Extracellular Heat Shock Protein (Hsp)70 and Hsp90α Assist in Matrix Metalloproteinase-2 Activation and Breast Cancer Cell Migration and Invasion

Breast cancer is second only to lung cancer in cancer-related deaths in women, and the majority of these deaths are caused by metastases. Obtaining a better understanding of migration and invasion, two early steps in metastasis, is critical for the development of treatments that inhibit breast cancer metastasis. In a functional proteomic screen for proteins required for invasion, extracellular heat shock protein 90 alpha (Hsp90α) was identified and shown to activate matrix metalloproteinase 2 (MMP-2). The mechanism of MMP-2 activation by Hsp90α is unknown. Intracellular Hsp90α commonly functions with a complex of co-chaperones, leading to our hypothesis that Hsp90α functions similarly outside of the cell. In this study, we show that a complex of co-chaperones outside of breast cancer cells assists Hsp90α mediated activation of MMP-2. We demonstrate that the co-chaperones Hsp70, Hop, Hsp40, and p23 are present outside of breast cancer cells and co-immunoprecipitate with Hsp90α in vitro and in breast cancer conditioned media. These co-chaperones also increase the association of Hsp90α and MMP-2 in vitro. This co-chaperone complex enhances Hsp90α-mediated activation of MMP-2 in vitro, while inhibition of Hsp70 in conditioned media reduces this activation and decreases cancer cell migration and invasion. Together, these findings support a model in which MMP-2 activation by an extracellular co-chaperone complex mediated by Hsp90α increases breast cancer cell migration and invasion. Our studies provide insight into a novel pathway for MMP-2 activation and suggest Hsp70 as an additional extracellular target for anti-metastatic drug development

Drained Inland Organic Soils

Organic soils are defined in Chapter 3 Annex 3A.5 of Volume 4 of the 2006 IPCC Guidelines and Section 5, Chapter 1, section 5 of this Wetlands Supplement. The guidance in this Chapter applies to all inland organic soils that have been drained, i.e., drainage of lands that started in the past and that still persists, or newly drained lands within the reporting period. This means that the water table level is at least temporarily below natural levels. Natural levels mean that the mean annual water table is near the soil surface but can experience seasonal fluctuations. Within each land-use category water table level is manipulated to varying degrees depending on land-use purpose, e.g., for cultivating cereals, rice, or for aquaculture, which can be reflected by different drainage classes. This Chapter deals with inland organic soils, which do not meet the definition of “coastal” defined in Chapter 4 of this Wetlands Supplement.The term “organic soils” refers to “inland organic soils” in this Chapter. This Chapter provides supplementary guidance on estimating greenhouse gas emissions and removals from drained inland organic soils in the following land-use categories as defined in the 2006 IPCC Guidelines Volume 4: Chapter 4 (Forest Land), Chapter 5 (Cropland), Chapter 6 (Grassland), Chapter 7 (Wetlands), Chapter 8 (Settlements) and Chapter 9 (Other Land). Managed coastal organic soils are covered in Chapter 4 of this Supplement. Rewetted organic soils are considered in Chapter 3 of the Wetlands Supplement

Intact and managed peatland soils as a source and sink of GHGs from 1850 to 2100

Land-use change disturbs the function of peatland as a natural carbon sink and triggers high GHG emissions1. Nevertheless, historical trends and future trajectories of GHG budgets from soil do not explicitly include peatlands2,3. Here, we provide an estimate of the past and future role of global peatlands as either a source or sink of GHGs based on scenario timelines of land conversion. Between 1850 and 2015, temperate and boreal regions lost 26.7 million ha, and tropical regions 24.7 million ha, of natural peatland. By 2100, peatland conversion in tropical regions might increase to 36.3 million ha. Cumulative emissions from drained sites reached 80 ± 20 PgCO2e in 2015 and will add up to 249 ± 38 Pg by 2100. At the same time, the number of intact sites accumulating peat will decline. In 1960 the global peatland biome turned from a net sink into a net source of soil-derived GHGs. Annual back-conversion of most of the drained area would render peatlands GHG neutral, whereas emissions from peatland may comprise 12–41% of the GHG emission budget for keeping global warming below +1.5 to +2 °C without rehabilitation