Brain tumors might not be able to escape gastrin

Abstract

One of the most terrifying characteristics of malignant tumors is the motility of transformed cells, which enables them to spread to adjacent tissue. If they are then able to travel in the bloodstream, they can invade other organs giving rise to secondary tumors. However, in the brain it is enough that primary tumor cells can disseminate quickly to surrounding structures, thus restricting the surgical removal of transformed tissue. Saving healthy, normal tissue is very important because each area of the brain is functionally unique and therefore precious, despite the brain's enormous plasticity.Neoplastic transformation occurs in glial cells, which then exhibit a remarkable capacity to invade normal tissue diffusely. Fortunately, enough cell lines obtained from glioblastoma tumor biopsies retain this ability, allowing in vitro studies of proliferation and migration. Among various factors studied in this context, cholecystokinin (CCK) and its close relative gastrin were candidate growth factors because they control the growth of both normal tissue and some cancers. It was found that various tumors express CCK2-type gastrin receptors. Indeed, in the case of human glioblastoma cells it was found that gastrin acts via CCK2 receptors; however, it was not possible to block the effect of gastrin completely using known gastrin receptor antagonists.Recent results indicating that the most malignant forms of glial brain tumors do not express the CCK2 receptor caught the attention of Pannequin and co-workers [1xc-Terminal heptapeptide of gastrin inhibits astrocytomas motility by interacting with new gastrin binding sites. Pannequin, J. et al. J. Pharmacol. Exp. Ther. 2002; 302: 274–282Crossref | PubMed | Scopus (5)See all References][1]. They hypothesized that gastrin exerted its anti-motility action through a new, as yet unknown, gastrin receptor. When testing several human glioma cell lines, they did not observe any binding of various CCK or gastrin receptor agonists, and the presence of mRNAs encoding either CCK1 or CCK2 receptors were consistently undetected. Screening various modified gastrin analogs showed that only C-terminal heptapeptide G-7 had the capacity to bind to cell membranes. Kinetic studies and pharmacological profiling confirmed the existence of a single specific site, different from the classical CCK1 or CCK2 receptors. This new target is probably a member of the G-protein-coupled receptor class. However, G-7 did not cause accumulation of inositol phosphate or cAMP second messengers, nor did it stimulate the proliferation of the cells. It did, however, have a strong stimulatory action on the expression of c-Fos – the transcription factor that is an important element of a proliferation-controlling mechanism. The most intriguing observation was a dose-dependent, significant decrease of tumor cell migration.The authors propose the existence of a new, specific gastrin-binding receptor and suggest that it might be coupled to the Rho protein. Although this is a very interesting result, it is not rare that new receptors are discovered during studies of atypical responses to novel ligands. The true achievement of the authors is the discovery of a new agent that can decrease the motility of malignant astrogliomas. This might constitute a novel target for the development of new therapeutic approaches against these tumors; today no effective treatment is available.