The oncogenic and druggable hPG80 (Progastrin) is overexpressed in multiple cancers and detected in the blood of patients

Benoit You, Frédéric Mercier, Eric Assenat, Carole Langlois-Jacques, Olivier Glehen, Julien Soulé, Léa Payen, Vahan Kepenekian, Marie Dupuy, Fanny Belouin, Eric Morency, Véronique Saywell, Maud Flacelière, Philippe Elies, Pierre Liaud, Thibault Mazard, Delphine Maucort-Boulch, Winston Tan, Bérengère Vire, Laurent VilleneuveMarc Ychou, Manish Kohli, Dominique Joubert, Alexandre Prieur

Research output: Contribution to journalArticle

Abstract

Background: In colorectal cancer, hPG80 (progastrin) is released from tumor cells, promotes cancer stem cells (CSC) self-renewal and is detected in the blood of patients. Because the gene GAST that encodes hPG80 is a target gene of oncogenic pathways that are activated in many tumor types, we hypothesized that hPG80 could be expressed by tumors from various origins other than colorectal cancers, be a drug target and be detectable in the blood of these patients. Methods: hPG80 expression was monitored by fluorescent immunohistochemistry and mRNA expression in tumors from various origins. Cancer cell lines were used in sphere forming assay to analyze CSC self-renewal. Blood samples were obtained from 1546 patients with 11 different cancer origins and from two retrospective kinetic studies in patients with peritoneal carcinomatosis or hepatocellular carcinomas. These patients were regularly sampled during treatments and assayed for hPG80. Findings: We showed that hPG80 was present in the 11 tumor types tested. In cell lines originating from these tumor types, hPG80 neutralization decreased significantly CSC self-renewal by 28 to 54%. hPG80 was detected in the blood of patients at significantly higher concentration than in healthy blood donors (median hPG80: 4.88 pM versus 1.05 pM; p < 0.0001) and shown to be correlated to GAST mRNA levels in the matched tumor (i.e., lung cancers, Spearman r = 0.8; p = 0.0023). Furthermore, we showed a strong association between longitudinal hPG80 concentration changes and anti-cancer treatment efficacy in two independent retrospective studies. In the peritoneal carcinomatosis cohort, median hPG80 from inclusion to the post-operative period decreased from 5.36 to 3.00 pM (p < 0.0001, n = 62) and in the hepatocellular carcinoma cohort, median hPG80 from inclusion to remission decreased from 11.54 pM to 1.99 pM (p < 0.0001, n = 63). Interpretation: Because oncogenic hPG80 is expressed in tumor cells from different origins and because circulating hPG80 in the blood is related to the burden/activity of the tumor, it is a promising cancer target for therapy and for disease monitoring. Fundings: ECS-Progastrin.

Original languageEnglish (US)
Article number102574
JournalEBioMedicine
Volume51
DOIs
StatePublished - Jan 2020

Keywords

  • Blood biomarker
  • Cancer
  • Monitoring
  • Progastrin
  • Therapy
  • hPG80

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    You, B., Mercier, F., Assenat, E., Langlois-Jacques, C., Glehen, O., Soulé, J., Payen, L., Kepenekian, V., Dupuy, M., Belouin, F., Morency, E., Saywell, V., Flacelière, M., Elies, P., Liaud, P., Mazard, T., Maucort-Boulch, D., Tan, W., Vire, B., ... Prieur, A. (2020). The oncogenic and druggable hPG80 (Progastrin) is overexpressed in multiple cancers and detected in the blood of patients. EBioMedicine, 51, [102574]. https://doi.org/10.1016/j.ebiom.2019.11.035