Cholecystokinin and gastrin receptors targeting in gastrointestinal cancer

Abstract

Cholecystokinin and Gastrin are amongst the first gastrointestinal hormone discovered. In addition to classical actions (contraction of gallbladder, growth and secretion in the stomach and pancreas), these also act as growth stimulants for gastrointestinal malignancies and cell lines. Growth of these tumours is inhibited by antagonists of the cholecystokinin and gastrin receptors. These receptors provides most promising approach in clinical oncology and several specific radiolabelled ligands have been synthesized for specific tumour targeting and therapy of tumours overexpressing these receptors. Therefore, definition of the molecular structure of the receptor involved in the autocrine/paracrine loop may contribute to novel therapies for gastrointestinal cancer. Hence, this review tries to focus on the role and distribution of these hormones and their receptors in gastrointestinal cancer with a brief talk about the clinical trial using available agonist and antagonist in gastrointestinal cancers.

Introduction

Gastrointestinal/gut hormones are chemical messengers that exist in multiple molecular forms and bind to multiple cell-surface receptors which are coupled to one of the several possible signal transduction systems. Thus activation of these receptors by their cognitive ligand leads diverse biologic responses and regulates a broad range of physiologic functions. Although these are primarily expressed within the tissues of gut, these peptide hormones are widely distributed throughout the body and act on multiple target tissues [1]. These also regulate gastrointestinal homeostasis by affecting cell proliferation, differentiation, apoptosis and gene expression. The aberrant control of these biological processes is thought to play an important role in the establishment of gastrointestinal neoplasia [2].

Since gut peptides receptors are (over)expressed on cancer cells, these represent the basis for receptor-targeted tumour imaging in nuclear medicine with radiolabeled peptides as well as growth factor and growth factor receptor alterations may provide new potential targets for the cancer therapy [3], [4]. For e.g., cholectstokinin type-B receptor/gastrin receptor (CCK2R/GR) ligands allow for a sensitive and reliable staging of patients with metastatic medullary thyroid cancer (MTC) and thus adding in diagnosis and therapy of these tumours expressing CCK2R/GR [5]. As a consequence several radiolabeled cholecystokinin (CCK) or gastrin (Gs) analogues/derivatives have been formulated and use of these analogues for diagnostic imaging and possible therapy of cancers that overexpress these receptors in patients using in vivo CCK receptor scintigraphy are being explored proving the feasibility of targeting CCK receptors in human tumours [6], [7], [8], [9]. Thus knowing the exact contribution and type of these receptor in carcinogenesis will allow the development of noncytotoxic modalities therapy with hormones, antihormones or hormone ablation [10], [11].