Role of tumour-associated macrophages in tumour progression

Two different approaches – the use of various transgenic mouse models and the analysis of human tumours – have demonstrated a close link between the activity of tumour-associated macrophages (TAMs) and tumour progression. TAMs are abundant in most forms of solid tumour, where they often display a relatively immature phenotype and are positively correlated with tumour angiogenesis and/or progression .Pollard's group crossed PyMT-MMTV mice (which spontaneously develop mammary tumours) with the transgenic op/op mouse model lacking the gene for colony-stimulating factor-1, a crucial growth factor for macrophages and their precursors from the bone marrow, namely blood monocytes. The tumours that developed in these macrophage-depleted mice showed a slower rate of progression to malignancy and formed far fewer metastases in the lungs than those in non-macrophage-depleted mice. Moreover, Pollard's group recently characterised the development of the vasculature in PyMT-MMTV tumours during progression to malignancy and showed that the onset of the 'angiogenic switch' (the formation of the high-density vessel network associated with the transition to malignancy) was regulated by TAMs. Preinvasive mammary lesions in op/op mice exhibited both a delayed angiogenic switch and transition to malignancy, whereas genetic restoration of the macrophage population in tumours reversed this. Although these studies suggest that TAMs have a key role in promoting tumour angiogenesis, progression to malignancy and metastasis, they have yet to be confirmed in similar studies with other macrophage-depleted, transgenic mouse tumour models.
However, these data accord well with our finding that high numbers of TAMs correlate with increased tumour angiogenesis, lymph node status and reduced survival of breast cancer patients. Moreover, we showed that TAMs in breast carcinomas express numerous tumour-promoting factors such as the important mitogen epidermal growth factor and the pro-angiogenic cytokine vascular endothelial growth factor (VEGF). TAMs have also been shown to release a variety of other cytokines and enzymes known to promote tumour invasion, angiogenesis and metastasis. Recent studies indicate that when macrophages migrate into tumours they downregulate their expression of the potent anti-angiogenic cytokine IL-12 .
These findings have prompted investigations into how the tumour microenvironment 'educates' macrophages to perform these pro-tumour activities. Here we outline the important role of tumour hypoxia in this, both in the form of a direct effect on the expression of pro-tumour genes by TAMs, and indirectly by upregulating the pro-angiogenic cytokine angiopoietin-2 (Ang-2), which in turn has profound effects on TAM function.

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