Malignant inflammation in cutaneous T-cell lymphoma: a hostile takeover

Cutaneous T-cell lymphomas (CTCL) are characterized by the presence of chronically inflamed skin lesions containing malignant T cells. Early disease presents as limited skin patches or plaques and exhibits an indolent behavior. For many patients, the disease never progresses beyond this stage, but in approximately one third of patients, the disease becomes progressive, and the skin lesions start to expand and evolve. Eventually, overt tumors develop and the malignant T cells may disseminate to the blood, lymph nodes, bone marrow, and visceral organs, often with a fatal outcome. The transition from early indolent to progressive and advanced disease is accompanied by a significant shift in the nature of the tumor-associated inflammation. This shift does not appear to be an epiphenomenon but rather a critical step in disease progression. Emerging evidence supports that the malignant T cells take control of the inflammatory environment, suppressing cellular immunity and anti-tumor responses while promoting a chronic inflammatory milieu that fuels their own expansion. Here, we review the inflammatory changes associated with disease progression in CTCL and point to their wider relevance in other cancer contexts. We further define the term "malignant inflammation" as a pro-tumorigenic inflammatory environment orchestrated by the tumor cells and discuss some of the mechanisms driving the development of malignant inflammation in CTCL

Increased IL6 plasma levels in indolent systemic mastocytosis patients are associated with high risk of disease progression

Systemic mastocytosis (SM) is a heterogeneous disease with altered interleukin (IL)-6 and IL13 plasma levels. However, no study has simultaneously investigated the plasma levels of IL1 beta, IL6, IL13, CCL23 and clusterin in SM at diagnosis and correlated them with disease outcome. Here we investigated IL1 beta, IL6, IL13, CCL23 and clusterin plasma levels in 75 SM patients-66 indolent SM (ISM) and 9 aggressive SM-and analyzed their prognostic impact among ISM cases grouped according to the extent of hematopoietic involvement of the bone marrow cells by the KIT D816V mutation. Although increased IL1 beta, IL6 and CCL23 levels were detected in SM patients versus healthy controls, only IL6 and CCL23 levels gradually increased with disease severity. Moreover, increased IL6 plasma levels were associated with ISM progression to more aggressive disease, in particular among ISM patients with multilineal KIT mutation (ISM-ML), these patients also showing a higher frequency of organomegalies, versus other ISM-ML patients. Of note, all ISM patients who progressed had increased IL6 plasma levels already at diagnosis. Our results indicate that SM patients display an altered plasma cytokine profile already at diagnosis, increased IL6 plasma levels emerging as an early marker for disease progression among ISM cases, in particular among high-risk ISM patients who carry multilineage KIT mutation

Blood and skin-derived Sezary cells: differences in proliferation-index, activation of PI3K/AKT/mTORC1 pathway and its prognostic relevance

Sézary syndrome (SS) is a rare and aggressive variant of Cutaneous T-Cell Lymphoma characterized by neoplastic distribution mainly involving blood, skin, and lymph-node. Although a role of the skin microenvironment in SS pathogenesis has long been hypothesized, its function in vivo is poorly characterized. To deepen this aspect, here we compared skin to blood-derived SS cells concurrently obtained from SS patients highlighting a greater proliferation-index and a PI3K/AKT/mTORC1 pathway activation level, particularly of mTOR protein, in skin-derived-SS cells. We proved that SDF-1 and CCL21 chemokines, both overexpressed in SS tissues, induce mTORC1 signaling activation, cell proliferation and Ki67 up-regulation in a SS-derived cell line and primary-SS cells. In a cohort of 43 SS cases, we observed recurrent copy number variations (CNV) of members belonging to this cascade, namely: loss of LKB1 (48%), PTEN (39%) and PDCD4 (35%) and gains of P70S6K (30%). These alterations represent druggable targets unraveling new therapeutic treatments as metformin here evaluated in vitro. Moreover, CNV of PTEN, PDCD4, and P70S6K, evaluated individually or in combination, are associated with reduced survival of SS patients. These data shed light on effects in vivo of skin-SS cells interaction underlying the prognostic and therapeutic relevance of mTORC1 pathway in SS

The Apaf-1-binding protein Aven is cleaved by Cathepsin D to unleash its anti-apoptotic potential

The anti-apoptotic molecule Aven was originally identified in a yeast two-hybrid screen for Bcl-x(L)-interacting proteins and has also been found to bind Apaf-1, thereby interfering with Apaf-1 self-association during apoptosome assembly. Aven is expressed in a wide variety of adult tissues and cell lines, and there is increasing evidence that its overexpression correlates with tumorigenesis, particularly in acute leukemias. The mechanism by which the anti-apoptotic activity of Aven is regulated remains poorly understood. Here we shed light on this issue by demonstrating that proteolytic removal of an inhibitory N-terminal Aven domain is necessary to activate the anti-apoptotic potential of the molecule. Furthermore, we identify Cathepsin D (CathD) as the protease responsible for Aven cleavage. On the basis of our results, we propose a model of Aven activation by which its N-terminal inhibitory domain is removed by CathD-mediated proteolysis, thereby unleashing its cytoprotective function

The origin, composition and rates of organic nitrogen deposition: A missing piece of the nitrogen cycle?

Organic forms of nitrogen are widespread in the atmosphere and their deposition may constitute a substantive input of atmospheric N to terrestrial and aquatic ecosystems. Recent studies have expanded the pool of available measurements and our awareness of their potential significance. Here, we use these measurements to provide a coherent picture of the processes that produce both oxidized and reduced forms of organic nitrogen in the atmosphere, examine how those processes are linked to human activity and how they may contribute to the N load from the atmosphere to ecosystems. We summarize and synthesize data from 41 measurements of the concentrations and fluxes of atmospheric organic nitrogen (AON). In addition, we examine the contribution of reduced organic nitrogen compounds such as amino acids, bacterial/particulate N, and oxidized compounds such as organic nitrates to deposition fluxes of AON. The percentage contribution of organic N to total N loading varies from site to site and with measurement methodology but is consistently around a third of the total N load with a median value of 30% (Standard Deviation of 16%). There are no indications that AON is a proportionally greater contributor to N deposition in unpolluted environments and there are not strong correlations between fluxes of nitrate and AON or ammonium and AON. Possible sources for AON include byproducts of reactions between NO_x and hydrocarbons, marine and terrestrial sources of reduced (amino acid) N and the long- range transport of organic matter (dust, pollen etc.) and bacteria. Both dust and organic nitrates such as PAN appear to play an important role in the overall flux of AON to the surface of the earth. For estimates of organic nitrate deposition, we also use an atmospheric chemical transport model to evaluate the spatial distribution of fluxes and the globally integrated deposition values. Our preliminary estimate of the magnitude of global AON fluxes places the flux between 10 and 50 Tg of N per year with substantial unresolved uncertainties but clear indications that AON deposition is an important aspect of local and global atmospheric N budgets and deserves further consideration