The resistance of many human cancers to immunebased therapies, including adoptive immunotherapy and the administration of therapeutic cancer vaccines, has been attributed to tumor-associated immune suppression, due in part to immunosuppressive molecules located within the tumor microenvironment. Adenosine is a purine nucleoside found within the interstitial fluid of solid tumors at concentrations that are able to inhibit cell-mediated immune responses to tumor cells. It is well established that extracellular adenosine inhibits T lymphocyte activation and effector function, including T cell adhesion to tumor cells and cytotoxic activity, by signaling primarily through A 2a and A 3 adenosine receptors on the surface of T cells. Importantly, A 2a adenosine receptordeficient mice exhibit enhanced anti-tumor immune responses by CD8 + T cells, as well as a dramatic reduction in the growth of experimental tumors in comparison to wild-type controls. A 2a adenosine receptor signaling has also been implicated in adenosine-mediated inhibition of cytokine production and cytotoxic activity by activated natural killer (NK) cells, although the process of NK cell granule exocytosis is apparently suppressed via a distinct and as yet uncharacterized adenosine receptor. In this report, we review the evidence that adenosine is a potent inhibitor of cellular immune responses and may therefore be a major barrier to the successful immunotherapy of human carcinomas. The signaling pathways through which adenosine exerts its inhibitory effects on cell-mediated immune responses are also discussed. The accumulated evidence suggests that the effectiveness of immune-based therapies for solid tumors may be enhanced by selective antagonism of the adenosine receptor subtypes through which adenosine inhibits the antitumor activity of T lymphocytes and NK cells. Contents

Apigenin (4',5,7-trihydroxyflavone, 5,7-dihydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one) is a flavonoid found in many fruits, vegetables, and herbs, the most abundant sources being the leafy herb parsley and dried flowers of chamomile. Present in dietary sources as a glycoside, it is cleaved in the gastrointestinal lumen to be absorbed and distributed as apigenin itself. For this reason, the epithelium of the gastrointestinal tract is exposed to higher concentrations of apigenin than tissues at other locations. This would also be true for epithelial cancers of the gastrointestinal tract. We consider the evidence for actions of apigenin that might hinder the ability of gastrointestinal cancers to progress and spread. Apigenin has been shown to inhibit cell growth, sensitize cancer cells to elimination by apoptosis, and hinder the development of blood vessels to serve the growing tumor. It also has actions that alter the relationship of the cancer cells with their microenvironment. Apigenin is able to reduce cancer cell glucose uptake, inhibit remodeling of the extracellular matrix, inhibit cell adhesion molecules that participate in cancer progression, and oppose chemokine signaling pathways that direct the course of metastasis into other locations. As such, apigenin may provide some additional benefit beyond existing drugs in slowing the emergence of metastatic disease.

The RIE-1 cell line is an untransformed, epithelial cell line derived from the rat small intestine. We report that epidermal growth factor (EGF), which regulates the proliferation of RIE-1 cells, also directs their movement. We measured cell migration through gelatin-coated filters in blind-well Boyden chambers. The migration of RIE-1 cells was stimulated up to approximately 100-fold by EGF, with a half-maximal response at 1-2 ng/ml and a maximal effect at 10 ng/ml. Further analysis showed that the RIE-1 cells responded directionally to a gradient of EGF in solution. Other growth factors tested did not stimulate RIE-1 cell migration, and EGF did not stimulate the migration of fibroblasts in this assay. We conclude that EGF is a potent and specific chemo-attractant for RIE-1 intestinal epithelial cells and suggest that EGF might influence epithelial cell migration in vivo.

No abstract