Progastrin is an intracellular protein that is, or not, maturated into gastrin.
Non Pathologic Condition
Progastrin is not found in the blood of healthy people.
When progastrin is maturated into gastrin, it is released from the cells.
When gastrin is produced by the G cells of the stomach antrum, it plays its role to control acidic secretions during digestion.
When progastrin is not maturated into gastrin, it is released from the cells as such and named hPG80.
This only happens in tumor cells, whatever the tumor cell: progastrin becomes a circulating protein, hPG80, which can be detected in the blood of cancer patients.
hPG80 (circulating progastrin) is detected in the blood of cancer patients.
The ROCHE laboratory markets a test for the detection of Progastrin-releasing peptide (Pro-GRP) to differentiate between 2 types of lung cancer. hPG80 (Progastrin) and Progastrin-releasing peptide (Pro-GRP) are two completely different proteins even though they share the word "Progastrin / Pro-Gastrin” with the same phonetics.
Activation – Non activation of Wnt/ß-Catenin Pathway
The Wnt signaling pathway is an evolutionarily conserved signal transduction pathway that regulates a wide range of cellular functions during development and adulthood. It controls multiple aspects of development, including cell proliferation, cell fate determination, apoptosis, cell migration and cell polarity during development and stem cell maintenance in adults. Inappropriate activation of the Wnt pathway is also a major factor in human oncogenesis (Ng et al, Cells, 2019).
Normal Cell: ON
Normal Cell: OFF
An early event in cancer development
Chronic activation of the Wnt/ß-catenin pathway is a central mechanism in cancer biology that is implicated in:
Induction of cellular proliferation and blocking of differentiation leading to primary tumor growth,
Induction of epithelial mesenchymal transition (EMT) leading to metastasis formation,
Regulation of cancer stem cell pathways leading to chemoresistance and relapse.
hPG80: the gene GAST coding for hPG80
is a direct Wnt/ß-catenin Target Gene
In normal cells: Tunable (On/Off) activation of the Wnt/ß-catenin target genes.
In cancer cells: Constitutively activated Wnt/ß-catenin pathway leads to continuous expression of the gene GAST coding for hPG80 and secretion of hPG80.
Tumor Cell: always ON
Cancer stem cells (CSCs) play an important role in tumor initiation and progression.
CSCs are cells within a tumor that possess the capacity to self-renew, to give rise to the heterogeneous lineages, to be resistant to standard therapy and to initiate tumor recurrence and metastasis (Curtin el al, Oncotarget 2010).
CSCs need hPG80 for their survival (Giraud et al, Cancer Research, 2016; Prieur et al, Clin Cancer Research, 2017).
CSCs secrete 100 to 1000 more of hPG80 than non-CSC cancer cells (Prieur et al, Clin Cancer Research, 2017).
Secreted hPG80 maintains the stemness of CSCs (Prieur et al, Clin Cancer Research, 2017).
Neutralization of secreted hPG80 by a therapeutic antibody decreases CSCs frequency, metastatic seeding, increases chemosensitivity and delays relapses (Prieur et al, Clin Cancer Research, 2017).