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Serpins promote cancer cell survival and vascular co-option in brain metastasis.

ABSTRACT: Brain metastasis is an ominous complication of cancer, yet most cancer cells that infiltrate the brain die of unknown causes. Here, we identify plasmin from the reactive brain stroma as a defense against metastatic invasion, and plasminogen activator (PA) inhibitory serpins in cancer cells as a shield against this defense. Plasmin suppresses brain metastasis in two ways: by converting membrane-bound astrocytic FasL into a paracrine death signal for cancer cells, and by inactivating the axon pathfinding molecule L1CAM, which metastatic cells express for spreading along brain capillaries and for metastatic outgrowth. Brain metastatic cells from lung cancer and breast cancer express high levels of anti-PA serpins, including neuroserpin and serpin B2, to prevent plasmin generation and its metastasis-suppressive effects. By protecting cancer cells from death signals and fostering vascular co-option, anti-PA serpins provide a unifying mechanism for the initiation of brain metastasis in lung and breast cancers.

SUBMITTER: Valiente M

PROVIDER: S-EPMC3988473 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Serpins promote cancer cell survival and vascular co-option in brain metastasis.

Valiente Manuel M Obenauf Anna C AC Jin Xin X Chen Qing Q Zhang Xiang H-F XH Lee Derek J DJ Chaft Jamie E JE Kris Mark G MG Huse Jason T JT Brogi Edi E Massagué Joan J

Cell 20140201 5

Brain metastasis is an ominous complication of cancer, yet most cancer cells that infiltrate the brain die of unknown causes. Here, we identify plasmin from the reactive brain stroma as a defense against metastatic invasion, and plasminogen activator (PA) inhibitory serpins in cancer cells as a shield against this defense. Plasmin suppresses brain metastasis in two ways: by converting membrane-bound astrocytic FasL into a paracrine death signal for cancer cells, and by inactivating the axon path ...[more]

PMID: 24581498

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Project description:Background Brain metastasis (BM) is one of the most common metastatic sites in patients with small cell lung cancer (SCLC), and the prognosis remains very poor. This study aimed to establish a novel nomogram for predicting the cancer-specific survival (CSS) in SCLC patients with BM. Methods SCLC patients with BM from the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2015 were retrospectively collected. Univariate and multivariate Cox regression analyses were performed to identify independent prognostic factors, which were further used to construct the prognostic nomogram. The discrimination and calibration of nomogram were evaluated by concordance index (C-index), receiver operating characteristic (ROC) curve, the area under ROC curve (AUC) and calibration plot. Decision curve analysis (DCA) was used to assess the clinical usefulness. Kaplan-Meier survival curve was applied to analyze the survival outcome. Results A total of 2,462 patients were enrolled in this study, and randomly assigned into training cohort (n=1,723) and validation cohort (n=739). Age, N stage, surgery, radiation, chemotherapy, bone metastasis, liver metastasis and lung metastasis were identified as independent prognostic factors of CSS. The C-indexes of nomogram was 0.683 [95% confidence interval (CI): 0.667–0.699] in the training cohort, and 0.659 (95% CI: 0.634–0.684) in the validation cohort. The AUC values of 6-, 9- and 12-month CSS were 0.723, 0.742 and 0.737 respectively in the training cohort, while 0.715, 0.737 and 0.739 in the validation cohort. The ROC, calibration and DCA curves showed good discrimination, calibration and clinical applicability of this nomogram in predicting prognosis. Moreover, patients in high-risk group had a worse survival outcome than patients in medium-risk and low-risk groups. Conclusions A novel nomogram was constructed and validated for predicting individual prognosis in SCLC patients with BM. This nomogram could help clinicians make effective treatment strategies for patients.

Project description:Protease nexin-1 (PN-1), a serpin encoded by the SERPINE2 gene, has serine protease inhibitory activity and neurotrophic properties in the brain. PN-1 inhibits retinal angiogenesis; however, PN-1's neurotrophic capacities in the retina have not yet been evaluated. Pigment epithelium-derived factor (PEDF) is a serpin that exhibits neurotrophic and antiangiogenic activities but lacks protease inhibitory properties. The aim of this study is to compare PN-1 and PEDF.Sequence comparisons were performed using computer bioinformatics programs. Mouse and bovine eyes, human retina tissue, and ARPE-19 cells were used to prepare RNA and protein samples. Interphotoreceptor matrix lavage was obtained from bovine eyes. Gene expression and protein levels were evaluated with reverse-transcription PCR (RT-PCR) and western blotting, respectively. Recombinant human PN-1, a version of PN-1 referred to as PN-1[R346A] lacking serine protease inhibitory activity, and PEDF proteins were used, as well as synthetic peptides designed from PEDF and PN-1 sequences. Survival activity in serum-starved, rat-derived retinal precursor (R28) cells was assessed with terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) cell death assays. Bcl2 levels were measured with RT-PCR.PN-1 is analogous in primary and tertiary structure to PEDF. A region in PN-1 shares homology with the neurotrophic active region of PEDF, a 17-residue region within alpha helix C. The native human retina, ARPE-19 cells, and murine RPE and retina expressed the gene for PN-1 (SERPINE2 and Serpine2 mRNA). The retina, ARPE-19 cell lysates, and bovine interphotoreceptor matrix contained PN-1 protein. The addition of PN-1, PN-1[R346A], or the 17mer peptide of PN-1 to serum-starved retina cells decreased the number of TUNEL-positive nuclei relative to the untreated cells, such as PEDF. PN-1, PN-1[R346A], and PN-1-17mer treatments increased the Bcl2 transcript levels in serum-starved cells, as seen with PEDF.PN-1 and PEDF share structural and functional features, and expression patterns in the retina. These serpins' mechanisms of action as cell survival factors are independent of serine protease inhibition. We have identified PN-1 as a novel factor for the retina that may play a neuroprotective role in vivo, and small peptides as relevant candidates for preventing retinal degeneration.

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Serpins promote cancer cell survival and vascular co-option in brain metastasis.

Publications

Serpins promote cancer cell survival and vascular co-option in brain metastasis.

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