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The dynamic tumour microenvironment : from tumour perfusion to differential gene expression Bennewith, Kevin Leslie

Abstract

Solid tumours can contain areas of poor oxygenation and nutrient status, and tumour cells in these regions can limit tumour response to therapy. Increasing evidence suggests that the tumour microenvironment can be dynamic, with temporally varying blood flow and oxygen tensions in different tumour regions inducing a variety of gene expression profiles in populations of cells. Cellular hypoxia that varies over time is a poorly understood feature of many tumours, but is thought to represent a key factor contributing to therapy failure. This thesis investigated the solid tumour microenvironment by demonstrating the therapeutic relevance of transient tumour perfusion and transiently hypoxic tumour cells, while developing methods to specifically identify and quantify these cells in human tumour xenografts. During the course of these studies, a number of interesting and novel insights into tumour hypoxia and the dynamic tumour microenvironment became evident, which may have far-reaching implications for clinical cancer therapy. The therapeutic relevance of dynamic tumour perfusion was established by pharmaceutically manipulating tumour blood flow to increase the radiation sensitivity of specific tumour cell subpopulations. Changes in tumour cell hypoxia over time were studied by sequentially administering two exogenous "markers" of hypoxia followed by quantification of tumour cells containing bound marker by flow cytometry. Tumour hypoxia was measured continuously (i.e. was "integrated") over periods of time ranging from hours to days using multiple injections or oral administration of the hypoxia marker pimonidazole, indicating temporal changes in the hypoxic status of some tumour cells. Tumour hypoxia was also studied more implicitly in vitro, using multicellular spheroids to mimic the disparate tumour microenvironments associated with tumour hypoxia. Global gene expression patterns of cells from different microenvironmental conditions were compared using serial analysis of gene expression, and a number of genes were significantly differentially expressed. Products of these differentially expressed genes may provide a means to selectively study the therapeutic implications of transiently hypoxic tumour cells in vivo. Overall, improving our understanding of the dynamic tumour microenvironment (from temporally varying tumour perfusion and hypoxia to differential gene expression) has important implications for the strategic improvement of clinical cancer therapy.

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