Patients with small cell lung cancer (SCLC) die because of chemoresistance. Fibroblast growth factor-2 (FGF-2) increases the expression of antiapoptotic proteins, XIAP and Bcl-X L , and triggers chemoresistance in SCLC cells. Here we show that these effects are mediated through the formation of a specific multiprotein complex comprising B-Raf, PKCe and S6K2. S6K1, Raf-1 and other PKC isoforms do not form similar complexes. RNAi-mediated downregulation of B-Raf, PKCe or S6K2 abolishes FGF-2-mediated survival. In contrast, overexpression of PKCe increases XIAP and Bcl-X L levels and chemoresistance in SCLC cells. In a tetracycline-inducible system, increased S6K2 kinase activity triggers upregulation of XIAP, Bcl-X L and prosurvival effects. However, increased S6K1 kinase activity has no such effect. Thus, S6K2 but not S6K1 mediates prosurvival/chemoresistance signalling.

Background:At least 30% of patients with primary resectable non-small cell lung cancer (NSCLC) will experience a relapse in their disease within 5 years following definitive treatment. Clinicopathological predictors have proved to be suboptimal in identifying high-risk patients. We aimed to establish whether inflammation-based scores offer an improved prognostic ability in terms of estimating overall (OS) and recurrence-free survival (RFS) in a cohort of operable, early-stage NSCLC patients.Methods:Clinicopathological, demographic and treatment data were collected prospectively for 220 patients operated for primary NSCLC at the Hammersmith Hospital from 2004 to 2011. Pretreatment modified Glasgow Prognostic Score (mGPS), neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) were tested together with established prognostic factors in uni- and multivariate Cox regression analyses of OS and RFS.Results:Half of the patients were male, with a median age of 65. A total of 57% were classified as stage I with adenocarcinoma being the most prevalent subtype (60%). Univariate analyses of survival revealed stage (P<0.001), grade (P=0.02), lymphovascular (LVI, P=0.001), visceral pleural invasion (VPI, P=0.003), mGPS (P=0.02) and NLR (P=0.04) as predictors of OS, with stage (P<0.001), VPI (P=0.02) and NLR (P=0.002) being confirmed as independent prognostic factors on multivariate analyses. Patients with more advanced stage (P<0.001) and LVI (P=0.008) had significantly shorter RFS.Conclusions:An elevated NLR identifies operable NSCLC patients with a poor prognostic outlook and an OS difference of almost 2 years compared to those with a normal score at diagnosis. Our study validates the clinical utility of the NLR in early-stage NSCLC.

SummaryCancer cells reprogram their metabolism, altering both uptake and utilization of extracellular nutrients. We individually depleted amino acid nutrients from isogenic cells expressing commonly activated oncogenes to identify correspondences between nutrient supply and viability. In HME (human mammary epithelial) cells, deprivation of cystine led to increased cell death in cells expressing an activated epidermal growth factor receptor (EGFR) mutant. Cell death occurred via synchronous ferroptosis, with generation of reactive oxygen species (ROS). Hydrogen peroxide promoted cell death, as both catalase and inhibition of NADPH oxidase 4 (NOX4) blocked ferroptosis. Blockade of EGFR or mitogen-activated protein kinase (MAPK) signaling similarly protected cells from ferroptosis, whereas treatment of xenografts derived from EGFR mutant non-small-cell lung cancer (NSCLC) with a cystine-depleting enzyme inhibited tumor growth in mice. Collectively, our results identify a potentially exploitable sensitization of some EGFR/MAPK-driven tumors to ferroptosis following cystine depletion.

The p90 ribosomal S6 kinases (RSK) are implicated in various cellular processes, including cell proliferation, survival, migration, and invasion. In cancer, RSKs modulate cell transformation, tumorigenesis, and metastasis. Indeed, changes in the expression of RSK isoforms have been reported in several malignancies, including breast, prostate, and lung cancers. Four RSK isoforms have been identified in humans on the basis of their high degree of sequence homology. Although this similarity suggests some functional redundancy between these proteins, an increasing body of evidence supports the existence of isoform-based specificity among RSKs in mediating particular cellular processes. This review briefly presents the similarities between RSK family members before focusing on the specific function of each of the isoforms and their involvement in cancer progression. Cancer Res; 73(17); 5301-8. Ó2013 AACR.

A poptosis, or programmed cell death, is important for the normal development of organisms and maintaining tissue homeostasis. Misregulation of apoptosis may lead to neurodegenerative disorders when apoptosis is increased and tumor formation when apoptosis is inhibited; thus, the pathway is tightly controlled, with both pro-and antiapoptotic factors playing a role. Of particular interest are members of the inhibitor of apoptosis (IAP) and Bcl-2 families of proteins that intercept virtually all apoptotic signals in the cell.X chromosome-linked inhibitor of apoptosis (XIAP) is the most potent member of the IAP family; it directly interacts with and inhibits caspases 3, 7, and 9 and is therefore a key regulator of apoptosis (20). In contrast, Bcl-x L controls apoptosis by maintaining mitochondrial membrane homeostasis (14). Interestingly, both the XIAP and Bcl-x L mRNAs contain an internal ribosome entry site (IRES) that allows them to be translated during cellular stress by a cap-independent mechanism when cap-dependent translation is inhibited, which is necessary for their protective roles in the cell (4,11,16,24,49). Under normal growth conditions, translation of cellular mRNAs occurs through a cap-dependent mechanism that requires interaction of specific initiation factors (such as eukaryotic initiation factor 4E [eIF4E]) with the 5= cap of the mRNA, followed by recruitment of ribosomal subunits, recognition of the AUG start codon, and commencement of polypeptide chain elongation (reviewed in reference 26). However, certain cellular stresses such as nutrient deprivation, hypoxia, or low-dose irradiation cause attenuation of cap-dependent translation, and yet, under these conditions, a sizeable proportion of cellular mRNAs, perhaps as much as 10%, have been shown to be translated by a cap-independent mechanism, such as through an IRES (23,28,39). IRES elements are located within the 5= untranslated region (UTR) of some cellular mRNAs and are believed to recruit the ribosome directly, thereby bypassing the requirement for the mRNA 5= cap and eIF4E. Moreover, while IRES-dependent translation requires some canonical translation initiation factors, most (if not all) cellular IRES elements require the activity of auxiliary RNA binding proteins that function as IRES trans-acting factors (ITAFs) (reviewed in references 28 and 32). The mechanism by which ITAFs function is poorly understood, and since different IRESs require different sets of ITAFs, elucidating the identity of all known ITAFs has proven challenging. Furthermore, it has been shown that ITAFs can function as either positive or negative regulators of IRES-mediated translation. For example, heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) was shown to act as a repressor of XIAP IRES-mediated translation (33), whereas La autoantigen (19), hnRNPC1 and hnRNPC2 (18), and HuR (11) have all been shown to have a stimulating effect on XIAP IRES-mediated translation.We have previously demonstrated that treatment of small-cell lung cancer cells with fibroblast gr...

Most women diagnosed with malignant ovarian germ cell tumors have curable disease and experience excellent survival with manageable treatment-associated morbidity, related both to tumor biology and improvements in treatment over the last 4 decades. Malignant ovarian germ cell tumors occur predominantly in girls, adolescents, and young women and are often unilateral tumors of early stage, although advanced-stage disease occurs in approximately 30% of patients. Tumors are usually chemosensitive, thereby allowing fertility-sparing surgery in most women with high chance of cure. Differences in practice do exist among providers in various subspecialties and geographic areas. In most settings, collaborative efforts among specialties allow the optimal treatment of women with these rare tumors, and implementation of standard guidelines at an international level should translate to effective clinical trial design, rapid accrual to clinical trials, and universally improved patient outcomes. This consensus guideline represents a summary of recommendations for diagnosis and management that has been agreed upon by cooperative groups worldwide. It builds upon individual publications including previously published summary documents and provides the most current practice standards validated worldwide.

Primary human alveolar type 2 (AT2) cells were immortalized by transduction with the catalytic subunit of telomerase and simian virus 40 large-tumor antigen. Characterization by immunochemical and morphologic methods demonstrated an AT1-like cell phenotype. Unlike primary AT2 cells, immortalized cells no longer expressed alkaline phosphatase, pro-surfactant protein C, and thyroid transcription factor-1, but expressed increased caveolin-1 and receptor for advanced glycation end products (RAGE). Live cell imaging using scanning ion conductance microscopy showed that the cuboidal primary AT2 cells were approximately 15 mm and enriched with surface microvilli, while the immortal AT1 cells were attenuated more than 40 mm, resembling these cells in situ. Transmission electron microscopy highlighted the attenuated morphology and showed endosomal vesicles in some immortal AT1 cells (but not primary AT2 cells) as found in situ. Particulate air pollution exacerbates cardiopulmonary disease. Interaction of ultrafine, nano-sized particles with the alveolar epithelium and/or translocation into the cardiovasculature may be a contributory factor. We hypothesized differential uptake of nanoparticles by AT1 and AT2 cells, depending on particle size and surface charge. Uptake of 50-nm and 1-mm fluorescent latex particles was investigated using confocal microscopy and scanning surface confocal microscopy of live cells. Fewer than 10% of primary AT2 cells internalized particles. In contrast, 75% immortal AT1 cells internalized negatively charged particles, while less than 55% of these cells internalized positively charged particles; charge, rather than size, mattered. The process was rapid: one-third of the total cellassociated negatively charged 50-nm particle fluorescence measured at 24 hours was internalized during the first hour. AT1 cells could be important in translocation of particles from the lung into the circulation.

Lung cancer is the commonest cancer killer. Small cell lung cancer (SCLC) is initially chemosensitive, but rapidly relapses in a chemoresistant form with an overall survival of <5%. Consequently, novel therapies are urgently required and will likely arise from an improved understanding of the disease biology. Our previous work showed that fibroblast growth factor-2 induces proliferation and chemoresistance in SCLC cells. Here, we show that the selective fibroblast growth factor receptor (FGFR) inhibitor PD173074 blocks H-510 and H-69 SCLC proliferation and clonogenic growth in a dose-dependent fashion and prevents FGF-2-induced chemoresistance. These effects correlate with the inhibition of both FGFR1 and FGFR2 transphosphorylation. We then determined the efficacy of daily oral administration of PD173074 for 28 days in two human SCLC models. In the H-510 xenograft, tumor growth was impaired similar to that seen with single-agent cisplatin administration, increasing median survival compared with control sham-treated animals. Crucially, the effect of cisplatin was significantly potentiated by coadministration of PD173074. More dramatically, in H-69 xenografts, PD173074 induced complete responses lasting >6 months in 50% of mice. These effects were not a consequence of disrupted tumor vasculature but instead correlated with increased apoptosis (caspase 3 and cytokeratin 18 cleavage) in excised tumors. Moreover, in vivo imaging with 3′-deoxy-3′-