  Cancer cells utilize large amounts of ATP to sustain growth, relying
primarily on non-oxidative, fermentative pathways for its production. In many
types of cancers this leads, even in the presence of oxygen, to the secretion
of carbon equivalents (usually in the form of lactate) in the cell's
surroundings, a feature known as the Warburg effect. While the molecular basis
of this phenomenon are still to be elucidated, it is clear that the spilling of
energy resources contributes to creating a peculiar microenvironment for
tumors, possibly characterized by a degree of toxicity. This suggests that
mechanisms for recycling the fermentation products (e.g. a lactate shuttle) may
be active, effectively inducing a mutually beneficial metabolic coupling
between aberrant and non-aberrant cells. Here we analyze this scenario through
a large-scale in silico metabolic model of interacting human cells. By going
beyond the cell-autonomous description, we show that elementary
physico-chemical constraints indeed favor the establishment of such a coupling
under very broad conditions. The characterization we obtained by tuning the
aberrant cell's demand for ATP, amino-acids and fatty acids and/or the
imbalance in nutrient partitioning provides quantitative support to the idea
that synergistic multi-cell effects play a central role in cancer sustainment.
