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posted on 01.08.2005by Markus R. Owen, Helen M. Byrne, Claire E. Lewis
Poor drug delivery and low rates of cell proliferation are two factors associated with
hypoxia that diminish the efficacy of many chemotherapeutic drugs. Since macrophages
are known to migrate specifically towards, and localise within, hypoxic tumour regions,
a promising resolution to these problems involves genetically engineering macrophages to
perform such anti-tumour functions as inducing cell lysis and inhibiting angiogenesis. In
this paper we outline a modelling approach to characterise macrophage infiltration into
early avascular solid tumours, and extensions to study the interaction of these cells with
macrophages already present within the tumour. We investigate the role of chemotaxis
and chemokine production, and the efficacy of macrophages as vehicles for drug delivery
to hypoxic tumour sites.
The model is based upon a growing avascular tumour spheroid, in which volume is filled
by tumour cells, macrophages and extracellular material, and tumour cell proliferation
and death is regulated by nutrient diffusion. Crucially, macrophages occupy volume, and
hence contribute to the volume balance and hence the size of the tumour. We also include
oxygen dependent production of macrophage chemokines, which can lead to accumulations
in the hypoxic region of the tumour. We find that the macrophage chemotactic sensitivity
is a key determinant of macrophage infiltration and tumour size. Although increased
infiltration should be beneficical from the point of view of macrophage-based therapies,
such infiltration in fact leads to increased tumour sizes.
Finally, we include terms representing the induced death of tumour cells by hypoxic
engineered macrophages. We demonstrate that reductions in tumour size can be achieved,
but predict that a combination of therapies would be required for complete eradication.
We also highlight some counter-intuitive predictions—for example, absolute and relative
measures of tumour burden lead to different conclusions about prognosis. In summary,
this paper illustrates how mathematical models may be used to investigate promising