Role of the inflammasome in lung cancer Inflammasome is involved in lung carcinogenesis

2014 - 2015Lung cancer is recognized as one of the most devastating tumor worldwide due to the low rate survival over 5 years from the time of diagnosis. Inflammation has been widely recognized as the seventh hallmark of cancer as it facilitates the establishment/development and progression of lung cancer. In this context, recent evidence highlighted the role of the inflammasome during carcinogenesis. However, little is still known. The inflammasome is a multiprotein complex that leads to caspase-1 activation which role in lung cancer is still under investigated. In this context, the aim of my PhD project was to understand the role of the inflammasome in lung cancer in a mouse model of carcinogen-induced lung cancer and in human non-small cell lung cancer (NSCLC). We found that both caspase-1-dependent, the canonical pathway, and caspase-8/caspase-11-dependent, the non-canonical pathway, inflammasome were involved during lung cancer establishment and progression in both mice and humans. Our data showed that the pharmacological inhibition of both caspase-1 and caspase-8 significantly reduced lung tumor outgrowth associated to lower pro-inflammatory response and to a reduced lung recruitment of immunesuppressive cells and that caspase-8 was upstream caspase-1 activation during lung carcinogenesis. Furthermore, we showed that caspase-11 was the primary/main orchestrator of the inflammasome-dependent lung cancer progression and that the enzyme could be upstream of caspase-1 to induce the amplification of the occurring inflammatory process associated to lung cancer development. Finally, we identified a novel mechanism by which lung tumor-associated macrophages could favor lung tumorigenesis via the activation of caspase-11-dependent inflammasome and the consequent release of the pro-tumorigenic IL-1α. [edited by author]XIV n.s

AIM2 Inflammasome Activation Leads to IL-1α and TGF-β Release From Exacerbated Chronic Obstructive Pulmonary Disease-Derived Peripheral Blood Mononuclear Cells

Chronic obstructive pulmonary disease (COPD) is now the fourth-leading cause of death worldwide and its prevalence is increasing. The progressive decline of lung function and airway remodelling are a consequence of chronic inflammatory responses. It was recently postulated the involvement of the inflammasome in COPD, although the underlying mechanism/s still need to be elucidated. Therefore, we isolated peripheral blood mononuclear cells (PBMCs) from exacerbated/unstable COPD patients. The stimulation of PBMCs with an AIM2 inflammasome activator, Poly dA:dT, led to IL-1α, but not IL-1β, release. The release of this cytokine was caspase-1- and caspase-4-dependent and correlated to higher levels of 8-OH-dG in COPD compared to non-smoker and smoker-derived PBMCs. Interestingly, AIM2-depedent IL-1α release was responsible for higher TGF-β levels, crucial mediator during pro-fibrotic processes associated to COPD progression. In conclusion, our data highlight the involvement of AIM2/caspase-1/caspase-4 in IL-1α-induced TGF-β release in unstable COPD-derived PBMCs, opening new therapeutic perspectives for unstable COPD patients

Intracellular Sphingosine-1-Phosphate Receptor 3 Contributes to Lung Tumor Cell Proliferation.

Background/Aims: The pleiotropic lipid mediator sphingosine-1-phosphate (S1P) exerts a multitude of effects on respiratory cell physiology and pathology through five S1P receptors (S1PR1-5). Epidemiological studies proved high levels of circulating S1P in non-small cell lung cancer (NSCLC) patients. Studies in literature suggest that high levels of S1P support carcinogenesis but the exact mechanism is still elusive. The aim of this study was to understand the mechanism/s underlying S1P-mediated lung tumor cell proliferation. Methods: We used human samples of NSCLC, a mouse model of first-hand smoking and of Benzo(a)pyrene (BaP)-induced tumor-bearing mice and A549 lung adenocarcinoma cells. Results: We found that the expression of S1PR3 was also into the nucleus of lung cells in vitro, data that were confirmed in lung tissues of NSCLC patients, smoking and tumor bearing BaP-exposed mice. The intranuclear, but not the membrane, localization of S1PR3 was associated to S1P-mediated proliferation of lung adenocarcinoma cells. Indeed, the inhibition of the membrane S1PR3 did not alter tumor cell proliferation after Toll Like Receptor (TLR) 9 activation. Instead, according to the nuclear localization of sphingosine kinase (SPHK) II, the inhibition of the kinase completely blocked the endogenous S1P-induced tumor cell proliferation. Conclusion: These results prove that the nuclear S1PR3/SPHK II axis is involved in lung tumor cell proliferation, highlighting a novel molecular mechanism which could provide differential therapeutic approaches especially in non-responsive lung cancer patients

Off-label long acting injectable antipsychotics in real-world clinical practice: a cross-sectional analysis of prescriptive patterns from the STAR Network DEPOT study

Introduction Information on the off-label use of Long-Acting Injectable (LAI) antipsychotics in the real world is lacking. In this study, we aimed to identify the sociodemographic and clinical features of patients treated with on- vs off-label LAIs and predictors of off-label First- or Second-Generation Antipsychotic (FGA vs. SGA) LAI choice in everyday clinical practice. Method In a naturalistic national cohort of 449 patients who initiated LAI treatment in the STAR Network Depot Study, two groups were identified based on off- or on-label prescriptions. A multivariate logistic regression analysis was used to test several clinically relevant variables and identify those associated with the choice of FGA vs SGA prescription in the off-label group. Results SGA LAIs were more commonly prescribed in everyday practice, without significant differences in their on- and off-label use. Approximately 1 in 4 patients received an off-label prescription. In the off-label group, the most frequent diagnoses were bipolar disorder (67.5%) or any personality disorder (23.7%). FGA vs SGA LAI choice was significantly associated with BPRS thought disorder (OR = 1.22, CI95% 1.04 to 1.43, p = 0.015) and hostility/suspiciousness (OR = 0.83, CI95% 0.71 to 0.97, p = 0.017) dimensions. The likelihood of receiving an SGA LAI grew steadily with the increase of the BPRS thought disturbance score. Conversely, a preference towards prescribing an FGA was observed with higher scores at the BPRS hostility/suspiciousness subscale. Conclusion Our study is the first to identify predictors of FGA vs SGA choice in patients treated with off-label LAI antipsychotics. Demographic characteristics, i.e. age, sex, and substance/alcohol use co-morbidities did not appear to influence the choice towards FGAs or SGAs. Despite a lack of evidence, clinicians tend to favour FGA over SGA LAIs in bipolar or personality disorder patients with relevant hostility. Further research is needed to evaluate treatment adherence and clinical effectiveness of these prescriptive patterns

The Role of Attitudes Toward Medication and Treatment Adherence in the Clinical Response to LAIs: Findings From the STAR Network Depot Study

Background: Long-acting injectable (LAI) antipsychotics are efficacious in managing psychotic symptoms in people affected by severe mental disorders, such as schizophrenia and bipolar disorder. The present study aimed to investigate whether attitude toward treatment and treatment adherence represent predictors of symptoms changes over time. Methods: The STAR Network \u201cDepot Study\u201d was a naturalistic, multicenter, observational, prospective study that enrolled people initiating a LAI without restrictions on diagnosis, clinical severity or setting. Participants from 32 Italian centers were assessed at three time points: baseline, 6-month, and 12-month follow-up. Psychopathological symptoms, attitude toward medication and treatment adherence were measured using the Brief Psychiatric Rating Scale (BPRS), the Drug Attitude Inventory (DAI-10) and the Kemp's 7-point scale, respectively. Linear mixed-effects models were used to evaluate whether attitude toward medication and treatment adherence independently predicted symptoms changes over time. Analyses were conducted on the overall sample and then stratified according to the baseline severity (BPRS < 41 or BPRS 65 41). Results: We included 461 participants of which 276 were males. The majority of participants had received a primary diagnosis of a schizophrenia spectrum disorder (71.80%) and initiated a treatment with a second-generation LAI (69.63%). BPRS, DAI-10, and Kemp's scale scores improved over time. Six linear regressions\u2014conducted considering the outcome and predictors at baseline, 6-month, and 12-month follow-up independently\u2014showed that both DAI-10 and Kemp's scale negatively associated with BPRS scores at the three considered time points. Linear mixed-effects models conducted on the overall sample did not show any significant association between attitude toward medication or treatment adherence and changes in psychiatric symptoms over time. However, after stratification according to baseline severity, we found that both DAI-10 and Kemp's scale negatively predicted changes in BPRS scores at 12-month follow-up regardless of baseline severity. The association at 6-month follow-up was confirmed only in the group with moderate or severe symptoms at baseline. Conclusion: Our findings corroborate the importance of improving the quality of relationship between clinicians and patients. Shared decision making and thorough discussions about benefits and side effects may improve the outcome in patients with severe mental disorders

Role of Plasmacytoid Dendritic Cells in Cancer

In the last decade several studies provided evidence that plasmacytoid dendritic cells (pDCs) actively participate in a wide spectrum of human diseases including infection, autoimmunity, and cancer. In particular, human neoplasms are populated by pDCs which presence is related to a poor prognosis. However, the role of tumor-associated pDCs (TApDCs) remains controversial. Various studies indicate that pDCs play an immunosuppressive role and facilitate tumor progression in both animal models and humans. In contrast, others found that the presence of activated pDCs results in tumor regression in mice. Given these findings, it is clear that pDC function plays a critical role in tumor biology. Understanding pDC biology in cancer represents an important necessity and will pave the road to novel therapeutic strategies to fight malignancies. In this chapter we will discuss novel findings about the therapeutic tools which are based on the pharmacological manipulation of tumor-associated pDCs

Inflammasome: Cancer's friend or foe?

High serum concentrations of IL-1β and IL-18 are correlated to malignancies with low-rate survival from the time of diagnosis. The multimeric complex of the inflammasome is responsible for IL-1β/IL-18 synthesis/release. A number of endogenous (damage-associated molecular patterns) and exogenous (pathogen-associated molecular patterns) stimuli can provide signals for inflammasome activation in cancer. These stimuli can behave as tumor promoters via inducing chronic inflammation that, rather than providing a protective response to loss of tissue homeostasis, aberrantly facilitates tumor development. This view is contrasted in animal models of colon cancer in which the activation of some inflammasome complexes is associated with tumor protection. More studies are needed to understand the biology of the inflammasome in cancer and explore its therapeutic potential

Drug resistance in non-small cell lung Cancer (NSCLC): Impact of genetic and non-genetic alterations on therapeutic regimen and responsiveness

The discovery of genetic alterations, that can be targeted therapeutically, has launched a new era for lung cancer research and personalized therapy. However, not all the identified new genetic driver mutations are therapeutically targetable due to high toxicity profile. On the other hand, those genetic alterations that could be pharmacologically targeted, are often subject of alternative mutations that lead to drug resistance, which represents one of the major clinical limitation. Mechanisms of acquired resistance in oncogene-driven malignancies occur after additional genetic alterations of the primary oncogene. In this scenario, the secondary genetic alteration can lead to up-regulation of bypass-signaling pathways, changes in tumor histology or alterations in drug metabolism, that are able to promote drug resistance with an ensuing lower survival rate of the patient. Another aspect to be considered is that non-genetically mutated patients still have poor pharmacological options and therefore still represent an unmet medical need. Therefore, identifying mechanisms underlying both drug resistance in genetically mutated patients and novel therapeutic alternatives for non-mutated NSCLC patients is still an area of intense investigation

Lung cancer biomarkers and their methods and diagnostic kits

The present invention relates to the use as a biomarker of the active form of a human caspase protein, preferably the human caspase-4 or caspase-1, or of the active form of the protein encoded by an orthologue gene of the human caspase protein, preferably by an orthologue gene of the human caspase-4, for example the murine caspase-11 protein, in a method of diagnosis and/or prognosis and/or of monitoring the progression of a tumor, particularly lung cancer