cholecystokinin and Leiomyosarcoma

The cholecystokinin-2 receptor (CCK2R), is expressed in cancers where it contributes to tumor progression. The CCK2R is over-expressed in a sub-set of tumors, allowing its use in tumor targeting with a radiolabel ligand. Since discrepancies between mRNA levels and CCK2R binding sites were noticed, we searched for abnormally spliced variants in tumors from various origins having been previously reported to frequently express cholecystokinin receptors, such as medullary thyroid carcinomas, gastrointestinal stromal tumors, leiomyomas and leiomyosarcomas, and gastroenteropancreatic tumors. A variant of the CCK2R coding for a putative five-transmembrane domains receptor has been cloned. This variant represented as much as 6% of CCK2R levels. Ectopic expression in COS-7 cells revealed that this variant lacks biological activity due to its sequestration in endoplasmic reticulum. When co-expressed with the CCK2R, this variant diminished membrane density of the CCK2R and CCK2R-mediated activity (phospholipase-C and ERK activation). In conclusion, a novel splice variant acting as a dominant negative on membrane density of the CCK2R may be of importance for the pathophysiology of certain tumors and for their in vivo CCK2R-targeting.

Topics: Alternative Splicing; Amino Acid Sequence; Animals; Binding Sites; Carcinoma, Medullary; Chlorocebus aethiops; Cholecystokinin; COS Cells; Extracellular Signal-Regulated MAP Kinases; Gastrins; Gastrointestinal Neoplasms; Gastrointestinal Stromal Tumors; Humans; Insulinoma; Leiomyoma; Leiomyosarcoma; Molecular Sequence Data; Pancreatic Neoplasms; Protein Structure, Tertiary; Receptor, Cholecystokinin B; RNA, Messenger; Signal Transduction; Thyroid Neoplasms; Type C Phospholipases

Gastrin and cholecystokinin (CCK) are two major regulatory peptides synthesized by human gut and brain tissues as well as by selected tumors, in particular gastrin-producing neuroendocrine tumors. In the present study we have evaluated gastrin and CCK gene expression in a group of primary human tumors, including neuronal, renal, and myogenic stem cell tumors, using in situ hybridization techniques. In addition, CCK-A and CCK-B receptors were evaluated in the same group of tumors with receptor autoradiography. Most tumors had gastrin messenger ribonucleic acid (mRNA): 10 of 11 medulloblastomas, 5 of 5 central primitive neuroectodermal tumors, 11 of 11 Ewing sarcomas, 8 of 10 neuroblastomas, 4 of 4 Wilms' tumors, 5 of 5 rhabdomyosarcomas, and 10 of 10 leiomyosarcomas. CCK mRNA was restricted predominantly to Ewing sarcomas (9 of 11) and leiomyosarcomas (5 of 10). CCK-A and CCK-B receptors were not frequently found in these tumors, except for leiomyosarcomas. These data suggest that gastrin and CCK may play a previously unrecognized role in this group of human stem cell tumors. If the increased gastrin mRNA indeed translates into increased gastrin production, measurement of gastrinemia may have a diagnostic significance in the early detection of these tumors. As these two hormones have been reported to act as potent growth factors, they may be of pathophysiological relevance for patients with such stem cell tumors.

Topics: Blotting, Northern; Brain Neoplasms; Cholecystokinin; Gastrins; Humans; In Situ Hybridization; Kidney Neoplasms; Leiomyosarcoma; Medulloblastoma; Neuroblastoma; Neuroectodermal Tumors, Primitive; Receptor, Cholecystokinin A; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Rhabdomyosarcoma; RNA, Messenger