Histamine and histamine receptor regulation of gastrointestinal cancers

Histamine is a neurotransmitter released throughout the body that regulates multiple physiological responses. Primarily histamine is acknowledged for its role in inflammatory reactions to foreign pathogens that enter the body. Aside from inflammatory responses, histamine expression and synthesis has been detected in various cancer cell lines and multiple malignancies. Through experimentation histamine has demonstrated its ability to manage proliferation and angiogenesis in these cancerous cells, in either a positive or inhibitory manner. Regulation of angiogenesis and proliferation have been proven to be carried out by the stimulation or inhibition of numerous pathways and secondary response elements, such as VEGFA/C, IP₃/Ca²⁺, G-proteins, cAMP, and many more. The activation of these different response pathways is linked to the binding of ligands to the histamine receptors H1-H4HR. These receptors exhibit various effects dependent on whether it binds an agonist, antagonist, or its specific ligand, histamine. In cancer cell lines and different tumor cells the binding of these different compounds has shown to be one of the main components in exerting proliferative or antiproliferative changes in the microenvironment. It is also known that the histamine receptors have varying degrees of expression in different forms of cancer, and this expression can impact the tumor in various ways. This clearly indicates the significance of histamine receptors in cancer formation, and one of the aims of this review is to cover this topic concisely and in depth. Histamine is produced from numerous cells such as basophils and mast cells and is synthesized from the enzyme histidine decarboxylase (HDC). In this review we will prominently discuss the function of mast cells and HDC in histamine expression in various gastrointestinal carcinomas. We also briefly discuss current studies to support these claims. In this review we hope to give the reader a clear and comprehensible overview of histamine in various gastrointestinal cancers, and how its regulation can affect the cancer cells in varying ways.