Table 2.

Examples of ‘mass action cooperation’ (Heckathorn 1996) in cancers, where mutualisms form between different clones and cells within the microenvironment

Behaviour	Cooperative characteristics
Angiogenesis	Tumours require nutrients and oxygen to grow. Therefore, they must recruit new blood vessels into the area (neoangiogenesis) by secreting vascular endothelial growth factor (VEGF). The recruitment of blood vessels to an area not only benefits the secreting cells but also any cells within the local vicinity. Therefore, VEGF can be thought of as a communal product, the production of which is likely to carry an energetic cost to the producer, and a growth benefit to any recipients. Evidence for this behaviour has already been shown in cancer–stromal–cell interactions, and there is growing evidence that it may also be important between cancer cells (Kalas et al. 2005).
Self-sufficiency in growth signals	Cancer cells produce many growth factors (such as VEGF, PDGF and TGF-β) (Mueller and Fusenig 2004) that induce stromal reactions for angiogenesis and inflammation, and activate other stromal cells, such as fibroblasts, to secrete other growth factors (GFs) and proteases (de Jong et al. 1998; Klein 2003; Weaver and Gilbert 2004). Although not systematically tested, there is some evidence that cancer cells secreting GFs are frequently adjacent to cells which express GF receptors, and therefore have the potential to respond to GF signals (de Jong et al. 1998; Royuela et al. 2004). This suggests that cancer cells are able to share GFs between each other, and also recruit GFs from noncancerous cells, which will aid tumour growth.
Tissue invasion	Cancer cells interact with stromal cells to stabilize the tumour microenvironment. Normally, tissue cells remain confined to their territory because they respond to signals from neighbouring cells, and the extra cellular matrix (ECM). Any cells which become detached receive apoptotic signals from the invaded tissues, and as such are eliminated. Malignant tumour cells effectively ignore these signals, and so are able to migrate beyond the defined boundaries of the tissue (Liotta and Kohn 2001). Stromelysin-3 secreted by fibroblasts peripheral to the tumour is known to reduce the death rate of cancer cells invading adjacent connective tissues. In addition, proteases from nearby stromal and cancer cells are known to contribute to neoplastic progression by degrading ECM, aiding in cell proliferation, tissue invasion and metastasis (Tlsty 2001).