Long Pentraxin-3 Follows and Modulates Bladder Cancer Progression

Abstract

Bladder tumors are a diffuse type of cancer. Long pentraxin-3 (PTX3) is a component of the innate immunity with pleiotropic functions in the regulation of immune response, tissue remodeling, and cancer progression. PTX3 may act as an oncosuppressor in different contexts, functioning as an antagonist of the fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) system, rewiring the immune microenvironment, or acting through mechanisms not yet fully clarified. In this study we used biopsies and data mining to assess that PTX3 is differentially expressed during the different stages of bladder cancer (BC) progression. BC cell lines, representative of different tumor grades, and transgenic/carcinogen-induced models were used to demonstrate in vitro and in vivo that PTX3 production by tumor cells decreases along the progression from low-grade to high-grade advanced muscle invasive forms (MIBC). In vitro and in vivo data revealed for the first time that PTX3 modulation and the consequent impairment of FGF/FGR systems in BC cells have a significant impact on different biological features of BC growth, including cell proliferation, motility, metabolism, stemness, and drug resistance. PTX3 exerts an oncosuppressive effect on BC progression and may represent a potential functional biomarker in BC evolution. Moreover, FGF/FGFR blockade has an impact on drug resistance and stemness features in BC.

Long-Pentraxin 3 Affects Primary Cilium in Zebrafish Embryo and Cancer Cells via the FGF System

“…Indeed, when compared to tyrosine kinase FGFR inhibitors, NSC12 is characterized by a reduced toxicity that may result in a more favorable therapeutic window [ 54 ]. Here we show that NSC12 inhibits the proliferation of FGF-dependent murine prostate cancer TRAMP-C2 cells, human bladder carcinoma 5637 cells, and murine fibrosarcoma MC17-51 cells (see also [ 26 , 27 , 37 ]) and that this inhibition is paralleled by the elongation of the primary cilium in all the cell lines tested. These data were confirmed in vivo, where NSC12 was able to inhibit tumor growth, and to induce a ciliogenic effect in TRAMP-C2 tumor grafts.…”

“…Alterations of primary cilia may contribute to cancer progression [ 11 , 12 ]. Based on the results obtained in ptx3b zebrafish morphants and the well-known impact of PTX3 on FGF-dependent tumors [ 23 , 24 , 25 , 26 , 27 , 37 ], we decided to investigate whether the modulation of PTX3 expression may affect primary cilia in FGF-dependent cancer cells.…”

“…In common with other pentraxins, the C -terminal portion of PTX3 includes the pentraxin-signature [ 17 ] whereas its unique N -terminal extension is responsible for binding to different members of the fibroblast growth factor (FGF) superfamily (including FGF2, FGF6, FGF8b, FGF10, and FGF17), thus preventing their interaction with all members of the FGFR family (FGFR1–4) [ 18 , 19 , 20 ]. Thus, PTX3 inhibits FGF-dependent responses, such as endothelial cell proliferation in vitro and angiogenesis in vivo [ 19 , 21 , 22 ], and exerts an oncosuppressive effect on FGF-dependent tumors, including multiple myeloma, melanoma, fibrosarcoma, lung, prostate, and bladder cancers [ 23 , 24 , 25 , 26 , 27 , 28 , 29 ]. In a therapeutic perspective, these findings led to the identification of the PTX3-derived small molecule NSC12 as the first orally available FGF trap able to inhibit the activity of all the members of the canonical FGF family by preventing their binding to FGFR1, 2, 3, and 4 [ 24 ].…”

Pathogenesis and Diagnosis of Genitourinary Cancer

“…These comprehensive innovative analyses have led to new molecular classification based on the genomic expression profiles and the discovery of potential diagnostic and therapeutic molecular targets. The current special series includes 11 articles by international leading researchers who are involved in the investigation of several challenging issues, particularly novel potential biomarkers in GU cancers, using a variety of innovative approaches [ 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ].…”

“…Long pentraxin-3 (PTX3) is a member of the pentraxin family which regulates tumor progression through cell proliferation, angiogenesis, mobility, and immune modulation. Matarazzo et al evaluated the differential expression of PTX3 during BC progression in cell lines, animal models, and patient samples and found that PTX3 modulation and the consequent impairment of FGF/FGR systems in BC cells have a significant impact on BC growth [ 8 ]. In addition, Ide et al reviewed the role of steroid hormone receptors, such as androgen receptor, estrogen receptor-α, estrogen receptor-β, glucocorticoid receptor, progesterone receptor, and vitamin D receptor, in urothelial tumorigenesis [ 11 ].…”