TY - JOUR
T1 - The oncogenic and druggable hPG80 (Progastrin) is overexpressed in multiple cancers and detected in the blood of patients
AU - You, Benoit
AU - Mercier, Frédéric
AU - Assenat, Eric
AU - Langlois-Jacques, Carole
AU - Glehen, Olivier
AU - Soulé, Julien
AU - Payen, Léa
AU - Kepenekian, Vahan
AU - Dupuy, Marie
AU - Belouin, Fanny
AU - Morency, Eric
AU - Saywell, Véronique
AU - Flacelière, Maud
AU - Elies, Philippe
AU - Liaud, Pierre
AU - Mazard, Thibault
AU - Maucort-Boulch, Delphine
AU - Tan, Winston
AU - Vire, Bérengère
AU - Villeneuve, Laurent
AU - Ychou, Marc
AU - Kohli, Manish
AU - Joubert, Dominique
AU - Prieur, Alexandre
N1 - Publisher Copyright:
© 2019 The Author(s)
PY - 2020/1
Y1 - 2020/1
N2 - 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.
AB - 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.
KW - Blood biomarker
KW - Cancer
KW - Monitoring
KW - Progastrin
KW - Therapy
KW - hPG80
UR - http://www.scopus.com/inward/record.url?scp=85076692687&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85076692687&partnerID=8YFLogxK
U2 - 10.1016/j.ebiom.2019.11.035
DO - 10.1016/j.ebiom.2019.11.035
M3 - Article
C2 - 31877416
AN - SCOPUS:85076692687
SN - 2352-3964
VL - 51
JO - EBioMedicine
JF - EBioMedicine
M1 - 102574
ER -