Nucleotides are basic constituents of tumour microenvironment where they 1) modulate tumour growth, progression and metastatsis formation, 2) stimulate mitochondrial metabolism and aerobic glycolysis acting at the P2X7 receptor, 3) are substrate for ecto-enzymes producing adenosine, a powerful immunosuppressant, and cyclic ADP ribose, an intracellular messenger that participates in the homeostasis of intracellular calcium. We hypothesize that the signaling network based on P2 receptors and on the associated enzymes is a fundamental pathway in cancer. Within tumour microenvironment concentration of immunostimulatory mediators is very low, while on the contrary concentration of immunosoppressive factors is increased, therefore tumour-associated immune cells often have an immunosoppressive phenotype. Thus, biochemical characterization of tumour microenvironment is vital for the design of innovative anti-cancer treatments. Our Group has directly shown that tumour interstitium contains high ATP concentrations (1), and that extracellular ATP accumulates in all sites of inflammation (2). ATP accumulation on one hand can lead to the activation of a distorted Th2 response and to the accumulation of adenosine (3, 4) , and on the other to the activation of the P2X7 receptor, with the associated recruitment and activation of dendritic cells, IL-1 release and efficient presentation of tumour antigens (5). Furthermore, metabolites generated from hydrolysis of extracellular ATP and NAD have a powerful modulatory activity on Treg lymphocytes (CD4+/CD25+/FOXP3+). Treg lymphocytes over-express the ecto-enzymes CD39 and CD73, which are responsible of the hydrolysis of extracellular nucleotides and of generation of the potent immunosuppressant adenosine. Tumour progression and invasiveness depend on the expression level of CD39/CD73 by infiltrating immune cells. Recent data show that anti-CD73 Abs inhibit tumour growth and metastasis (6). Accumulation of ATP within tumour microenvironment can also directly activate tumour cell P2X7 receptor, thus causing NFAT and NFkB activation, stimulation of Warburg effect and growth. Extracellular nucleotides modulate functions of normal and neoplastic precursors. ATP and UTP are growth factors for CD34+ hemopoietic stem cells and stimulates engrafting and bone-marrow repopulation (7). Furthermore, extracellular nucleotides stimulate stem cell migration via Rac2/Rho proteins (8). This evidence suggest that the purinergic network is a useful target for the development of novel anti-cancer strategies. Several P2X7 inhibitors are currently under experimentation by Pharma Industry: CE-224535 by Pfizer is now in Phase II/III; AZD-9056 by Astra-Zeneca is now in Phase II; EVT-401 by Renovis is now in Phase I. Furthermore, Ablynx has produced humanized anti-P2X7 mAb for therapeutical applications, and preclinical studies are under way by several other Companies, among which Affectis Pharma AG (Germany) and Cordex Inc (USA), with which our Group has an established collaboration. All this clinical studies are focused on the treatment of chronic inflammatory diseases. To our knowledge, there are no Phase II/III studies aimed to test the efficacy of P2X7 blockers in cancer. Should our studies demonstrate that purinergic signalling ha san important role in cancer growth, availability of drugs already allowed for use in humans will strongly accelerate bench-to-bed transition.
I recettori purinergici P2 e le ectonucleotidasi: nuovi bersagli per lo sviluppo di farmaci anti-tumorali/P2 purinergic receptors and ectonucleotidases: novel targets for anti-cancer drugs (FIRB Accordi di programma n. RBAP11FXBC)
DI VIRGILIO, Francesco
2012
Abstract
Nucleotides are basic constituents of tumour microenvironment where they 1) modulate tumour growth, progression and metastatsis formation, 2) stimulate mitochondrial metabolism and aerobic glycolysis acting at the P2X7 receptor, 3) are substrate for ecto-enzymes producing adenosine, a powerful immunosuppressant, and cyclic ADP ribose, an intracellular messenger that participates in the homeostasis of intracellular calcium. We hypothesize that the signaling network based on P2 receptors and on the associated enzymes is a fundamental pathway in cancer. Within tumour microenvironment concentration of immunostimulatory mediators is very low, while on the contrary concentration of immunosoppressive factors is increased, therefore tumour-associated immune cells often have an immunosoppressive phenotype. Thus, biochemical characterization of tumour microenvironment is vital for the design of innovative anti-cancer treatments. Our Group has directly shown that tumour interstitium contains high ATP concentrations (1), and that extracellular ATP accumulates in all sites of inflammation (2). ATP accumulation on one hand can lead to the activation of a distorted Th2 response and to the accumulation of adenosine (3, 4) , and on the other to the activation of the P2X7 receptor, with the associated recruitment and activation of dendritic cells, IL-1 release and efficient presentation of tumour antigens (5). Furthermore, metabolites generated from hydrolysis of extracellular ATP and NAD have a powerful modulatory activity on Treg lymphocytes (CD4+/CD25+/FOXP3+). Treg lymphocytes over-express the ecto-enzymes CD39 and CD73, which are responsible of the hydrolysis of extracellular nucleotides and of generation of the potent immunosuppressant adenosine. Tumour progression and invasiveness depend on the expression level of CD39/CD73 by infiltrating immune cells. Recent data show that anti-CD73 Abs inhibit tumour growth and metastasis (6). Accumulation of ATP within tumour microenvironment can also directly activate tumour cell P2X7 receptor, thus causing NFAT and NFkB activation, stimulation of Warburg effect and growth. Extracellular nucleotides modulate functions of normal and neoplastic precursors. ATP and UTP are growth factors for CD34+ hemopoietic stem cells and stimulates engrafting and bone-marrow repopulation (7). Furthermore, extracellular nucleotides stimulate stem cell migration via Rac2/Rho proteins (8). This evidence suggest that the purinergic network is a useful target for the development of novel anti-cancer strategies. Several P2X7 inhibitors are currently under experimentation by Pharma Industry: CE-224535 by Pfizer is now in Phase II/III; AZD-9056 by Astra-Zeneca is now in Phase II; EVT-401 by Renovis is now in Phase I. Furthermore, Ablynx has produced humanized anti-P2X7 mAb for therapeutical applications, and preclinical studies are under way by several other Companies, among which Affectis Pharma AG (Germany) and Cordex Inc (USA), with which our Group has an established collaboration. All this clinical studies are focused on the treatment of chronic inflammatory diseases. To our knowledge, there are no Phase II/III studies aimed to test the efficacy of P2X7 blockers in cancer. Should our studies demonstrate that purinergic signalling ha san important role in cancer growth, availability of drugs already allowed for use in humans will strongly accelerate bench-to-bed transition.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
