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. 2020 Apr 28;12(8):7585-7602.
doi: 10.18632/aging.103169. Epub 2020 Apr 28.

PTX3 modulates the immunoflogosis in tumor microenvironment and is a prognostic factor for patients with clear cell renal cell carcinoma

Giuseppe Stefano Netti  1 , Giuseppe Lucarelli  2 , Federica Spadaccino  1 , Giuseppe Castellano  3 , Margherita Gigante  1 , Chiara Divella  3 , Maria Teresa Rocchetti  1 , Federica Rascio  4 , Vito Mancini  5 , Giovanni Stallone  4 , Giuseppe Carrieri  5 , Loreto Gesualdo  3 , Michele Battaglia  2 , Elena Ranieri  1
Affiliations

PTX3 modulates the immunoflogosis in tumor microenvironment and is a prognostic factor for patients with clear cell renal cell carcinoma

Giuseppe Stefano Netti et al. Aging (Albany NY). .

Abstract

Pentraxin-3 (PTX3) belongs to the pentraxine family, innate immune regulators involved in angiogenesis, proliferation and immune escape in cancer. Here, we evaluated PTX3 tissue expression and serum levels as biomarkers of clear cell renal cell carcinoma (ccRCC) and analyzed the possible role of complement system activation on tumor site. A 10-year retrospective cohort study including patients undergoing nephrectomy for ccRCC was also performed. PTX3 expression was elevated in both neoplastic renal cell lines and tissues, while it was absent in both normal renal proximal tubular cells (HK2) and normal renal tissues. Analysis of complement system activation on tumor tissues showed the co-expression of PTX3 with C1q, C3aR, C5R1 and CD59, but not with C5b-9 terminal complex. RCC patients showed higher serum PTX3 levels as compared to non-neoplastic patients (p<0.0001). Higher PTX3 serum levels were observed in patients with higher Fuhrman grade (p<0.01), lymph node (p<0.0001), and visceral metastases (p<0.001). Patients with higher PTX3 levels also showed significantly lower survival rates (p=0.002). Our results suggest that expression of PTX3 can affect the immunoflogosis in the ccRCC microenvironment, by activating the classical pathway of CS (C1q) and releasing pro-angiogenic factors (C3a, C5a). The up-regulation of CD59 also inhibits the complement-mediated cellular lysis.

Keywords: biomarker; complement system; pentraxin 3; renal cell carcinoma.

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Conflict of interest statement

CONFLICTS OF INTEREST: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Gene Set Enrichment Analysis (GSEA) of the GSE47032 dataset (A and B). Complement system pathway from Ingenuity Pathway Analysis (C). Genes in green and red are respectively under- and over-expressed in the ccRCC-gene signature.
Figure 2
Figure 2
PTX3 expression in neoplastic (A) and proximal tubular epithelial cells (PTEC) (B) by confocal microscopy and quantification of specific fluorescence (C)
Figure 3
Figure 3
PTX3 expression in neoplastic (A-C) and normal renal tissues (D-F) by confocal microscopy and quantification of specific fluorescence (G).
Figure 4
Figure 4
Complement system factors’ expression and co-localization with PTX3 in renal clear cell carcinoma. Intra-tumoral expression of PTX3 (green) and co-localization with C1q (A-D), C5b9 (E-H), CD59 (I-L), C3aR (M-P), C5R (Q-T).
Figure 5
Figure 5
PTX3 serum levels at baseline in patients with renal clear cell carcinoma before and after surgery (A) and at different Furhman grading (B), lymphnode involvement (C) and metastasis staging (D).
Figure 6
Figure 6
Kaplan-Meier estimate of 12-year cancer-specific survival (CSS: A) and progression-free survival (PFS: B) of ccRCC patients according to different PTX3 serum levels at baseline.
See this image and copyright information in PMC

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