Clinical Studies Pentraxin 3: A Novel Biomarker for Predicting Progression from Prostatic Inflammation to Prostate Cancer Giovanni Stallone 1 , Luigi Cormio 2 , Giuseppe Stefano Netti 3 , Barbara Infante 1 , Oscar Selvaggio 2 , Giuseppe Di Fino 2 , Elena Ranieri 3 , Francesca Bruno 1 , Clelia Prattichizzo 1 , Francesca Sanguedolce 4 , Simona Tortorella 4 , Pantaleo Bufo 4 , Giuseppe Grandaliano 1 , and Giuseppe Carrieri 2 Abstract Pentraxin-3 (PTX3) is a member of the pentraxin family of innate immune regulators, which includes C-reactive protein (CRP). PTX3 has been implicated in angiogenesis, proliferation, and immune escape in cancer. In the present study, we evaluated PTX3 tissue expression and serum concentration as a biomarker to discriminate prostatic inflammation and benign prostatic hyperplasia (BPH) from prostate cancer, and to determine whether PTX3 status may predict progression from BPH to prostate cancer. We analyzed 40 patients with biopsy-proven BPH who underwent a second prostate biopsy 12 to 36 months later when they were diagnosed with prostate cancer or inflammation/BPH (n ¼ 20 patients each group). Furthermore, we evaluated PTX3 serum concentra- tions in an independent set of patients with biopsy-proven inflammation/BPH (n ¼ 61) and prostate cancer (n ¼ 56). We found reduced PTX3 tissue expression in patients with prostatic inflammation/BPH compared with patients who developed prostate cancer. In the latter group, there was an increase in PTX3 tissue expression between the first and second prostate biopsy. PTX3 serum levels were also higher in patients with prostate cancer than in patients with inflammation/BPH. In contrast, there was no difference in serum PSA or CRP levels in these two groups. ROC curve analysis confirmed the reliability of PTX3 serum levels in predicting prostate cancer development, identifying a cutoff value of 3.25 ng/mL with a sensitivity and a specificity of 89.3% and 88.5%, respectively. In summary, our results encourage further evaluation of PTX3 as a tissue biopsy and blood-borne biomarker to discriminate BPH from prostate cancer. Cancer Res; 74(16); 4230–8. Ó2014 AACR. Introduction Prostate cancer is the most common solid-organ malignan- cy and the second leading cause of cancer-related death in males (1). In the vast majority of cases, prostate cancer is diagnosed by a prostate biopsy (PBx) performed because of an elevated PSA level and/or an abnormal digital rectal exami- nation (DRE). In current clinical practice, however, the diag- nostic yield of a first extended PBx is in the range of 40% (2) even selecting patients by "improved" nomograms (3). Patients with an initial negative PBx have an approximately 20% incidence of prostate cancer at a subsequent PBx (4). Although studies on saturation biopsy (5) provide evidence that the first PBx misses some of these cancers, studies on prostate cancer chemoprevention (6, 7) demonstrate that other cancers may develop in the time span to second PBx due to progressive changes in the prostate microenvironment. Chronic inflammation has been reported to cause as much as 20% of human cancers and to be implicated in prostate carcinogenesis by several mechanisms (8). Basically, chronic inflammation creates a milieu rich in proinflammatory cyto- kines and growth factors that may lead to an uncontrolled proliferative response and genetic mutations of rapidly divid- ing cells (9, 10). An increased number of CD4 þ CD25 þ and CD8 þ Foxp3 þ regulatory T cells have been observed in prostate glands and in the peripheral blood of patients with prostate cancer, suggesting an important role for active immune sup- pression of antitumor immunity (11–13). Pentraxins, a superfamily of evolutionary conserved pro- teins, are essential components of the humoral arm of the innate immune system and play a pivotal role in vascular biology (14, 15). Pentraxin-3 (PTX3), the prototype of long pentraxins, differs from short pentraxins for gene organization, cellular source, and ligand-binding capacities (15, 16). Like short pentraxins, PTX3 facilitates dysregulation of mitogenic signaling pathways, sustains cellular proliferation, angiogene- sis, insensitivity to apoptosis, cancer cell invasion and migra- tion, and tumor escape from immunosurveillance (17, 18). Unlike short pentraxins, such as C-reactive protein (CRP), 1 Nephrology Dialysis and Transplantation Unit, University of Foggia, Viale Luigi Pinto, Foggia, Italy. 2 Urology and Renal Transplantation Unit, Uni- versity of Foggia, Viale Luigi Pinto, Foggia, Italy. 3 Clinical Pathology Unit, Department of Medical and Surgical Sciences, University of Foggia, Viale Luigi Pinto, Foggia, Italy. 4 Pathology Unit, Department of Clinical and Experimental Medicine, University of Foggia, Viale Luigi Pinto, Foggia, Italy. G. Stallone and L. Cormio contributed equally to this article. G. Grandaliano and G. Carrieri contributed equally as senior investigators. Corresponding Author: Giuseppe Grandaliano, Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, Uni- versity of Foggia, Viale Luigi Pinto, 251, 71122 Foggia, Italy. Phone: 39- 0881-736002; Fax: 39-0881-736001; E-mail: giusepppe.grandaliano@unifg.it doi: 10.1158/0008-5472.CAN-14-0369 Ó2014 American Association for Cancer Research. Cancer Research Cancer Res; 74(16) August 15, 2014 4230 Downloaded from http://aacrjournals.org/cancerres/article-pdf/74/16/4230/2705507/4230.pdf by guest on 11 September 2022