centre B cells ('germinal centre B-like DLBCL'); the second type expressed genes normally induced during in vitro activation of peripheral blood B cells ('activated B-like DLBCL'). Patients with germinal centre B-like DLBCL had a significantly better overall survival than those with activated B-like DLBCL. The molecular classification of tumours on the basis of gene expression can thus identify previously undetected and clinically significant subtypes of cancer.     

Experimental evidence for apparent competition in a tropical forest food web

The herbivorous insects of tropical forests constitute some of the most diverse communities of living organisms. For this reason it has been difficult to discover the degree to which these communities are structured, and by what processes. Interspecific competition for resources does occur, but its contemporary importance is limited because most pairs of potentially competing insects feed on different host plants. An alternative way in which species can interact is through shared natural enemies, a process called apparent competition. Despite extensive theoretical discussion there are few field demonstrations of apparent competition, and none in hyper-diverse tropical communities. Here, we experimentally removed two species of herbivore from a community of leaf-mining insects in a tropical forest. We predicted that other species that share natural enemies with the two removed species would experience lower parasitism and have higher population densities in treatment compared with control sites. In both cases (on removal of a dipteran and a coleopteran leaf-miner species) we found significantly lower parasitism, and in one case (removal of the dipteran) we found significantly higher abundance a year after the manipulation. Our results suggest that apparent competition may be important in structuring tropical insect communities.     

The hard cell

Ethical quandaries aside, stem-cell science is attracting researchers worldwide. Ricki Lewis reports.