5-Fluorouracil resistance mechanisms in colorectal cancer: From classical pathways to promising processes

Abstract

Colorectal cancer (CRC) is a public health problem. It is the third most common cancer in the world, with nearly 1.8 million new cases diagnosed in 2018. The only curative treatment is surgery, especially for early tumor stages. When there is locoregional or distant invasion, chemotherapy can be introduced, in particular 5-fluorouracil (5-FU). However, the disease can become tolerant to these pharmaceutical treatments: resistance emerges, leading to early tumor recurrence. Different mechanisms can explain this 5-FU resistance. Some are disease-specific, whereas others, such as drug efflux, are evolutionarily conserved. These mechanisms are numerous and complex and can occur simultaneously in cells exposed to 5-FU. In this review, we construct a global outline of different mechanisms from disruption of 5-FU-metabolic enzymes and classic cellular processes (apoptosis, autophagy, glucose metabolism, oxidative stress, respiration, and cell cycle perturbation) to drug transporters and epithelial-mesenchymal transition induction. Particular interest is directed to tumor microenvironment function as well as epigenetic alterations and miRNA dysregulation, which are the more promising processes that will be the subject of much research in the future.

Keywords: 5-fluorouracil; colorectal cancer; resistance mechanism.

FIGURE 1

5‐Fluorouracil (5‐FU) metabolism. 5‐FUPA, fluoroureidopropionic acid; 5‐FUH2, 5‐fluorodihydrouracil; 5‐FdUDP, 5‐fluorodeoxyuridine diphosphate; 5‐FdUMP, 5‐fluorodeoxyuridine monophosphate; 5‐FdUTP, 5‐fluorodeoxyuridine triphosphate; 5‐FUdR, 5‐fluorouracil deoxyribose; 5‐FUDP, 5‐fluorouridine diphosphate; 5‐FUMP, 5‐fluorouridine monophosphate; 5‐FUR, 5‐fluorouracil ribonucleoside; 5‐FUTP, 5‐fluorouridine triphosphate; CH2THF, 5,10‐methylene tetrahydrofolic acid; DHF, dihydrofolic acid; DPD, dihydropyrimidine dehydrogenase; DPYS, dihydropyrimidinase; dTDP, deoxythymidine diphosphate; dTMP, deoxythymidine monophosphate; dTTP, deoxythymidine triphosphate; dUDP, deoxyuridine diphosphate; dUMP, deoxyuridine monophosphate; dUTP, deoxyuridine triphosphate; NDK, nucleoside diphosphate kinase; OPRT, orotate phosphoribosyltransferase; PRPP, phosphoribosyl pyrophosphate; PP, pyrophosphate; TK, thymidine kinase; TP, thymidine phosphorylase; TS, thymidylate synthase; UP, uridine phosphorylase; UBP1, β‐ureidopropionase 1; UK, uridine kinase; UMPK, uridine monophosphate kinase.

FIGURE 2

Tumor microenvironment (TME) implication in 5‐fluorouracil (5‐FU) resistance. Colorectal cancer (CRC) tumors are mainly composed of CRC cells and cancer stem cells (CSCs), which interact with other cellular partners like immunity cells M1 (macrophage type 1), tumor‐associated macrophages (TAMs), T lymphocytes (TLs), and dendritic cells and also with cancer‐associated fibroblasts (CAFs). Each association is responsible of a reaction playing a key function in 5‐FU resistance driving to apoptosis inhibition, cell cycle arrest, proliferative induction, immune escape and CSC maintenance. A, M1 response. B, Activation of TAMs and released soluble factors. C, CAFs, CAF‐released soluble factors, and CSCs. D, E, Implication of other players like cytokines (chemokine [C‐C motif] ligand 21 [CCL21], transforming growth factor‐β [TGF‐β]) and chemokines (programmed cell death‐ligand 1 [PD‐L1]). CCR, chemokine (C‐C motif) receptor; CM, conditioned medium; IL, interleukin; PD‐1, programmed cell death‐1;