title: Histamine and Histaminergic Receptors in Colorectal Cancer: From Basic Science to Evidence-based Medicine.
abstract: Histamine is an imidazolic compound performing a crucial function in the pathogenesis of inflammation. Several studies have also emphasized its pro-carcinogenic effect in colorectal cancer (CRC).
  
  
  
  In fact, increased histamine levels have been observed in CRC and a decreased catabolism of this molecule is typical of colorectal adenomas. Additional data have demonstrated that CRC is characterized by an altered balance of histamine receptors (HRs); in fact, HR1 and HR4 are down-regulated in CRC, while HR2 is overexpressed.
  
  
  
  Based on this evidence, we reviewed several studies investigating the role of HR2 antagonists (HR2A), such as cimetidine in CRC.
  
  
  
  From a clinical point of view, HR2A may prolong the survival rates of patients with CRC, and a recent meta-analysis seems to confirm this finding. From a biological perspective, it has been demonstrated that HR2A could have a beneficial effect on CRC for many reasons: i) promotion of peri-tumoral lymphocyte growth and improvement of immune response against the tumor, ii) suppression of adhesion molecules which might favor metastasis, iii) anti-angiogenetic activity (reduction of VEGF), iv) increased production of some cytokines which may counteract tumor growth, such as tumor necrosis factor (TNF) alpha, interleukin (IL)-10 and IL-15. On the contrary, HR1 antagonists did not demonstrate any beneficial effect on CRC. Therefore, it is presumable that histamine could be a relevant player in the development of CRC, but its effect might be mediated by an imperfect homeostasis of its receptors.
  
  
  
  In this scenario, HR2A could inhibit carcinogenesis whereas HR2 might act as a pro-carcinogenetic, while HR1 and HR4, being suppressed in CRC, may antagonize neoplastic development.
authors.affiliation: Gastroenterology Division, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Losurdo
authors.affiliation: Gastroenterology Division, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
authors.forename: Mariabeatrice
authors.initials: M
authors.lastname: Principi
authors.affiliation: Gastroenterology Division, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
authors.forename: Bruna
authors.initials: B
authors.lastname: Girardi
authors.affiliation: Gastroenterology Division, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Pricci
authors.affiliation: Gastroenterology Division, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Barone
authors.affiliation: Gastroenterology Division, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
authors.forename: Enzo
authors.initials: E
authors.lastname: Ierardi
authors.affiliation: Gastroenterology Division, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Di Leo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D019317:Evidence-Based Medicine; D006632:Histamine / Q000378:metabolism*; D006633:Histamine Antagonists / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D011968:Receptors, Histamine / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D006633:Histamine Antagonists; D011968:Receptors, Histamine; D006632:Histamine
keywords: Colorectal cancer; carcinogenesis; histamine; histamine receptor 2 antagonists; histaminergic receptors; receptors.