Autocrine Secretion of Progastrin Promotes the Survival and Self-Renewal of Colon Cancer Stem–like Cells

Giraud, Julie; Failla, Laura M.; Pascussi, Jean‐Marc; Lagerqvist, Ebba L.; Ollier, Jérémy; Finetti, Pascal; Bertucci, François; Chu, Ying; Gasmi, Imène; Bourgaux, Jean–François; Prudhomme, Michel; Mazard, Thibault; Aït-Arsa, Imade; Houhou, Leila; Birnbaum, Daniel; Pèlegrin, André; Vincent, Charles; Ryall, James G.; Joubert, Dominique; Pannequin, Julie; Hollande, Frédéric

doi:10.1158/0008-5472.can-15-1497

Cited by 47 publications

(45 citation statements)

References 54 publications

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“…ANOVA was used for comparisons among three groups of quantitative variables, and pairwise comparisons were carried out using the Tukey post hoc test as indicated. Statistical significance of stem cell frequencies quantified using Extreme Limiting Dilution Analysis (ELDA) was assessed using the x 2 test, as described previously (18).…”

Section: Discussionmentioning

confidence: 99%

“…To establish whether this is reflected by an increased self-renewal frequency of ALDH High cells, we FACSpurified ALDH High T84 cells and transfected them in suspension with claudin-2-selective or control siRNA. 12 hours later these cells were seeded in an ELDA assay and the stem cell frequency of each cell population was quantified after 10 days as described previously (18). Claudin-2 downregulation significantly decreased the stem cell frequency from 1 in every 6.24 cells (confidence interval 1/3.31-1/11.8) to 1 in every 39.8 cells (1/21.2-1/74.8; x 2 test (x 2 ¼ 14.6; Ã , P ¼ 0.000132; Fig.…”

Section: Claudin-2 Regulates the Self-renewal Capacity Of Aldh High Cmentioning

confidence: 99%

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Tight Junction Protein Claudin-2 Promotes Self-Renewal of Human Colorectal Cancer Stem-like Cells

et al. 2018

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Posttreatment recurrence of colorectal cancer, the third most lethal cancer worldwide, is often driven by a subpopulation of cancer stem cells (CSC). The tight junction (TJ) protein claudin-2 is overexpressed in human colorectal cancer, where it enhances cell proliferation, colony formation, and chemoresistance While several of these biological processes are features of the CSC phenotype, a role for claudin-2 in the regulation of these has not been identified. Here, we report that elevated claudin-2 expression in stage II/III colorectal tumors is associated with poor recurrence-free survival following 5-fluorouracil-based chemotherapy, an outcome in which CSCs play an instrumental role. In patient-derived organoids, primary cells, and cell lines, claudin-2 promoted colorectal cancer self-renewal and in multiple mouse xenograft models. Claudin-2 enhanced self-renewal of ALDH CSCs and increased their proportion in colorectal cancer cell populations, limiting their differentiation and promoting the phenotypic transition of non-CSCs toward the ALDH phenotype. Next-generation sequencing in ALDH cells revealed that claudin-2 regulated expression of nine miRNAs known to control stem cell signaling. Among these, miR-222-3p was instrumental for the regulation of self-renewal by claudin-2, and enhancement of this self-renewal required activation of YAP, most likely upstream from miR-222-3p. Taken together, our results indicate that overexpression of claudin-2 promotes self-renewal within colorectal cancer stem-like cells, suggesting a potential role for this protein as a therapeutic target in colorectal cancer. Claudin-2-mediated regulation of YAP activity and miR-222-3p expression drives CSC renewal in colorectal cancer, making it a potential target for therapy. .

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Section: Discussionmentioning

confidence: 99%

Section: Claudin-2 Regulates the Self-renewal Capacity Of Aldh High Cmentioning

confidence: 99%

Tight Junction Protein Claudin-2 Promotes Self-Renewal of Human Colorectal Cancer Stem-like Cells

et al. 2018

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“…Initially believed to be biologically inactive, hPG80 was shown to participate in some features of a tumor, such as the disruption of cellÀcell junctions [6], cell proliferation [7], inhibition of apoptosis [8], regulation of cancer stem cells [9], and angiogenesis [10]. In addition, our team demonstrated that targeting hPG80 with a specific antibody promotes apoptosis, decreases proliferation and migration/ invasion of human colorectal cancer cells, and inhibits self-renewal of colon cancer stem cells (CSC), as well as Wnt-driven tumorigenesis in mice [5].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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

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“…Novel roles of gastrins, including progastrin, are currently under discussion (Giraud et al. ; Rehfeld ). This study suggests that N‐terminal progastrin fragments infused in high doses can acutely inhibit gastrin‐stimulated acid secretion in man.…”

Section: Discussionmentioning

confidence: 99%

Acute effects of N‐terminal progastrin fragments on gastric acid secretion in man

Goetze

Hansen

Rehfeld

2017

Physiological Reports

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We previously identified an N‐terminal fragment of progastrin in human antrum and plasma, where it circulates in high concentrations. In this study, we examined the effects of N‐terminal progastrin fragments on gastric acid secretion by infusion in healthy individuals. Increasing doses of progastrin fragment 1‐35 were infused intravenously during constant gastric acid stimulation by gastrin‐17. In addition, the effects of progastrin fragment 1‐35, fragment 6‐35, and fragment 1‐19 on gastrin‐17 stimulated acid secretion were tested. The gastrin‐17 stimulated acid secretion decreased 30% after administration of a high dose of progastrin fragment 1‐35 (P < 0.05). In extension, a 1‐h infusion of fragment 1‐35 also decreased gastric acid output. In contrast, fragment 6‐35 did not affect acid secretion, and a single infusion of gastrin‐17 alone did not reveal fading of gastric acid output during the time course of the experiments. The results show that N‐terminal fragments of progastrin may acutely affect gastrin‐stimulated gastric acid secretion in vivo. Structure‐function analysis suggests that the N‐terminal pentapeptide of progastrin is required for the effect.

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Autocrine Secretion of Progastrin Promotes the Survival and Self-Renewal of Colon Cancer Stem–like Cells

Cited by 47 publications

References 54 publications

Tight Junction Protein Claudin-2 Promotes Self-Renewal of Human Colorectal Cancer Stem-like Cells

Tight Junction Protein Claudin-2 Promotes Self-Renewal of Human Colorectal Cancer Stem-like Cells

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

Acute effects of N‐terminal progastrin fragments on gastric acid secretion in man

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