big-gastrin and Neoplasms

The singular gene for a peptide hormone is expressed not only in a specific endocrine cell type but also in other endocrine cells as well as in entirely different cells such as neurons, adipocytes, myocytes, immune cells, and cells of the sex-glands. The cellular expression pattern for each gene varies with development, time and species. Endocrine regulation is, however, based on the release of a given hormone from an endocrine cell to the general circulation from whose cappilaries the hormone reaches the specific target cell elsewhere in the body. The widespread expression of hormone genes in different cells and tissues therefore requires control of biogenesis and secretion in order to avoid interference with the function of a specific hormonal peptide from a particular endocrine cell. Several mechanisms are involved in such control, one of them being cell-specific processing of prohormones. The following pages present four examples of such cell-specific processing and the implications of the phenomenon for the use of peptide hormones as markers of diseases. Notably, sick cells - not least the neoplastic cells - often process prohormones in a manner different from that of the normal endocrine cells.

Topics: Animals; Cholecystokinin; Endocrine System; Gastrins; Gene Expression Regulation; Hormones; Humans; Models, Biological; Neoplasms; Neurotensin; Peptides; Proglucagon; Protein Precursors; Signal Transduction

In 1905, a Cambridge physiologist, John Sydney Edkins, initially identified a hormone responsible of gastric acid secretion, which he called gastric secretin, or gastrin. While gastrin's role in acid secretion is now well defined, more recent studies have implicated the various isoforms of gastrin in cancer. Important advances in the last decade have included the recognition of biological activity for processing intermediates such as progastrin and the glycine-extended gastrin. Here, we give an overview of the roles of these peptides in cancer, highlighted by molecular, cellular and integrated studies on animal models for progastrin-derived peptides and their receptors.

Topics: Animals; Gastrins; Hormones; Humans; Neoplasms; Protein Isoforms; Protein Precursors; Signal Transduction

hPG

Topics: Gastrins; Humans; Neoplasms; Protein Precursors

In colorectal cancer, hPG80 (progastrin) is released from tumor cells, promotes cancer stem cells (CSC) self-renewal and is detected in the blood of patients. Because the gene GAST that encodes hPG80 is a target gene of oncogenic pathways that are activated in many tumor types, we hypothesized that hPG80 could be expressed by tumors from various origins other than colorectal cancers, be a drug target and be detectable in the blood of these patients.. hPG80 expression was monitored by fluorescent immunohistochemistry and mRNA expression in tumors from various origins. Cancer cell lines were used in sphere forming assay to analyze CSC self-renewal. Blood samples were obtained from 1546 patients with 11 different cancer origins and from two retrospective kinetic studies in patients with peritoneal carcinomatosis or hepatocellular carcinomas. These patients were regularly sampled during treatments and assayed for hPG80.. We showed that hPG80 was present in the 11 tumor types tested. In cell lines originating from these tumor types, hPG80 neutralization decreased significantly CSC self-renewal by 28 to 54%. hPG80 was detected in the blood of patients at significantly higher concentration than in healthy blood donors (median hPG80: 4.88 pM versus 1.05 pM; p < 0.0001) and shown to be correlated to GAST mRNA levels in the matched tumor (i.e., lung cancers, Spearman r = 0.8; p = 0.0023). Furthermore, we showed a strong association between longitudinal hPG80 concentration changes and anti-cancer treatment efficacy in two independent retrospective studies. In the peritoneal carcinomatosis cohort, median hPG80 from inclusion to the post-operative period decreased from 5.36 to 3.00 pM (p < 0.0001, n = 62) and in the hepatocellular carcinoma cohort, median hPG80 from inclusion to remission decreased from 11.54 pM to 1.99 pM (p < 0.0001, n = 63).. Because oncogenic hPG80 is expressed in tumor cells from different origins and because circulating hPG80 in the blood is related to the burden/activity of the tumor, it is a promising cancer target for therapy and for disease monitoring.. ECS-Progastrin.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Neoplasm; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cohort Studies; Female; Gastrins; Gene Expression Regulation, Neoplastic; Humans; Kinetics; Male; Middle Aged; Neoplasms; Oncogenes; Organ Specificity; Protein Precursors; RNA, Messenger; Spheroids, Cellular; Young Adult