Glycolytic competence in gastric adenocarcinomas negatively impacts survival outcomes of patients treated with salvage p
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ORIGINAL ARTICLE
Glycolytic competence in gastric adenocarcinomas negatively impacts survival outcomes of patients treated with salvage paclitaxel‑ramucirumab Annamaria Ruzzo1 · Francesco Graziano2 · Irene Bagaloni1 · Maria Di Bartolomeo3 · Michele Prisciandaro3 · Giuseppe Aprile4 · Elena Ongaro5 · Bruno Vincenzi6 · Giuseppe Perrone6 · Daniele Santini6 · Lorenzo Fornaro7 · Caterina Vivaldi7 · Gianluca Tomasello8 · Fotios Loupakis9 · Sara Lonardi9 · Matteo Fassan10 · Michele Valmasoni11 · Donatella Sarti2 · Paola Lorenzini2 · Vincenzo Catalano2 · Renato Bisonni12 · Michela Del Prete12 · Guido Collina13 · Mauro Magnani1 Received: 25 February 2020 / Accepted: 23 April 2020 © The Author(s) 2020
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. Keywords Glycolysis · Warburg effect · Ramucirumab · Paclitaxel · Angiogenesis
Background
Annamaria Ruzzo and Francesco Graziano have contributed equally. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10120-020-01078-0) contains supplementary material, which is available to authorized users. * Annamaria Ruzzo [email protected] * Francesco Graziano [email protected] Extended author information available on the last page of the article
For energy production under aerobic conditions, normal cells generally transform glucose into carbonic anhydride by means of oxidative phosphorylation. Conversely, glycolysis with ultimate production of lactate is predominant in invasive cancer cells, even in the presence of sufficient levels of o
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