Adenosine stimulation of cell proliferation and migration: Implications for the role of the cellular microenvironment in tumour expansion.

摘要

Solid tumours have a poorly formed and disorganised vasculature that leads to regions of hypoxia. In these hypoxic regions, the purine nucleoside adenosine is produced at an elevated level due to activation of 5' -nucleotidase and inhibition of adenosine kinase. The local extracellular concentration of adenosine within the solid tumour microenvionment is likely in the 3--10muM range. We and others have shown that adenosine is a potent immunosuppressant; inhibiting several anti-cancer immune responses. The objective of this thesis was to evaluate further potential tumour-promoting actions of adenosine. Specifically, I investigated the effect of adenosine on colon carcinoma cell growth and cell migration.;The effect of adenosine on tumour cell growth is unclear. Some groups have shown that adenosine induces tumour cell death while others have demonstrated that adenosine increases tumour cell growth. These contradictory results may derive from the use of nonphysiological adenosine analogues or indirect approaches through inhibition of adenosine breakdown. My first aim was to determine if authentic adenosine increased or decreased colon carcinoma cell growth. I found that adenosine consistently stimulated DNA synthesis, cell cycle progression, and cell proliferation in five human colon carcinoma cell lines at pathophysiologically relevant concentrations. The adenosine response was however, modulated by the precise conditions of the culture environment.;Adenosine also stimulated the migration of HRT-18 colon carcinoma cells at concentrations that are expected to be present in the tumour microenvironment. Checkerboard analysis revealed that adenosine increased both chemotaxis and chemokinesis of HRT-18 cells. The adenosine-mediated increase in cell migration was inhibited by antagonists to the adenosine A2a and A2b receptor subtypes. The A2a selective agonist CGS21680 stimulated migration of HRT-18 cells. These data suggest that adenosine likely stimulates HRT-18 cell migration through A2 receptors.;Tumour cell growth and cell migration are integral to tumour expansion. Given that adenosine has been shown to stimulate both of these processes, as well as being immunosuppressive, interventions focused on the control of the local level of adenosine in the tumour microenvironment may be novel and effective therapeutic strategies in the pharmacotherapy of solid tumours.