title: Secreted phosphoprotein-1 directly provokes vascular leakage to foster malignant pleural effusion.
abstract: Secreted phosphoprotein-1 (SPP1) promotes cancer cell survival and regulates tumor-associated angiogenesis and inflammation, both central to the pathogenesis of malignant pleural effusion (MPE). Here, we examined the impact of tumor- and host-derived SPP1 in MPE formation and explored the mechanisms by which the cytokine exerts its effects. We used a syngeneic murine model of lung adenocarcinoma-induced MPE. To dissect the effects of tumor- versus host-derived SPP1, we intrapleurally injected wild-type and SPP1-knockout C57/BL/6 mice with either wild-type or SPP1-deficient syngeneic lung cancer cells. We demonstrated that both tumor- and host-derived SPP1 promoted pleural fluid accumulation and tumor dissemination in a synergistic manner (P<0.001). SPP1 of host origin elicited macrophage recruitment into the cancer-affected pleural cavity and boosted tumor angiogenesis, whereas tumor-derived SPP1 curtailed cancer cell apoptosis in vivo. Moreover, the cytokine directly promoted vascular hyper-permeability independently of vascular endothelial growth factor. In addition, SPP1 of tumor and host origin differentially affected the expression of proinflammatory and angiogenic mediators in the tumor microenvironment. These results suggest that SPP1 of tumor and host origin impact distinct aspects of MPE pathobiology to synergistically promote pleural fluid formation and pleural tumor progression. SPP1 may present an attractive target of therapeutic interventions for patients with MPE.
authors.affiliation: Marianthi Simou Laboratory, 1st Department of Critical Care & Pulmonary Services, Athens Medical School, Evangelismos Hospital, Athens, Greece. jpsallidas@med.uoa.gr
authors.forename: I
authors.initials: I
authors.lastname: Psallidas
authors.forename: G T
authors.initials: GT
authors.lastname: Stathopoulos
authors.forename: N A
authors.initials: NA
authors.lastname: Maniatis
authors.forename: S
authors.initials: S
authors.lastname: Magkouta
authors.forename: C
authors.initials: C
authors.lastname: Moschos
authors.forename: S P
authors.initials: SP
authors.lastname: Karabela
authors.forename: A
authors.initials: A
authors.lastname: Kollintza
authors.forename: D C M
authors.initials: DC
authors.lastname: Simoes
authors.forename: M
authors.initials: M
authors.lastname: Kardara
authors.forename: S
authors.initials: S
authors.lastname: Vassiliou
authors.forename: S A
authors.initials: SA
authors.lastname: Papiris
authors.forename: C
authors.initials: C
authors.lastname: Roussos
authors.forename: I
authors.initials: I
authors.lastname: Kalomenidis
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002199:Capillary Permeability / Q000502:physiology; D018827:Carcinoma, Lewis Lung / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D053495:Osteopontin / Q000378:metabolism*; D035422:Pleural Cavity / Q000378:metabolism / Q000473:pathology; D016066:Pleural Effusion, Malignant / Q000378:metabolism* / Q000473:pathology*; D010997:Pleural Neoplasms / Q000378:metabolism* / Q000473:pathology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D016328:NF-kappa B; C506896:Spp1 protein, mouse; D042461:Vascular Endothelial Growth Factor A; D053495:Osteopontin