Cancer-associated adipocytes exhibit an activated phenotype and contribute to breast cancer invasion

Early local tumor invasion in breast cancer results in a likely encounter between cancer cells and mature adipocytes, but the role of these fat cells in tumor progression remains unclear. We show that murine and human tumor cells cocultivated with mature adipocytes exhibit increased invasive capacities in vitro and in vivo, using an original two-dimensional coculture system. Likewise, adipocytes cultivated with cancer cells also exhibit an altered phenotype in terms of delipidation and decreased adipocyte markers associated with the occurrence of an activated state characterized by overexpression of proteases, including matrix metalloproteinase-11, and proinflammatory cytokines [interleukin (IL)-6, IL-1β]. In the case of IL-6, we show that it plays a key role in the acquired proinvasive effect by tumor cells. Equally important, we confirm the presence of these modified adipocytes in human breast tumors by immunohistochemistry and quantitative PCR. Interestingly, the tumors of larger size and/or with lymph nodes involvement exhibit the higher levels of IL-6 in tumor surrounding adipocytes. Collectively, all our data provide in vitro and in vivo evidence that (i) invasive cancer cells dramatically impact surrounding adipocytes; (ii) peritumoral adipocytes exhibit a modified phenotype and specific biological features sufficient to be named cancer-associated adipocytes (CAA); and (iii) CAAs modify the cancer cell characteristics/phenotype leading to a more aggressive behavior. Our results strongly support the innovative concept that adipocytes participate in a highly complex vicious cycle orchestrated by cancer cells to promote tumor progression that might be amplified in obese patients.     

In vivo and ex vivo percutaneous absorption of [<Superscript>14</Superscript>C]-bisphenol A in rats: a possible extrapolation to human absorption?

Bisphenol A (BPA) is a monomer used mainly in the synthesis of polycarbonates and epoxy resins. Percutaneous absorption is the second source of exposure, after inhalation, in the work environment. However, studies on this route of absorption are lacking or incomplete. In this study, percutaneous BPA absorption was measured in vivo and ex vivo in the rat, and ex vivo in humans. An approximately 12-fold difference in permeability between rat skin and human skin was found, with permeability being higher in the rat. In addition, inter- and intra-individual variability of up to tenfold was observed in humans. No accumulation of BPA in the skin was found during exposure. The skin clearance rate following exposure was estimated at 0.4 μg/cm2/h. Ex vivo and in vivo percutaneous absorption fluxes of BPA in the rat were in the same range (about 2.0 μg/cm2/h), suggesting that extrapolation to the in vivo situation in humans may be possible. The European tolerable daily intake (TDI) of BPA is 50 μg/kg body weight. However, many research projects have highlighted the significant effects of BPA in rodents at doses lower than 10 μg/kg/day. A 1-h occupational exposure over 2,000 cm2 (forearms and hands) may lead to a BPA absorption of 4 μg/kg/day. This is 8% of the European TDI and is very close to the value at which effects have been observed in animals. This absorption must therefore be taken into account when evaluating risks of BPA exposure, at least until more relevant results on the toxicity of BPA in humans are available.     

Socioeconomic environment and disparities in cancer survival for 19 solid tumor sites: An analysis of the French Network of Cancer Registries (FRANCIM) data

Social inequalities are concerning along the cancer continuum. In France, social gradient in health is particularly marked but little is known about social gradient in cancer survival. We aimed to investigate the influence of socioeconomic environment on cancer survival, for all cancers reported in the French Network of Cancer Registries. We analyzed 189,657 solid tumors diagnosed between 2006 and 2009, recorded in 18 registries. The European Deprivation Index (EDI), an ecological index measuring relative poverty in small geographic areas, assessed social environment. The EDI was categorized into quintiles of the national distribution. One- and five-year age-standardized net survival (ASNS) were estimated for each solid tumor site and deprivation quintile, among men and among women. We found that 5-year ASNS was lower among patients living in the most deprived areas compared to those living in the least deprived ones for 14/16 cancers among men and 16/18 cancers among women. The extent of cancer survival disparities according to deprivation varied substantially across the cancer sites. The reduction in ASNS between the least and the most deprived quintile reached 34% for liver cancer among men and 59% for bile duct cancer among women. For pancreas, stomach and esophagus cancer (among men), and ovary and stomach cancer (among women), deprivation gaps were larger at 1-year than 5-year survival. In conclusion, survival was worse in the most deprived areas for almost all cancers. Our results from population-based cancer registries data highlight the need for implementing actions to reduce social inequalities in cancer survival in France.     

Selection of a macaque Fab with framework regions like those in humans, high affinity, and ability to neutralize the protective antigen (PA) of Bacillus anthracis by binding to the segment of PA between residues 686 and 694

Human anthrax infection cannot always be treated successfully by antibiotics, as highlighted by recent bioterrorist attacks; thus, adjunct therapies are clearly needed for the future. There is a particular need to further develop adjunct therapies that can neutralize secreted toxins, such as antibodies directed towards the 83-kDa protective antigen (PA(83)). In the absence of human donors, we immunized a macaque (Macaca fascicularis) with PA(83) to obtain such antibodies suitable as an adjunct therapy for human anthrax infection. By using bone marrow as a template, we PCR amplified specific Fab-encoding genes and cloned them as an immune library (10(7) clones). We isolated a high-affinity (equilibrium dissociation constant [K(D)], 3.4 nM), highly neutralizing (50% inhibitory concentration, 5.6 +/- 0.13 nM) Fab (designated 35PA(83)) from this library by panning. Its epitope was localized by Pepscan analysis between residues 686 and 694 of PA(83) and is part of the region which directly interacts with the cell receptor. 35PA(83) may thus neutralize the anthrax toxin by competing directly for its receptor. The genes encoding 35PA(83) were similar to those of a human immunoglobulin germ line and were assigned to subgroups of human V, (D), or J genes by IMGT/V-QUEST analysis. The 35PA(83) framework regions were 92% identical to a representative allele of each subgroup. When compared to framework regions coded by related human germ line genes, only 2 of 74 (VH) or 75 (VK) analyzed amino acids of 35PA(83) have different chemical characteristics. A very high degree of identity with human framework regions makes 35PA(83) well suited for expression as a whole primatized immunoglobulin G and demonstrates the practicality of using macaque Fabs when immunized human plasma cell donors are not available.