Malignant pleural effusion: Tumor-host interactions unleashed

Malignant pleural effusion (MPE) poses a significant clinical problem. Current nonetiologic management is suboptimal in terms of efficacy and safety. In light of recent research progress, we propose herein a new view of MPE development, which may rapidly translate into meaningful changes in therapeutics. In addition to tumor-induced impairment of pleural fluid drainage, pertinent findings point toward another pathway to MPE formation: a vicious loop of interactions between pleural-based tumor cells and the host vasculature and immune system that results in increased net fluid production via enhanced plasma extravasation into the pleural space. The ability of tumor cells to trigger this cascade likely rests on a specific and distinct transcriptional repertoire, which results in important vasoactive events in the pleural space. Although the characterization of tumor-derived factors responsible for MPE development is in the making, an additional, indirect path to MPE was recently demonstrated: tumor cells recruit and co-opt host cells and mediators, which, in turn, amplify tumor cell-primed fluid leakage and impact tumor cell functions. Importantly, recent evidence suggests that the biologic events that culminate in clinical MPE are likely amenable to therapeutic inhibition and even prevention. In this perspective, the scientific basis for an update of current concepts of MPE formation is highlighted. Key questions for future research are posed. Finally, a vision for novel, effective, safe, and convenient treatment modalities that can be offered to outpatients with MPE is set forth. Copyright © 2012 by the American Thoracic Society

KRAS pathway alterations in malignant pleural mesothelioma: An underestimated player.

Malignant pleural mesothelioma (MPM) is a rare, incurable cancer of the mesothelial cells lining the lungs and the chest wall that is mainly caused by asbestos inhalation. The molecular mechanisms of mesothelial carcinogenesis are still unclear despite comprehensive studies of the mutational landscape of MPM, and the most frequently mutated genes BAP1, NF2, CDKN2A, TP53, and TSC1 cannot cause MPM in mice in a standalone fashion. Although KRAS pathway alterations were sporadically detected in older studies employing targeted sequencing, they have been largely undetected by next generation sequencing. We recently identified KRAS mutations and copy number alterations in a significant proportion of MPM patients. Here, we review and analyze multiple human datasets and the published literature to show that, in addition to KRAS, multiple other genes of the KRAS pathway are perturbed in a significant proportion of patients with MPM

Immune resistance in lung adenocarcinoma.

Lung cancer is the leading cancer killer worldwide, imposing grievous challenges for patients and clinicians. The incidence of lung adenocarcinoma (LUAD), the main histologic subtype of lung cancer, is still increasing in current-, ex-, and even non-smokers, whereas its five-year survival rate is approximately 15% as the vast majority of patients usually present with advanced disease at the time of diagnosis. The generation of novel drugs targeting key disease driver mutations has created optimism for the treatment of LUAD, but, as these mutations are not universal, this therapeutic line benefits only a subset of patients. More recently, the advent of targeted immunotherapies and their documented clinical efficacy in many different cancers, including LUAD, have started to change cancer management. Immunotherapies have been developed in order to overcome the cancer’s ability to develop mechanisms of immune resistance, i.e., to adapt to and evade the host inflammatory and immune responses. Identifying a cancer’s immune resistance mechanisms will likely advance the development of personalized immunotherapies. This review examines the key pathways of immune resistance at play in LUAD and explores therapeutic strategies which can unleash potent antitumor immune responses and significantly improve therapeutic efficacy, quality of life, and survival in LUAD

Shared epithelial pathways to lung repair and disease.

Chronic lung diseases present tremendous health burdens and share a common pathobiology of dysfunctional epithelial repair. Lung adenocarcinoma, the leading cancer killer worldwide, is caused mainly by chemical carcinogens of tobacco smoke that induce mutations in pulmonary epithelial cells leading to uncontrolled epithelial proliferation. Lung epithelial cells that possess the capacity for self-renewal and regeneration of other lung cell types are believed to underlie the pathobiology of chronic obstructive, fibrotic and neoplastic lung disorders. However, the understanding of lung epithelial progenitor cell hierarchy and turnover is incomplete and a comprehensive model of the cellular and transcriptional events that underlie lung regeneration and carcinogenesis is missing. The mapping of these processes is extremely important, since their modulation would potentially allow effective cure and/or prevention of chronic lung diseases. In this review we describe current knowledge on cellular and molecular pathways at play during lung repair and carcinogenesis and summarise the critical lung cell populations with regenerative and cancerous potential

Translational research in pleural infection and beyond.

The incidence of pleural infection has been rising in recent years. Intrapleural therapy with tissue plasminogen activator (tPA) and deoxyribonuclease (DNase) has significantly reduced the need of surgery and its impact on clinical care is rising worldwide. Efforts are underway to optimize the delivery regime and establish the short and longer term effects of this therapy. The complex interactions of bacterial infection within the pleura with inflammatory responses and clinical interventions (antibiotics and tPA/DNase) require further studies to improve future treatment options. Intrapleural instillation of tPA potently induces pleural fluid formation, principally via a monocyte chemotactic protein (MCP)-1 dependent mechanism. Activation of transcriptional programs in pleural resident cells and infiltrating cells during pleural infection and malignancy results in the local secretion of a cocktail of pro-inflammatory signalling molecules (including MCP-1) within the pleural confines that contributes to effusion formation. Understanding the biology of these molecules and their interaction may provide novel targets for pleural fluid control

Lung carcinogenesis and fibrosis taken together: Just coincidence?

PURPOSE OF REVIEW: The pathogenesis of lung cancer and pulmonary fibrotic disorders partially overlaps. This review focuses on the common features of the two disease categories, aimed at advancing our translational understanding of their pathobiology and at fostering the development of new therapies. RECENT FINDINGS: Both malignant and collagen-producing lung cells display enhanced cellular proliferation, increased resistance to apoptosis, a propensity for invading and distorting the lung parenchyma, as well as stemness potential. These characteristics are reinforced by the tissue microenvironment and inflammation seems to play an important adjuvant role in both types of disorders. SUMMARY: Unraveling the thread of the common and distinct characteristics of lung fibrosis and cancer might contribute to a more comprehensive approach of the pathobiology of both diseases and to a pathfinder for novel and personalized therapeutic strategies

Biologically based models of cancer risk in radiation research.

PURPOSE: In radiation risk analysis the state-of-the-art approach is based on descriptive models which link excess rates of cancer incidence and mortality to radiation exposure by statistical association. To estimate the number of sporadic and radiation-induced cases descriptive models apply parametric dose response function which directly determine the radiation risk. In biologically-based models of cancer risk (BBCR models) dose responses are implemented for key events on the biological level such as early mutations or clonal expansion of initiated cells. Influenced by radiation these events then shape the risk response on the epidemiological level. Although BBCR models facilitate a more comprehensive consideration of biological processes for risk assessment, their range of application in radiation research remains limited. Therefore, we emphasize their ability to improve understanding of radiation-related carcinogenesis by integrating molecular biology with epidemiology. We highlight the potential of BBCR models to harness information from adverse outcome pathways (AOPs) for risk estimation with closer links to radiobiology. The AOP concept originates from toxicology and may be applied profitably in radiation research. CONCLUSION: The conceptual design of BBCR models can be guided by the high-dimensional data environment provided by AOPs. Risk estimates from BBCR models pertain not only to classical radioepidemiological covariables such as radiation dose or attained age but also to well characterized molecular pathways. By additionally deploying biological information BBCR models facilitate finer risk stratification for a more personalized risk assessment. They leave behind the one-size-fits-all approach of descriptive modeling with the downside of more involved model development. Importantly, predictions from BBCR models can be validated against molecular measurements. Validated predictions would confirm the model design and strengthen the link between molecular biology and epidemiology. But the availability of cancer tissue in good quality from patients with known radiation exposure constitutes a major bottleneck. More ambitious initiative is needed to recover stored tissue samples and make them available for molecular investigations. To conclude, risk estimation will not only on rely on statistical association but will be quantitatively informed with radiobiological insight. Combined with the AOP framework BBCR models could improve accuracy and reduce uncertainty of radiation risk estimates in future research

A method for the establishment and characterization of mouse lung adenocarcinoma cell lines that mimic traits of human adenocarcinomas.

Lung adenocarcinoma (LADC) is the leading cause of cancer death worldwide and is largely inflicted by carcinogens contained in tobacco smoke. The generation of cell lines mimicking traits of human LADC will profoundly advance our understanding of the pathobiology of the disease, as they offer an easy and valuable tool to study the cellular and molecular aspects of carcinogenesis. Here we describe a detailed protocol for the generation of such cell lines, following the exposure of experimental mouse strains to different tobacco carcinogens and isolation of the resulting lung tumors