Complement c5a receptor facilitates cancer metastasis by altering t-cell responses in the metastatic niche

The impact of complement on cancer metastasis has not been well studied. In this report, we demonstrate in a preclinical mouse model of breast cancer that the complement anaphylatoxin C5a receptor (C5aR) facilitates metastasis by suppressing effector CD8(+) and CD4(+) T-cell responses in the lungs. Mechanisms of this suppression involve recruitment of immature myeloid cells to the lungs and regulation of TGF beta and IL10 production in these cells. TGF beta and IL10 favored generation of T regulatory cells (T-reg) and Th2-oriented responses that rendered CD8(+) T cells dysfunctional. Importantly, pharmacologic blockade of C5aR or its genetic ablation in C5aR-deficient mice were sufficient to reduce lung metastases. Depletion of CD8(+) T cells abolished this beneficial effect, suggesting that CD8(+) T cells were responsible for the effects of C5aR inhibition. In contrast to previous findings, we observed that C5aR signaling promoted T-reg generation and suppressed T-cell responses in organs where metastases arose. Overall, our findings indicated that the immunomodulatory functions of C5aR are highly context dependent. Furthermore, they offered proof-of-concept for complement-based immunotherapies to prevent or reduce cancer metastasis. (C) 2014 AACR

Patterns of CO_2 and radiocarbon across high northern latitudes during International Polar Year 2008

High-resolution in situ CO_2 measurements were conducted aboard the NASA DC-8 aircraft during the ARCTAS/POLARCAT field campaign, a component of the wider 2007–2008 International Polar Year activities. Data were recorded during large-scale surveys spanning the North American sub‐Arctic to the North Pole from 0.04 to 12 km altitude in spring and summer of 2008. Influences on the observed CO_2 concentrations were investigated using coincident CO, black carbon, CH_3CN, HCN, O_3, C_2Cl_4, and Δ^(14)CO_2 data, and the FLEXPART model. In spring, the CO_2 spatial distribution from 55°N to 90°N was largely determined by the long-range transport of air masses laden with Asian anthropogenic pollution intermingled with Eurasian fire emissions evidenced by the greater variability in the mid-to-upper troposphere. At the receptor site, the enhancement ratios of CO_2 to CO in pollution plumes ranged from 27 to 80 ppmv ppmv^(−1) with the highest anthropogenic content registered in plumes sampled poleward of 80°N. In summer, the CO_2 signal largely reflected emissions from lightning-ignited wildfires within the boreal forests of northern Saskatchewan juxtaposed with uptake by the terrestrial biosphere. Measurements within fresh fire plumes yielded CO_2 to CO emission ratios of 4 to 16 ppmv ppmv^(−1) and a mean CO_2 emission factor of 1698 ± 280 g kg^(−1) dry matter. From the ^(14)C in CO_2 content of 48 whole air samples, mean spring (46.6 ± 4.4‰) and summer (51.5 ± 5‰) Δ^(14)CO_2 values indicate a 5‰ seasonal difference. Although the northern midlatitudes were identified as the emissions source regions for the majority of the spring samples, depleted Δ^(14)CO_2 values were observed in <1% of the data set. Rather, ARCTAS Δ^(14)CO_2 observations (54%) revealed predominately a pattern of positive disequilibrium (1–7‰) with respect to background regardless of season owing to both heterotrophic respiration and fire-induced combustion of biomass. Anomalously enriched Δ^(14)CO_2 values (101–262‰) measured in emissions from Lake Athabasca and Eurasian fires speak to biomass burning as an increasingly important contributor to the mass excess in Δ^(14)CO_2 observations in a warming Arctic, representing an additional source of uncertainty in the quantification of fossil fuel CO_2

The ribosomal protein S19 suppresses antitumor immune responses via the complement C5a receptor 1

Relatively little is known about factors that initiate immunosuppression in tumors and act at the interface between tumor cells and host cells. In this article, we report novel immunosuppressive properties of the ribosomal protein S19 (RPS19), which is upregulated in human breast and ovarian cancer cells and released from apoptotic tumor cells, whereupon it interacts with the complement C5a receptor 1 expressed on tumor infiltrating myeloid-derived suppressor cells. This interaction promotes tumor growth by facilitating recruitment of these cells to tumors. RPS19 also induces the production of immunosuppressive cytokines, including TGF-b, by myeloid-derived suppressor cells in tumor-draining lymph nodes, leading to T cell responses skewed toward Th2 phenotypes. RPS19 promotes generation of regulatory T cells while reducing infiltration of CD8+ T cells into tumors. Reducing RPS19 in tumor cells or blocking the C5a receptor 1-RPS19 interaction decreases RPS19-mediated immunosuppression, impairs tumor growth, and delays the development of tumors in a transgenic model of breast cancer. This work provides initial preclinical evidence for targeting RPS19 for anticancer therapy enhancing antitumor T cell responses

Notch transactivates Rheb to maintain the multipotency of TSC-null cells

Differentiation abnormalities are a hallmark of tuberous sclerosis complex (TSC) manifestations; however, the genesis of these abnormalities remains unclear. Here we report on mechanisms controlling the multi-lineage, early neuronal progenitor and neural stem-like cell characteristics of lymphangioleiomyomatosis (LAM) and angiomyolipoma cells. These mechanisms include the activation of a previously unreported Rheb-Notch-Rheb regulatory loop, in which the cyclic binding of Notch1 to the Notch-responsive elements (NREs) on the Rheb promoter is a key event. This binding induces the transactivation of Rheb. The identified NRE2 and NRE3 on the Rheb promoter are important to Notch-dependent promoter activity. Notch cooperates with Rheb to block cell differentiation via similar mechanisms in mouse models of TSC. Cell-specific loss of Tsc1 within nestin-expressing cells in adult mice leads to the formation of kidney cysts, renal intraepithelial neoplasia, and invasive papillary renal carcinoma