Progastrin Peptides Increase the Risk of Developing Colonic Tumors: Impact on Colonic Stem Cells

Singh, Pomila; Sarkar, Shubhashish; Kantara, Carla; Maxwell, Carrie

doi:10.1007/s11888-012-0144-3

Cited by 16 publications

(15 citation statements)

References 94 publications

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“…This evidence has prompted several pharmacological strategies to neutralize the activity of gastrin peptides, with successful results in murine models but, unfortunately, few and indefinite results in patients [30]. Our findings suggest that, at least in humans, progastrin can play a multifaceted role in the progression of colorectal tumors, as its proliferative activity on epithelial cells would be opposed by a potentially anti-tumoral action exerted on macrophages.…”

Section: Discussionmentioning

confidence: 82%

Progastrin Represses the Alternative Activation of Human Macrophages and Modulates Their Influence on Colon Cancer Epithelial Cells

et al. 2014

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Macrophage infiltration is a negative prognostic factor for most cancers but gastrointestinal tumors seem to be an exception. The effect of macrophages on cancer progression depends on their phenotype, which may vary between M1 (pro-inflammatory, defensive) to M2 (tolerogenic, pro-tumoral). Gastrointestinal cancers often become an ectopic source of gastrins and macrophages present receptors for these peptides. The aim of the present study is to analyze whether gastrins can affect the pattern of macrophage infiltration in colorectal tumors. We have evaluated the relationship between gastrin expression and the pattern of macrophage infiltration in samples from colorectal cancer and the influence of these peptides on the phenotype of macrophages differentiated from human peripheral monocytes in vitro. The total number of macrophages (CD68+ cells) was similar in tumoral and normal surrounding tissue, but the number of M2 macrophages (CD206+ cells) was significantly higher in the tumor. However, the number of these tumor-associated M2 macrophages correlated negatively with the immunoreactivity for gastrin peptides in tumor epithelial cells. Macrophages differentiated from human peripheral monocytes in the presence of progastrin showed lower levels of M2-markers (CD206, IL10) with normal amounts of M1-markers (CD86, IL12). Progastrin induced similar effects in mature macrophages treated with IL4 to obtain a M2-phenotype or with LPS plus IFNγ to generate M1-macrophages. Macrophages differentiated in the presence of progastrin presented a reduced expression of Wnt ligands and decreased the number and increased cell death of co-cultured colorectal cancer epithelial cells. Our results suggest that progastrin inhibits the acquisition of a M2-phenotype in human macrophages. This effect exerted on tumor associated macrophages may modulate cancer progression and should be taken into account when analyzing the therapeutic value of gastrin immunoneutralization.

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Section: Discussionmentioning

confidence: 82%

Progastrin Represses the Alternative Activation of Human Macrophages and Modulates Their Influence on Colon Cancer Epithelial Cells

et al. 2014

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“…Cell surface Annexin A2 (CS-ANXA2), represents a non-conventional receptor for PG [ 22 ], and is required for mediating mitogenic/co-carcinogenic effects of PG on target cells [ 23 ]. Both PG and CS-ANXA2 regulate tumorigenic and metastatic potential of colon cancer cells [ 14 , 21 – 23 ]. CS-ANXA2 is increasingly expressed by aggressive epithelial tumor cells and is required for metastasis of many cancer cells [ 14 , 21 – 26 ].…”

Section: Introductionmentioning

confidence: 99%

Methods for detecting circulating cancer stem cells (CCSCs) as a novel approach for diagnosis of colon cancer relapse/metastasis

Kantara

O’Connell

Luthra

et al. 2015

Laboratory Investigation

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Cancer stem cells (CSCs) are believed to be resistant to currently available therapies and maybe responsible for relapse of cancer in patients. Measuring circulating tumor cells (CTCs) in blood of patients has emerged as a non-invasive diagnostic procedure for screening patients who may be at high risk for developing metastatic cancers or relapse of the cancer disease. However, accurate detection of CTCs has remained a problem, since epithelial-cell-markers used to-date, are not always reliable for detecting CTCs, especially during epithelial-mesenchymal-transition. Since CSCs are required to initiate metastatic tumors, our goal was to optimize and standardize a method for identifying circulating CSCs (CCSCs) in patients, using established CSC markers. Here, we report for the first time the detection of CCSCs in blood of athymic nude mice, bearing metastatic tumors, and in the blood of patients positive for colonic adenocarcinomas. Using a simple and non-expensive method, we isolated a relatively pure population of CSCs (CD45−/CK19+), free of red blood cells and largely free of contaminating CD45+ white blood cells. Enriched CCSCs from patients with colon adenocarcinomas had a malignant phenotype and co-expressed CSC markers (DCLK1/LGR5) with CD44/Annexin A2. CSCs were not found in the blood of non-cancer patients, free of colonic growths. Enriched CCSCs from colon cancer patients grew primary spheroids, suggesting presence of tumor-initiating cells in the blood of these patients. In conclusion, we have developed a novel diagnostic assay for detecting CSCs in circulation, which may more accurately predict the risk of relapse or metastatic disease in patients. Since CSCs can potentially initiate metastatic growths, patients positive for CCSCs can be treated with inhibitory agents that selectively target CSCs, besides conventional treatments, to reduce the risk of relapse/metastatic disease for improving clinical outcomes.

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“…PG peptide induces hyper proliferation of colonic crypts and increases colon-carcinogenesis by many fold, in response to AOM±DSS (19,20,(24)(25)(26)(27). Besides, PG is expressed by >80% of human colon cancer cell lines (hCCCs) and CRCs (28,29). Surprisingly, overexpression of PG, resulted in imparting tumorigenic/metastatic phenotype to HEK293 cells, associated with significant up-regulation of DCLK1+ cell populations in HEKmGAS vs. HEKC cells (23).…”

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confidence: 99%

Epigenetic regulation of human DCLK-1 gene during colon-carcinogenesis: clinical and mechanistic implications

Singh

O’Connell

Sarkar

2016

Stem Cell Investig.

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Progastrin Peptides Increase the Risk of Developing Colonic Tumors: Impact on Colonic Stem Cells

Cited by 16 publications

References 94 publications

Progastrin Represses the Alternative Activation of Human Macrophages and Modulates Their Influence on Colon Cancer Epithelial Cells

Progastrin Represses the Alternative Activation of Human Macrophages and Modulates Their Influence on Colon Cancer Epithelial Cells

Methods for detecting circulating cancer stem cells (CCSCs) as a novel approach for diagnosis of colon cancer relapse/metastasis

Epigenetic regulation of human DCLK-1 gene during colon-carcinogenesis: clinical and mechanistic implications

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