Matrix Metalloproteinase-Induced Epithelial-Mesenchymal Transition in Breast Cancer

Matrix metalloproteinases (MMPs) degrade and modify the extracellular matrix (ECM) as well as cell-ECM and cell-cell contacts, facilitating detachment of epithelial cells from the surrounding tissue. MMPs play key functions in embryonic development and mammary gland branching morphogenesis, but they are also upregulated in breast cancer, where they stimulate tumorigenesis, cancer cell invasion and metastasis. MMPs have been investigated as potential targets for cancer therapy, but clinical trials using broad-spectrum MMP inhibitors yielded disappointing results, due in part to lack of specificity toward individual MMPs and specific stages of tumor development. Epithelial-mesenchymal transition (EMT) is a developmental process in which epithelial cells take on the characteristics of invasive mesenchymal cells, and activation of EMT has been implicated in tumor progression. Recent findings have implicated MMPs as promoters and mediators of developmental and pathogenic EMT processes in the breast. In this review, we will summarize recent studies showing how MMPs activate EMT in mammary gland development and in breast cancer, and how MMPs mediate breast cancer cell motility, invasion, and EMT-driven breast cancer progression. We also suggest approaches to inhibit these MMP-mediated malignant processes for therapeutic benefit

Worldwide comparison of survival from childhood leukaemia for 1995–2009, by subtype, age, and sex (CONCORD-2): a population-based study of individual data for 89 828 children from 198 registries in 53 countries

Background Global inequalities in access to health care are reflected in differences in cancer survival. The CONCORD programme was designed to assess worldwide differences and trends in population-based cancer survival. In this population-based study, we aimed to estimate survival inequalities globally for several subtypes of childhood leukaemia. Methods Cancer registries participating in CONCORD were asked to submit tumour registrations for all children aged 0-14 years who were diagnosed with leukaemia between Jan 1, 1995, and Dec 31, 2009, and followed up until Dec 31, 2009. Haematological malignancies were defined by morphology codes in the International Classification of Diseases for Oncology, third revision. We excluded data from registries from which the data were judged to be less reliable, or included only lymphomas, and data from countries in which data for fewer than ten children were available for analysis. We also excluded records because of a missing date of birth, diagnosis, or last known vital status. We estimated 5-year net survival (ie, the probability of surviving at least 5 years after diagnosis, after controlling for deaths from other causes [background mortality]) for children by calendar period of diagnosis (1995-99, 2000-04, and 2005-09), sex, and age at diagnosis (< 1, 1-4, 5-9, and 10-14 years, inclusive) using appropriate life tables. We estimated age-standardised net survival for international comparison of survival trends for precursor-cell acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML). Findings We analysed data from 89 828 children from 198 registries in 53 countries. During 1995-99, 5-year agestandardised net survival for all lymphoid leukaemias combined ranged from 10.6% (95% CI 3.1-18.2) in the Chinese registries to 86.8% (81.6-92.0) in Austria. International differences in 5-year survival for childhood leukaemia were still large as recently as 2005-09, when age-standardised survival for lymphoid leukaemias ranged from 52.4% (95% CI 42.8-61.9) in Cali, Colombia, to 91.6% (89.5-93.6) in the German registries, and for AML ranged from 33.3% (18.9-47.7) in Bulgaria to 78.2% (72.0-84.3) in German registries. Survival from precursor-cell ALL was very close to that of all lymphoid leukaemias combined, with similar variation. In most countries, survival from AML improved more than survival from ALL between 2000-04 and 2005-09. Survival for each type of leukaemia varied markedly with age: survival was highest for children aged 1-4 and 5-9 years, and lowest for infants (younger than 1 year). There was no systematic difference in survival between boys and girls. Interpretation Global inequalities in survival from childhood leukaemia have narrowed with time but remain very wide for both ALL and AML. These results provide useful information for health policy makers on the effectiveness of health-care systems and for cancer policy makers to reduce inequalities in childhood survival

Mesoproterozoic rifting and Pan-African continental collision in SE India: evidence from the Khariar alkaline complex

The suture zone between the Bhandara craton and the granulite-facies rocks of the Eastern Ghats Province in SE India contains a number of deformed alkaline and tholeiitic intrusives. The Khariar alkaline complex is one of the several occurrences which intruded in the Mesoproterozoic (1,48017 Ma, 2r) and was deformed during the Pan-African tectonothermal event. The geochemical signatures indicate a rift-related setting for the magmatic activity. The nepheline syenite parent magma may have been produced by in-mantle fractionation of clinopyroxene and Ti-rich amphibole from a basanitic primary magma derived from an enriched spinel lherzolite mantle source in the sub-continental lithosphere. Geochemical variations in the Khariar alkaline suite can be modeled by the fractionation of clinopyroxene, amphibole, titanite, zircon, apatite and allanite. The Mesoproterozoic alkaline magmatism at Khariar marks the initiation of a NE-SW rift which formed several craton margin basins and opened an ocean towards the south. The sediments of the cratogenic basins and the Eastern Ghats Province were deposited in these rift-related basins. A K-Ar age of 1,33053 Ma from glauconites in sandstone suggests that the NW-SE trending Godavari-Pranhita graben formed at approximately the same time as the rift at the craton margin. If the two are related, the Godavari-Pranhita graben may represent the failed arm of a rift system in which the NE-SW arm was the active segment. The granulite-facies deformation and metamorphism of the Eastern Ghats Province sediments may be related to an episode of Grenvillian basin inversion. The Mesoproterozoic rifting and Grenvillian basin closure may thus represent two well-defined parts of a Wilson cycle i.e. the opening and closure of an ocean. The Khariar and other alkaline bodies were, however, deformed during a Pan-African collisional event associated with the westward thrusting of the Eastern Ghats Province granulites over the cratonic foreland