The matrix metalloproteinases (MMPs) form an enzyme family of which gelatinase B (MMP-9) represents the largest and most complex member. We focus here on the biochemical properties, regulation, and functions of gelatinase B. The tight regulation of gelatinase B activity is highly complex and is established at five different levels. The transcription of the gelatinase B-gene depends on various cis-elements in its gene promotor and is induced or repressed by a large variety of soluble factors, including cytokines, growth factors, and hormones and by cellular contacts acting through specific signaling pathways. The specific regulation of its secretion occurs in cells storing gelatinase B in granules. After secretion, progelatinase B must be activated through an activation network. The enzyme activity is further regulated by inhibition and by other mechanisms, such as fine-tuning and stabilization by glycosylation. The ability of gelatinase B to degrade components of the extracellular matrix and to regulate the activity of a number of soluble proteins confers an important role in various physiological and pathological processes. These include reproduction, growth, development, inflammation, and vascular and proliferative diseases.

Biochemistry and Molecular Biology of Gelatinase B or Matrix Metalloproteinase-9 (MMP-9)

The poor selective toxicity of chemotherapeutic anticancer drugs leads to dose-limiting side effects that compromise clinical outcome. Solid tumors recruit new blood vessels to support tumor growth, and unique epitopes expressed on tumor endothelial cells can function as targets for the anti-angiogenic therapy of cancer. An NGR peptide that targets aminopeptidase N, a marker of angiogenic endothelial cells, was coupled to the surface of liposomal doxorubicin (NGR-SL[DXR]) and was used to treat orthotopic neuroblastoma (NB) xenografts in SCID mice. Pharmacokinetic studies indicated that liposomes coupled to NGR peptide had long-circulating profiles in blood. Their uptake into NB tumor was time dependent, being at least 10 times higher than that of nontargeted liposomes (SL[DXR]) after 24 h, with DXR spreading outside the blood vessels and into the tumors. No uptake was observed into tumors of mice treated with the mismatched peptide ARA-targeted SL[DXR]. Tumor-specific DXR uptake was completely blocked when mice were coinjected with a 50-fold molar excess of the soluble NGR peptide. Adrenal tumor-bearing mice treated with 2 mg/kg/week/x3 of NGR-SL[DXR] partly outlived the control mice (P 3 mg/kg/week/x3 were toxic. Histopathological analysis of cryosections taken from treated mice revealed pronounced destruction of the tumor vasculature with a marked decreased in vessel density. Double staining of tumors with terminal deoxynucleotidyl transferase-mediated nick end labeling and antifactor VIII antibody or antihuman NB demonstrated endothelial cell apoptosis in the vasculature, as well as increased tumor cell apoptosis. Moreover, mice injected with 3 mg/kg/week/x3 of NGR-SL[DXR] displayed rapid tumor regression, as well as inhibition of metastases growth (P = 0.0002). One day after the third treatment, four of six mice showed no evidence of tumors, and the two others showed a >80% reduction in tumor mass and a >90% suppression of blood vessel density (P < 0.01). In contrast, mice treated with ARA-SL[DXR] formed large well-vascularized tumors. Finally, a metronomic administration of NGR-SL[DXR] (1 mg/kg/every other 2 days x 9) induced complete tumor eradication in all animals (P < 0.0001). Our strategy markedly enhanced the therapeutic index of DXR and enabled metronomic administration of therapeutic doses. A dual mechanism of action is proposed: indirect tumor cell kill via the destruction of tumor endothelium by NGR-targeted liposomes and direct tumor cell kill via localization of liposomal DXR to the tumor interstitial space. This combined strategy has the potential to overcome some major limitations of conventional chemotherapy.

https://cancerres.aacrjournals.org/content/canres/63/21/7400.full.pdf

Vascular Damage and Anti-angiogenic Effects of Tumor Vessel-Targeted Liposomal Chemotherapy

TrkA alternative splicing: A regulated tumor-promoting switch in human neuroblastoma

Tumor angiogenesis, a major requirement for tumor outgrowth and metastasis, is regulated by pro- and antiangiogenic factors. Methylation-associated inactivation of the angiogenesis inhibitor thrombospondin-1 (TSP-1) has been observed recently in some adult tumors. To investigate the role of TSP-1 in pediatric cancer, we examined its pattern of expression and mechanisms of regulation in neuroblastoma (NB). TSP-1 was silenced in a subset of undifferentiated, advanced-stage tumors and NB cell lines. In contrast, most localized tumors expressed this angiogenesis inhibitor, and a significant correlation between morphological evidence of neuroblast differentiation and TSP-1 expression was observed. Luciferase assays demonstrated the presence of nuclear factors required for TSP-1 transcription in both TSP-1-positive and -negative cell lines, but no correlation between TSP-1 promoter activity and the level of TSP-1 mRNA expression was seen. Our studies indicate that the transcriptional silencing of TSP-1 was caused by methylation. TSP-1 promoter methylation was detected in all of the NB cell lines lacking TSP-1 mRNA and in 37% of the NB clinical tumors analyzed. Furthermore, treatment with the demethylating agent, 5-Aza-2'-deoxycytidine (5-Aza-dC), restored TSP-1 expression in NB cell lines. Disrupting methylation with 5-Aza-dC also led to significant inhibition of NB in vivo and re-expression of TSP-1 in a subset of NB xenografts. These results suggest that 5-Aza-dC inhibits NB growth by augmenting the expression of TSP-1 along with other genes that suppress tumor growth. Demethylating agents may prove to be effective candidates for the treatment of children with NB.

https://cancerres.aacrjournals.org/content/canres/63/19/6299.full.pdf

Methylation-associated silencing of the Thrombospondin-1 gene in human neuroblastoma

Neuroblastoma, a childhood neoplasm arising from neural crest cells, is characterized by a diversity of clinical behavior, ranging from spontaneous remission to rapid tumor progression and death. To some extent, outcome can be predicted by the stage of disease and age at diagnosis. The molecular eve

Advances in the diagnosis and treatment of neuroblastoma

Objective
Malignant ovarian germ cell tumors (MOGCT) carry an excellent prognosis, and the treatment aims to achieve results with the least possible treatment-related morbidity. The aim of this study was to assess the outcomes of pediatric patients with MOGCT.

Methods
Patients were treated according to their stage: surgery and surveillance for stage I; a modified bleomycin–etoposide–cisplatin (BEP) regimen for stages II (three cycles), III, and IV (three cycles) with surgery on residual disease.

Results
Seventy-seven patients were enrolled (median age 11.8 years), 26 with dysgerminoma (Dysg), 13 with immature teratoma and elevated serum alpha-fetoprotein levels (IT + AFP), and 38 with nondysgeminoma (Non-Dysg) staged as follows: 27 stage I, 13 stage II, 32 stage III, 5 stage IV. Among evaluable patients in stage I (5-year event-free survival [EFS] 72.1% [95% CI: 56.4–92.1%]; 5-year overall survival [OS] 100%), seven relapsed (three patients with Dysg and four patients with Non-Dysg) and were rescued with chemotherapy (plus surgery in three patients). Among the evaluable patients with stages II–IV, 48 (98%) achieved complete remission after chemotherapy ± surgery, one (IT + AFP, stage IV) had progressive disease. In the whole series (median follow-up 80 months), the 5-year OS and EFS were 98.5% (95% CI: 95.6–100%) and 84.5% (95% CI: 76.5–93.5%).

Conclusions
We confirm the excellent outcome for MOGCT. Robust data are lacking on surgical staging, surveillance for Non-Dysg with stage I, the management of IT + AFP, and the most appropriate BEP regimen. As pediatric oncologists, we support the role of surveillance after proper surgical staging providing cases are managed by experts at specialized pediatric centers.

/pdf/malignant-ovarian-germ-cell-tumors-in-pediatric-patients-the-24w3repulw.pdf

Malignant ovarian germ cell tumors in pediatric patients: The AIEOP (Associazione Italiana Ematologia Oncologia Pediatrica) study.

Neuroblastoma in the first year of life. The Italian contribution to a study of the Internation Society of Paediatric Oncology Europe Neuroblastoma Group

Probiotics may modulate the impact of aging on adults.

Angiogenesis extent and expression of matrix metalloproteinase-2 and -9 correlate with progression in human neuroblastoma

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Malignant ovarian germ cell tumors in pediatric patients: The AIEOP (Associazione Italiana Ematologia Oncologia Pediatrica) study.

Neuroblastoma in the first year of life. The Italian contribution to a study of the Internation Society of Paediatric Oncology Europe Neuroblastoma Group

Probiotics may modulate the impact of aging on adults.

Angiogenesis extent and expression of matrix metalloproteinase-2 and -9 correlate with progression in human neuroblastoma