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

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

Prognostic Value of Plasma hPG80 (Circulating Progastrin) in Metastatic Renal Cell Carcinoma

“…The close relationship between hPG80 and cancer progression has been previously reported in several studies [21,[24][25][26][27][28]. We have recently shown that tumor cells from many cell types overexpress hPG80 [17]. Its expression is related to cancer cell activity and represents a risk factor for tumor recurrence and therefore hPG80 may provide prognostic significance in metastatic stages of tumors which secrete hPG80 in measurable amounts.…”

“…We have reported previously [17] progastrin to be elevated in plasma of patients with metastatic kidney cancer. In physiology, progastrin is the precursor of gastrin synthetized by antrum G cells and processed into gastrin [18].…”

“…As a consequence, progastrin is barely detectable in the blood of healthy subjects even though few of them have been shown to be positive as observed the first time by Siddheshwar et al [20]. However, in line with the demonstration of the expression of the GAST gene, encoding progastrin, in colorectal tumors as well as other tumor types, high levels of hPG 80 (named as such when progastrin is released from tumor cells and detected in the blood) were reported in the blood of cancer patients [17,20,21]. Moreover, in addition to the fact that GAST is a direct target of the ß-catenin/Tcf4 pathway, activated in many cancers, including RCC [22,23], a large body of literature supports the functional role of hPG 80 in tumorigenesis [21,[24][25][26][27][28].…”

A novel method to detect hPG80 (human circulating progastrin) in the blood

“…The analytical sensitivity obtained for the DxPG 80 is a LoD of 1 pM and a LLoQ of 3.3 pM. Of note, the calculation is slightly different from the LoD and LLoQ described in 24,25 to follow the exact guideline EMEA/CHMP/EWP/192217/2009.…”

“…The presence of hPG 80 in the blood reects the variations in the tumor: (1) plasma levels correlate with mRNA expression (lung cancer; Spearman r ¼ 0.8; p ¼ 0.0023); (2) plasma levels signicantly decrease upon surgery (peritoneal carcinomatosis decrease from 5.36 pM (before surgery) to 3.00 pM (post surgery), p <0.0001 and upon remission (hepatocellular cancer, decrease from 11.54 pM to 1.99 pM (p < 0.0001); (3) the level of hPG 80 at diagnostic is a prognostic factor in metastatic renal cell carcinoma (mRCC) patients: Furthermore, mRCC patients with high hPG 80 levels (>4.5 pM) had signicantly lower OS (overall survival) compared to patients with low hPG 80 levels (<4.5 pM) (12 versus 31.2 months, respectively; p ¼ 0.0031); (4) efficacy of treatments correlates with hPG 80 level kinetic variations and recurrence is associated with an increase in hPG 80 level (hepatocellular cancer). 25 All these data re-inforce the value of hPG 80 as a new cancer target and prone to the usefulness of the detection of hPG 80 in the blood.…”