5-Fluorouracil Conversion Pathway Mutations in Gastric Cancer

Abstract

To date, 5-Fluorouracil (5FU) is a major component of several chemotherapy regimens, thus its study is of fundamental importance to better understand all the causes that may lead to chemoresistance and treatment failure. Given the evident differences between prognosis in Asian and Caucasian populations, triggered by clear genetic discordances and given the extreme genetic heterogeneity of gastric cancer (GC), the evaluation of the most frequent mutations in every single member of the 5FU conversion and activation pathway might reveal several important results. Here, we exploited the cBioPortal analysis software to query a large databank of clinical and wide-genome studies to evaluate the components of the three major 5FU transformation pathways. We demonstrated that mutations in such ways were associated with a poor prognosis and reduced overall survival, often caused by a deletion in the TYMP gene and amplification in TYMS. The use of prodrugs and dihydropyrimidine dehydrogenase (DPD) inhibitors, which normally catabolizes 5FU into inactive metabolites, improved such chemotherapies, but several steps forward still need to be taken to select better therapies to target the chemoresistant pools of cells with high anaplastic features and genomic instability.

Enhanced Vasculogenic Capacity Induced by 5-Fluorouracil Chemoresistance in a Gastric Cancer Cell Line

“…It is to date well established the involvement of the thymidine phosphorylase-thymidylate synthase axis in 5-FU metabolism and activation. As already reported [18] TYMP in particular plays a major role also in angiogenesis interacting with several pro-angiogenic factors. Indeed, evaluating such markers by qPCR, we evidenced a significant upregulation of both TYMP and TYMS in 5FUr cells, as shown in Figure 5a.…”

“…This phenomenon is routinely observed in clinical practice, when repeated chemotherapy treatments cause an initial reduction of the tumor mass, until a resistant cell subset arises from the heterogeneous pool of mutated cells and starts to grow back. These chemo- and radio-resistant cells often gain invasive and migratory capacities leading to cancer cell spreading and formation of metastases in distant tissues [ 18 ]. The tumor microenvironment might also contribute to chemoresistance, generating an intricate net of endothelial vessels to allow the tumor mass to reach a continuous source of nutrients and oxygen but preventing the delivery of chemotherapy.…”

“…Tumor angiogenesis was also found increased in sorafenib-resistant hepatocellular carcinomas through the upregulation of VEGF signaling associated with cancer stem cells [ 28 ]. TYMP is commonly reported to play a major role in 5-FU chemoresistance and is often found to be overexpressed in both diffuse and intestinal gastric adenocarcinomas [ 18 ]. TYMP is also closely associated with the metastatic phenotype, although no statistically relevant data about its expression in chemoresistant patients is available from the databanks [ 29 ].…”

“…If this mechanism of action is shared by thalidomide, TYMP inhibition could revert TYMP-induced chemoresistance and the relative increased vascular formation. It is clear that a complex phenomenon such as chemoresistance cannot most probably be explained just with the upregulation of a single enzyme and that other players are obviously involved in the modulation of the TYMP/TYMS axis [ 18 ].…”

Metabolism-associated genes in occurrence and development of gastrointestinal cancer: Latest progress and future prospect

“…For example, ASS1, a signaling pathway involved in the regulation of metabolic genes, promotes GC invasion and progression mainly through the regulation of autophagy[ 29 ]. TYMS5 is involved in the fluorouracil conversion pathway，which is associated with chemoresistance and treatment failure by 5-FU in GC[ 48 ]. Kong et al [ 49 ] reported that MIF is associated with the p53 pathway in GC[ 49 ].…”