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Accelerated tumor progression in mice lacking the ATP receptor P2X7

Significance statement

Role of inflammation in cancer has always been a focus of hot interest, ever since the pioneering observations of Rudolf Virchow in the nineteenth century. Despite Virchow’ s insightful studies, it was long thought that tumor-associated inflammation was a mere local tissue response to cancer cells. Only over the last few years the original Virchow’ s hypothesis that cancer-associated inflammation is indeed conducive to tumor growth and dissemination has rekindled interest and shown to be largely true. In fact, ample experimental evidence now shows that the inflammatory cell infiltrate release a large variety of factors that on one hand suppress the anti-tumor host response and on the other stimulate tumor cell growth. Our recent investigation of the role played by the purinergic P2X7 receptor (P2RX7) in cancer growth and dissemination challenges this established notion. Transplanted tumors growing in P2RX7-deleted hosts lack almost any inflammatory cell infiltrate, whether of the myeloid or lymphoid lineage. Under these conditions, tumors undergo unrestricted growth and dissemination. Our study thus suggests that there is “good” and “bad” cancer-associated inflammation, or in other words that inflammation (“good inflammation”), especially during the early phases of tumor development, is necessary to restrict tumor growth. However, during tumor progression, the inflammatory cell infiltrate is skewed towards a “tumor-supporting” phenotype (“bad inflammation”). Therefore, it appears that inflammation has a “Dr. Jekill/Mr. Hyde” role in tumor/host relationship. The challenge for current research in oncology will be the discovery of a suitable procedure to reconvert “bad” into “good” inflammation and restore the whole Dr. Jekill’ s anticancer therapeutic potential.

 

Accelerated tumor progression in mice lacking the ATP receptor P2X7. Global Medical Discovery

 

 

 

 

 

 

 

 

 

 

 

Journal Reference

Adinolfi E1, Capece M1, Franceschini A1, Falzoni S1, Giuliani AL1, Rotondo A2, Sarti AC1, Bonora M1, Syberg S3, Corigliano D4, Pinton P1, Jorgensen NR3,Abelli L5, Emionite L6, Raffaghello L7, Pistoia V7, Di Virgilio F8. Cancer Res. 2015 Feb 15;75(4):635-44.

1Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, University of Ferrara, Ferrara, Italy.

2Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, University of Ferrara, Ferrara, Italy. KU Leuven, Translational Research Center for Gastrointestinal Disorders, Leuven, Belgium.

3Research Center for Ageing and Osteoporosis, Departments of Diagnostics and Medicine, Glostrup Hospital, University of Copenhagen, Glostrup, Denmark.

4Department of Health Sciences, Università della Magna Grecia, Catanzaro, Italy.

5Department of Life Sciences and Biotechnology, Section of Biology and Evolution, University of Ferrara, Italy.

6Animal Facility, S. Martino Hospital, Genova, Italy.

7Laboratory of Oncology, Gaslini Hospital, Genova, Italy.

8Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, University of Ferrara, Ferrara, Italy. [email protected]

Abstract

The ATP receptor P2X7 (P2X7R or P2RX7) has a key role in inflammation and immunity, but its possible roles in cancer are not firmly established. In the present study, we investigated the effect of host genetic deletion of P2X7R in the mouse on the growth of B16 melanoma or CT26 colon carcinoma cells. Tumor size and metastatic dissemination were assessed by in vivo calliper and luciferase luminescence emission measurements along with postmortem examination. In P2X7R-deficient mice, tumor growth and metastatic spreading were accelerated strongly, compared with wild-type (wt) mice. Intratumoral IL-1β and VEGF release were drastically reduced, and inflammatory cell infiltration was abrogated nearly completely. Similarly, tumor growth was also greatly accelerated in wt chimeric mice implanted with P2X7R-deficient bone marrow cells, defining hematopoietic cells as a sufficient site of P2X7R action. Finally, dendritic cells from P2X7R-deficient mice were unresponsive to stimulation with tumor cells, and chemotaxis of P2X7R-less cells was impaired. Overall, our results showed that host P2X7R expression was critical to support an antitumor immune response, and to restrict tumor growth and metastatic diffusion.

©2014 American Association for Cancer Research.

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