Progastrin Peptides Increase the Risk of Developing Colonic Tumors: Impact on Colonic Stem Cells

Abstract

Pre-neoplastic lesions (ACF, aberrant-crypt-foci; Hp, hyperplastic/dysplastic polyps) are believed to be precursors of sporadic colorectal-tumors (Ad, adenomas; AdCA, adenocarcinomas). ACF/Hp likely originate due to abnormal growth of colonic-crypts in response to aberrant queues in the microenvironment of colonic-crypts. Thus identifying factors which regulate homeostatic vs aberrant proliferation/apoptosis of colonocytes, especially stem/progenitor cells, may lead to effective preventative/treatment strategies. Based on this philosophy, role of growth-factors/peptide-hormones, potentially available in the circulation/microenvironment of colonic-crypts is being examined extensively. Since the time gastrins were discovered as trophic (growth) factors for gastrointestinal-cells, the effect of gastrins on the growth of normal/cancer cells has been investigated, leading to many discoveries. Seminal discoveries made in the area of gastrins and colon-cancer, as it relates to molecular pathways associated with formation of colonic tumors will be reviewed, and possible impact on diagnostic/preventative/treatment strategies will be discussed.

Figure 1. Hypothetical Model of Molecular Pathways Associated with Development of Sporadic Hyperprolifative/Dysplastic/Adenomatous growths in the Colons: Role of Endocrine/Autocrine Progastrins

athways 1–3 represent genetic/epigenetic mechanisms believed to be associated with the development of sporadic colonic growths/tumors in humans and rodent models of investigation (reviewed in 17). At least three sub-types of sporadic Adenomas have been described, based on phenotype and associated genotype (in terms of MSI/CIMP/CIN (aneuploidy)) (reviewed in 17). Many of these genetic/epigenetic changes, associated with pathways 1–3, can potentially increase the expression of autocrine progastrins (PG) in the colonic growths and serum of patients with CRCs, as described in the text. In addition a 4^th pathway, termed growth factor/cytokine pathway, can significantly increase the risk for developing sporadic colonic growths, in response to DNA damaging agents and/or the indicated genetic/epigenetic changes, leading perhaps to more aggressive growths in a shorter time-frame. Risk factors, believed to be associated with the 4^th pathway are indicated and may include: 1) elevated levels of endocrine/paracrine progastrins, as in Hypergastrenemic patients; 2) elevated cytokines/growth factors associated with inflammation/obesity/specific infections, as discussed in the text. The 4^th pathway, associated with a sustained increase in the associated risk factors, likely results in sustained elevation of the indicated intracellular-kinases/transcription-factors, resulting in hyperproliferation of the affected colonic-crypts and possible transformation of the colonic-stem-cells, significantly increasing the risk for developing dysplastic/neoplastic growths. Abbreviations of key words used in here are described in the text. The role of specific molecules/pathways presented in here, were derived from a large number of reports in literature, referred to in the text.