Gene regulation of vasopressin and vasopressin receptors in cancer.
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.