Glycolytic competence in gastric adenocarcinomas negatively impacts survival outcomes of patients treated with salvage paclitaxel-ramucirumab

Abstract

Introduction For energy production, cancer cells maintain a high rate of glycolysis instead of oxidative phosphorylation converting glucose into lactic acid. This metabolic shift is useful to survive in unfavorable microenvironments. We investigated whether a positive glycolytic profile (PGP) in gastric adenocarcinomas may be associated with unfavorable outcomes under an anticancer systemic therapy, including the anti-angiogenic ramucirumab. Materials and methods Normal mucosa (NM) and primary tumor (PT) of 40 metastatic gastric adenocarcinomas patients who received second-line paclitaxel-ramucirumab (PR) were analyzed for mRNA expression of the following genes: HK-1, HK-2, PKM-2, LDH-A, and GLUT-1. Patients were categorized with PGP when at least a doubling of mRNA expression (PT vs. NM) in all glycolytic core enzymes (HK-1 or HK-2, PKM-2, LDH-A) was observed. PGP was also related to TP53 mutational status. Results Mean LDH-A, HK-2, PKM-2 mRNA expression levels were significantly higher in PT compared with NM. 18 patients were classified as PGP, which was associated with significantly worse progression-free and overall survival times. No significant association was observed between PGP and clinical-pathologic features, including TP53 positive mutational status, in 28 samples. Conclusions Glycolytic proficiency may negatively affect survival outcomes of metastatic gastric cancer patients treated with PR systemic therapy. TP53 mutational status alone does not seem to explain such a metabolic shift.

Apolipoprotein C‐II induces EMT to promote gastric cancer peritoneal metastasis via PI3K/AKT/mTOR pathway

“…Then, we tested whether APOC2 can affect the expression of glycolysis‐related proteins (GLUT1, HK2, PKM2, and LDHA). 37 We found that APOC2 knockdown significantly inhibited the expression of HK2 in AGS and BGC‐823 cells, except for GLUT1, PKM2, and LDHA. Regarding whether APOC2 can regulate the expression of lipid metabolism‐related proteins, we verified the relationship between APOC2 knockdown and its closely related lipid metabolism proteins (LIPL, LDLR, and LRP1).…”

Monocarboxylate Transporters 1 and 4 and MTCO1 in Gastric Cancer

“…Normal cells produce energy through mitochondrial oxidative phosphorylation. The last product of the glycolysis is pyruvate, which enters the mitochondria where it is oxidized by the citric acid cycle to generate energy [ 20 ]. However, in cancer cells, pyruvate is fermented into lactate, even in aerobic conditions and fully functioning mitochondria available.…”

“…Lactate is not only a waste for tumors; cancer cells also become more aggressive and resistant to therapy by acidifying their microenvironment. Low pH and lactate enable cancer cells to migrate, invade, promote angiogenesis, immune escape, and radioresistance [ 20 , 21 , 22 ]. The MCT family includes 14 members, among which MCT1-4 are catalyzing the proton-linked transport of pyruvate, lactate, and ketone bodies across the cell membrane [ 23 ].…”

Protein Phosphatase 2A Inhibits Gastric Cancer Cell Glycolysis by Reducing MYC Signaling

“…Therapies targeting the Warburg effect have a profound inhibitory effect on tumor progression. In gastric cancer, glycolytic pro ciency negatively affects survival outcomes of metastatic gastric cancer patients treated with paclitaxel-ramucirumab systemic therapy [8]. Notably, several reports have documented the regulators of the Warburg effect in gastric cancer, such as MACC1 [9], FBP1 [10], WTAP [11], and MUC16 [12].…”