Plasminogen activating inhibitor‐1 promotes angiogenesis in cutaneous angiosarcomas

Abstract

Plasminogen activating inhibitor‐1 (PAI‐1) is associated with poor clinical outcomes, and elevated levels of PAI‐1 in both tissue and serum are correlated with poor response to therapy in various cancers, including skin cancer. Cutaneous angiosarcoma (CAS) is a vascular tumor histologically characterized by detachment of endothelial cell‐derived tumor cells. Since CAS expresses multiple angiogenic growth factors and has increased expressions of angiogenic receptor tyrosine kinase transcripts including VEGFR1/2/3, angiogenesis‐promoting factors are potential drug targets in CAS. In this study, the expression of PAI‐1 was examined in 31 cases of CAS, and the immunomodulatory effects of PAI‐1 on a human CAS cell line, ISO‐HAS‐B, were evaluated. We found that, of the angiogenesis‐promoting factors, PAI‐1 was expressed in almost all cases of CAS, and PAI‐1 increased the mRNA expressions of IL‐23p19, VEGF‐C, CXCL5 and CCL20 on ISO‐HAS‐B. Moreover, PAI‐1 stimulated ISO‐HAS‐B culture supernatant promoted favourable tube networks, suggesting that these tumor‐derived factors promote the pro‐angiogenic effect on tumor development. In addition, IL‐23p19 was expressed in 61.3% of cases, whereas VEGF‐C was expressed in 41% of cases. The results of the present study suggest that PAI‐1 promotes angiogenesis that results in tumor progression in CAS.

LL-37 Might Promote Local Invasion of Melanoma by Activating Melanoma Cells and Tumor-Associated Macrophages

“…Among the pro-angiogenetic factors described above, IL-23p19 plays one of the central roles in promoting tumor growth in various cancers through its pro-angiogenesis activity [ 9 ]. Indeed, IL-23p19 increased the angiogenetic activity of cutaneous angiosarcoma [ 8 ]. In addition, IL-23p19 directly or indirectly promotes the infiltration of myeloid cells such as M2 macrophages and neutrophils, leading to the increased secretion of TGF-β, IL-10, and VEGF, and thus promoting angiogenesis in breast cancer [ 27 ].…”

“…Notably, in our present study, IL-23p19 was increased in both melanoma cells and CD163+ M2 macrophages. Since recombinant IL-23p19 forms favorable tube networks in vitro [ 8 ], IL-23p19 could, at least in part, promote angiogenetic activity in tumor microenvironment in melanoma.…”

“…Among such scavenger receptors, CD163 is a specific surface marker of macrophages [ 4 , 5 ]. The expression of LL-37 on myeloid cells in dermis is correlated with levels of proinflammatory cytokines such as IL-23p19, IL-17A, and TNF-α [ 6 , 7 ], which could promote tumor progression via angiogenesis in melanoma and non-melanoma skin cancers [ 8 , 9 , 10 , 11 ]. Moreover, LL-37 is expressed in melanoma cells, potentially promoting their own proliferation, migration and invasion by autocrine and/or paracrine fashions [ 11 , 12 , 13 ].…”

The Human Extracellular Matrix Diseasome Reveals Genotype–Phenotype Associations with Clinical Implications for Age-Related Diseases

“…Aging is a substantial risk factor for thrombosis and other thrombotic-related events, and with the addition of heightened interleukin 6 (IL-6) and C-reactive protein (CRP) levels, the risk of cardiovascular events is exacerbated in elderly individuals [ 64 ]. Plasminogen activator inhibitor 1 (PAI-1), a fibrinolysis inhibitor, is implicated in many age-related metabolic disorders and cancer [ 65 ], and PAI-1 levels significantly increase with age, predisposing elderly individuals to cardiovascular complications resulting from thrombosis and atherosclerosis [ 66 ]. Plasminogen and the inhibition of fibrinolytic activity may be opportune targets for ameliorating cardiovascular aging through the repurposing of identified drugs [ 67 ].…”

Clues for developing next‐generation cancer immunotherapy

“…Ohuchi et al suggested the possibility that plasminogen activating inhibitor‐1 (PAI‐1) in the TME promotes angiogenesis in cutaneous angiosarcoma 7 . Further investigation is required to validate the effects of PAI‐1 inhibitors in vitro and in vivo for future clinical applications.…”