Gene regulation of vasopressin and vasopressin receptors in cancer

Abstract

It is proposed that neuropeptide production by tumours is an important part of a special process of oncogenic transformation rather than a pre‐existing condition of progenitor cells; this concept is called Selective Tumour gene Expression of Peptides essential for Survival (STEPS). All small‐cell lung cancers and breast cancers evidently express the vasopressin gene, and this gene seems to be structurally normal in all but exceptional cases. Vasopressin gene expression in cancer cells leads to the production of both normal and abnormal forms of tumour vasopressin mRNA and proteins. Although the necessary post‐translational processing enzymes are expressed in these cells, most processing seems to be extragranular, and most of the protein products become components of the plasma membrane. Small‐cell lung cancer and breast cancer cells also express normal genes for all vasopressin receptors and produce normal vasopressin receptor mRNAs and V1a and V1b receptor proteins, and the vasopressin‐activated calcium mobilising (VACM) protein; plus both normal and abnormal forms of the V2 receptor. Through these receptors, vasopressin exercises multifaceted effects on tumour growth and metabolism. A normal protein vasopressin gene promoter seems to be present in small‐cell lung cancer cells, and this promoter contains all of the transcriptional elements known to be involved in gene regulation within hypothalamic neurones. Since these elements largely account for regulation of tumour gene expression observed in vitro, it is likely that as yet unknown factors are selectively produced by tumours in vivo to account for the observed seemingly autonomous or unregulated production of hormone in tumour patients. Promoter elements thought to be responsible for selective vasopressin gene expression in small‐cell lung cancer probably include an E‐box and a neurone restrictive silencer element close to the transcription start site. It is possible that transcription factors acting at these same elements can explain selective vasopressin expression, not only in small‐cell tumours, but also in all other tumours such as breast cancer. By extrapolation, similar mechanisms might also be responsible for the expression of additional features that characterize the ‘neuroendocrine’ profile of these cancers.

Oxytocin- and vasopressin-induced growth of human small-cell lung cancer is mediated by the mitogen-activated protein kinase pathway

“…Among such autocrine/paracrine loops, the neurohypophysial peptide system is implicated in the pathogenesis of an increasing number of cancers and particularly in small-cell lung carcinoma (SCLC) (North 2000. Ligands of this system include the neurohypophysial hormones oxytocin (OT) and vasopressin (VP).…”

The physiological and pathophysiological functions of renal and extrarenal vasopressin V2 receptors

“…Many tumors produce and secrete AVP, which has a mitogenic action on cellular growth (35,105,130). The presence of all AVP receptor subtypes, but particularly V2R, has been reported in transformed epithelial cells (86,89). V2R is present in a wide panel of human tumor cell lines, including human breast cancer cells (47), cervical cancer (85), lung cancer (95), and in corticotrophinomas (126).…”

Expression of V1A and GRP receptors leads to cellular transformation and increased sensitivity to substance-P analogue-induced growth inhibition

“…Small-cell lung cancer is a paradigm for neuropeptide-driven tumourigenesis. Small-cell lung cancer cells proliferate in response to a range of neuropeptide growth factors and in many cases these neuropeptides are involved in autocrine and paracrine growth loops, which fuel unrestrained proliferation (Moody et al, 1981;Sethi and Rozengurt, 1991;Sethi et al, 1992;North, 2000). This is thought to be part of a special process of oncogenic transformation called Selective Tumour gene Expression of Peptides essential for Survival (STEPS) (North, 2000).…”

“…Small-cell lung cancer cells proliferate in response to a range of neuropeptide growth factors and in many cases these neuropeptides are involved in autocrine and paracrine growth loops, which fuel unrestrained proliferation (Moody et al, 1981;Sethi and Rozengurt, 1991;Sethi et al, 1992;North, 2000). This is thought to be part of a special process of oncogenic transformation called Selective Tumour gene Expression of Peptides essential for Survival (STEPS) (North, 2000). The expression of neuropeptides and their receptors in tumour cells may render them sensitive to pharmacological therapeutic intervention and may be of diagnostic importance for the early detection of lung cancer and for the selection of appropriate treatment.…”