P2X7 receptor expression in evolutive and indolent forms of chronic B lymphocytic leukemia

Adinolfi, Elena; Melchiorri, Loredana; Falzoni, Simonetta; Chiozzi, Paola; Morelli, Anna; Tieghi, Alessia; Cuneo, Antonio; Castoldi, Gianluigi; Virgilio, Francesco Di; Baricordi, Olavio R.

doi:10.1182/blood.v99.2.706

Cited by 187 publications

(190 citation statements)

References 21 publications

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“…We then extended these observations to human chronic lymphocytic leukemia (CLL) cells. Peripheral lymphocytes from these patients turned out to have a several-fold higher P2X 7 expression level compared to lymphocytes isolated from healthy subjects and larger increases in cytoplasmic Ca 2+ in response to P2X 7 agonists [6]. These concordant findings instigated a thorough examination of the biochemical intracellular changes involved.…”

Section: Introductionmentioning

confidence: 83%

“…So far, no extensive screening of P2X 7 expression in malignant tumours has been performed; however, different laboratories have reported increased expression of this receptor in prostate [30], breast and skin cancers [31,32], neuroblastoma [9], leukemia [6] and thyroid papillary carcinoma [33]. In most cases, these studies simply report histological evidence of receptor overexpression in tissue slices, with no analysis of functional activity.…”

Section: P2x 7 and Cancermentioning

confidence: 99%

“…Interestingly, P2X 7 but not mock-transfectants were sensitive to the growth-inhibition by apyrase, further supporting the role of an ATP-based autocrine-paracrine loop. Indirect evidence for the role of P2X 7 in proliferation came from the finding that peripheral B lymphocytes from patients affected by the aggressive variant of chronic lymphocytic leukemia express P2X 7 to a level higher than patients with the indolent variant or healthy controls [6]. In B-leukemic lymphocytes, P2X 7 stimulation causes a large increase in intracellular Ca 2+ , while its blockade stops proliferation.…”

Section: Introductionmentioning

confidence: 99%

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P2X7: a growth-promoting receptor—implications for cancer

Virgilio

Ferrari

Adinolfi

2009

Purinergic Signalling

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131

114

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The P2X 7 receptor is widely referred to as the paradigmatic cytotoxic nucleotide receptor, and is often taken as an epitome of cytotoxic receptors as a whole. However, cytotoxicity is the result of sustained pharmacological stimulation, which is likely to occur in vivo only under severe pathological conditions. Over the years, we have gathered robust experimental proof that led us to adopt an entirely different view, pointing to P2X 7 as a survival/growth-promoting rather than death-inducing receptor. Evidence in favour of this role is manifold: (1) extracellular ATP and benzoyl ATP support cell proliferation in peripheral T lymphocytes via a P2X 7 -like receptor; (2) P2X 7 transfection into several cell lines confers growth advantage; (3) HEK293 cells transfected with P2X 7 show enhanced mitochondrial metabolic activity and growth; (4) lipopolysaccharide (LPS)-dependent growth arrest of microglia is mediated via P2X 7 down-modulation; (5) several malignant tumours express high P2X 7 levels and (6) the ATP concentration in tumour interstitium is severalfold higher than in healthy tissues, to a level in principle sufficient to activate the P2X 7 receptor. The molecular basis of P2X 7 -mediated growth-promoting activity is poorly known, but mitochondria appear to play a central role. A deeper understanding of the role played by P2X 7 in cell proliferation might provide an insight into the mechanism of normal and malignant cell growth and suggest novel anti-tumour therapies.

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Section: Introductionmentioning

confidence: 83%

Section: P2x 7 and Cancermentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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P2X7: a growth-promoting receptor—implications for cancer

Virgilio

Ferrari

Adinolfi

2009

Purinergic Signalling

Self Cite

131

114

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“…Various cancer cells over-express P2X7 receptors [84][85][86][87] that regulate their motility (e.g., C6 glioma cells [88] and breast cancer cells [89]). ATP enhances the migration of TGFβ1-treated A549 lung cancer cells, although the precise receptor responsible for this effect has not yet been identified [90].…”

Section: Cancer Cellsmentioning

confidence: 99%

New insights regarding the regulation of chemotaxis by nucleotides, adenosine, and their receptors

Corriden

Insel

2012

Purinergic Signalling

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The directional movement of cells can be regulated by ATP, certain other nucleotides (e.g., ADP, UTP), and adenosine. Such regulation occurs for cells that are "professional phagocytes" (e.g., neutrophils, macrophages, certain lymphocytes, and microglia) and that undergo directional migration and subsequent phagocytosis. Numerous other cell types (e.g., fibroblasts, endothelial cells, neurons, and keratinocytes) also change motility and migration in response to ATP, other nucleotides, and adenosine. In this article, we review how nucleotides and adenosine modulate chemotaxis and motility and highlight the importance of nucleotide-and adenosine-regulated cell migration in several cell types: neutrophils, microglia, endothelial cells, and cancer cells. We also discuss difficulties in conducting experiments and drawing conclusions regarding the ability of nucleotides and adenosine to modulate the migration of professional and non-professional phagocytes.

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“…Among the members of the P2X receptors family, the latest cloned P2X 7 receptors (P2X 7 R) (Rassendren et al, 1997) are very unique by different features, some of them are: (1) their sensitivity to ATP (North, 2002), (2) their facilitation under successive or sustained applications of agonist (Hibell et al, 2000;Roger et al, 2008Roger et al, , 2010a and (3) the appearance of a large, non-selective membrane pore after sustained stimulations with ATP (Pelegrin and Surprenant, 2006). Recently, several tumours have been shown to express P2X 7 R at unusually high levels (Adinolfi et al, 2002;Zhang et al, 2004;Slater et al, 2004a, b;Wang et al, 2004a;Raffaghello et al, 2006;Deli et al, 2007;Solini et al, 2008), however, their functionality and involvement in the physiology of cancer cells remain unclear. In some studies performed on breast and prostate cancers, it was suggested that P2X 7 R might be non-functional (Slater et al, 2004a, b), but proposed to serve as an early marker for cancer (Slater et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

P2X7 receptor activation enhances SK3 channels- and cystein cathepsin-dependent cancer cells invasiveness

et al. 2011

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ATP-gated P2X 7 receptors (P2X 7 R) are unusual plasma membrane ion channels that have been extensively studied in immune cells. More recently, P2X 7 R have been described as potential cancer cell biomarkers. However, mechanistic links between P2X 7 R and cancer cell processes are unknown. Here, we show, in the highly aggressive human breast cancer cell line MDA-MB-435s, that P2X 7 receptor is highly expressed and fully functional. Its activation is responsible for the extension of neurite-like cellular prolongations, of the increase in cell migration by 35% and in cell invasion through extracellular matrix by 150%. The change in cancer cell morphology and the increased migration appeared to be due to the activation of Ca 2 þ -activated SK3 potassium channels. The enhanced invasion through the extracellular matrix was related to the increase of mature forms of cysteine cathepsins in the extracellular medium, which was independent of SK3 channel activity and not associated with cell death. Pharmacological targeting of P2X 7 R in vivo was crucial for cell invasiveness in a zebrafish model of metastases. Our results demonstrate a novel mechanistic link between P2X 7 R functionality in cancer cells and invasiveness, a key parameter in tumour growth and in the development of metastases. They also suggest a potential therapeutic role for the newly developed P2X 7 R antagonists.

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P2X7 receptor expression in evolutive and indolent forms of chronic B lymphocytic leukemia

Cited by 187 publications

References 21 publications

P2X7: a growth-promoting receptor—implications for cancer

P2X7: a growth-promoting receptor—implications for cancer

New insights regarding the regulation of chemotaxis by nucleotides, adenosine, and their receptors

P2X7 receptor activation enhances SK3 channels- and cystein cathepsin-dependent cancer cells invasiveness

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