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Although progenitor cells of the conducting airway have been spatially localized and some insights have been gained regarding their molecular phenotype, relatively little is known about the mechanisms regulating their maintenance, activation, and differentiation. This study investigates the potential roles of E-cadherin in mouse Clara cells, as these cells were shown to represent the progenitor/stem cells of the conducting airways and have been implicated as the cell of origin of human non-small cell lung cancer. Postnatal inactivation of E-cadherin affected Clara cell differentiation and compromised airway regeneration under injury conditions. In steady-state adult lung, overexpression of the dominant negative E-cadherin led to an expansion of the bronchiolar stem cells and decreased differentiation concomitant with canonical Wnt signaling activation. Expansion of the bronchiolar stem cell pool was associated with an incessant proliferation of neuroepithelial body-associated Clara cells that ultimately gave rise to bronchiolar hyperplasia. Despite progressive hyperplasia, only a minority of the mice developed pulmonary solid tumors, suggesting that the loss of E-cadherin function leads to tumor formation when additional mutations are sustained. The present study reveals that E-cadherin plays a critical role in the regulation of proliferation and homeostasis of the epithelial cells lining the conducting airways.
Emotionales Befinden, Krankheitsverarbeitung und Überlebenszeit bei Bronchialkarzinompatienten
(2004)
Die vorliegende hypothesenprüfende Arbeit hat als erweiterte Replikationsstudie zum Ziel, den Zusammenhang zwischen emotionalem Befinden und Krankheitsverarbeitung bei Bronchialkarzinomkranken zu untersuchen und die Befunde bezüglich Krankheitsverarbeitung und Überlebenszeit aus der Vorstudie von Faller et al. (1999) beziehungsweise Faller und Bülzebruck (2002) zu überprüfen. 59 an einem Bronchialkarzinom erkrankte Patienten wurden vor Beginn der Primärbehandlung zu ihrem emotionalen Befinden und der Art ihrer Krankheitsbewältigung befragt. Neben der Selbsteinschätzung fand eine Fremdeinschätzung durch die Interviewer statt. Die Überlebensdaten wurden nach 3 - 5 Jahren erhoben. In der vorliegenden Studie konnte ein Zusammenhang zwischen emotionaler Belastung und depressiver Krankheitsverarbeitung nachgewiesen werden. Die Untersuchung zeigte zudem, dass unter Einbeziehung biomedizinischer prognostischer Faktoren eine selbsteingeschätzte depressive Krankheitsverarbeitung mit einer kürzeren Überlebenszeit einhergeht(hazard ratio 1.75, 95% confidence interval 1.04-2.93, p = 0.034). Der körperliche Leistungszustand (Karnofsky-Index) stellte ebenfalls einen unabhängigen Prädiktor für die Überlebenszeit dar. Diese Ergebnisse stimmen mit denjenigen der Vorstudie von Faller und Bülzebruck (2002) überein. Einschränkungen der Studie bestehen aufgrund der relativ kleinen Stichprobe sowie deren hoher Selektivität.
Background:
The aim of this work is to validate the Dynamic Planning Module in terms of usability and acceptance in the treatment planning workflow.
Methods:
The Dynamic Planning Module was used for decision making whether a plan adaptation was necessary within one course of radiation therapy. The Module was also used for patients scheduled for re-irradiation to estimate the dose in the pretreated region and calculate the accumulated dose to critical organs at risk. During one year, 370 patients were scheduled for plan adaptation or re-irradiation. All patient cases were classified according to their treated body region. For a sub-group of 20 patients treated with RT for lung cancer, the dosimetric effect of plan adaptation during the main treatment course was evaluated in detail. Changes in tumor volume, frequency of re-planning and the time interval between treatment start and plan adaptation were assessed.
Results:
The Dynamic Planning Tool was used in 20% of treated patients per year for both approaches nearly equally (42% plan adaptation and 58% re-irradiation). Most cases were assessed for the thoracic body region (51%) followed by pelvis (21%) and head and neck cases (10%). The sub-group evaluation showed that unintended plan adaptation was performed in 38% of the scheduled cases. A median time span between first day of treatment and necessity of adaptation of 17 days (range 4–35 days) was observed. PTV changed by 12 ± 12% on average (maximum change 42%). PTV decreased in 18 of 20 cases due to tumor shrinkage and increased in 2 of 20 cases. Re-planning resulted in a reduction of the mean lung dose of the ipsilateral side in 15 of 20 cases.
Conclusion:
The experience of one year showed high acceptance of the Dynamic Planning Module in our department for both physicians and medical physicists. The re-planning can potentially reduce the accumulated dose to the organs at risk and ensure a better target volume coverage. In the re-irradiation situation, the Dynamic Planning Tool was used to consider the pretreatment dose, to adapt the actual treatment schema more specifically and to review the accumulated dose.
The evolutionary conserved Myb-MuvB (MMB) multiprotein complex is a transcriptional master regulator of mitotic gene expression. The MMB subunits B-MYB, FOXM1 as well as target genes of MMB are often overexpressed in different cancer types. Elevated expression of these genes correlates with an advanced tumor state and a poor prognosis for patients. Furthermore, it has been reported that pathways, which are involved in regulating the mitotic machinery are attractive for a potential treatment of cancers harbouring Ras mutations (Luo et al., 2009).
This suggest that the MMB complex could be required for tumorigenesis by mediating overactivity of mitotic genes and that the MMB could be a useful target for lung cancer treatment. However, although MMB has been characterized biochemically, the contribution of MMB to tumorigenesis is largely unknown in particular in vivo.
In this thesis, it was demonstrated that the MMB complex is required for lung tumorigenesis in vivo in a mouse model of non small cell lung cancer. Elevated levels of B-MYB, NUSAP1 or CENPF in advanced tumors as opposed to low levels of these proteins levels in grade 1 or 2 tumors support the possible contribution of MMB to lung tumorigenesis and the oncogenic potential of B-MYB.The tumor growth promoting function of B-MYB was illustrated by a lower fraction of KI-67 positive cells in vivo and a significantly high impairment in proliferation after loss of B-Myb in vitro. Defects in cytokinesis and an abnormal cell cycle profile after loss of B-Myb underscore the impact of B-MYB on proliferation of lung cancer cell lines. The incomplete recombination of B-Myb in murine lung tumors and in the tumor derived primary cell lines illustrates the selection pressure against the complete loss of B-Myb and further demonstrats that B-Myb is a tumor-essential gene. In the last part of this thesis, the contribution of MMB to the proliferation of human lung cancer cells was demonstrated by the RNAi-mediated depletion of B-Myb. Detection of elevated B-MYB levels in human adenocarcinoma and a reduced proliferation, cytokinesis defects and abnormal cell cycle profile after loss of B-MYB in human lung cancer cell lines underlines the potential of B-MYB to serve as a clinical marker.
Purpose
The purpose of this study is to investigate changes over time in quality of life (QoL) in incurable lung cancer patients and the impact of determinants like molecular alterations (MA).
Methods
In a prospective, longitudinal, multicentric study, we assessed QoL, symptom burden, psychological distress, unmet needs, and prognostic understanding of patients diagnosed with incurable lung cancer at the time of the diagnosis (T0) and after 3 (T1), 6 (T2) and 12 months (T3) using validated questionnaires like FACT-L, National Comprehensive Cancer Network (NCCN) Distress Thermometer (DT), PHQ-4, SCNS-SF-34, and SEIQoL.
Results
Two hundred seventeen patients were enrolled, 22 (10%) with reported MA. QoL scores improved over time, with a significant trend for DT, PHQ-4, and SCNS-SF-34. Significant determinants for stable or improving scores over time were survival > 6 months, performance status at the time of diagnosis, and presence of MA. Patients with MA showed better QoL scores (FACT-L at T1 104.4 vs 86.3; at T2 107.5 vs 90.0; at T3 100.9 vs 92.8) and lower psychological distress (NCCN DT at T1 3.3 vs 5; at T2 2.7 vs 4.5; at T3 3.7 vs 4.5; PHQ-4 at T1 2.3 vs 4.1; at T2 1.7 vs 3.6; at T3 2.2 vs 3.6), but also a worsening of the scores at 1 year and a higher percentage of inaccurate prognostic understanding (27 vs 17%) compared to patients without MA.
Conclusion
Patients with tumors harboring MA are at risk of QoL deterioration during the course of the disease. Physicians should adapt their communication strategies in order to maintain or improve QoL.
Lung cancer is the most common cancer worldwide and the leading cause of cancer-related deaths in both men and women. Despite the development of novel therapeutic interventions, the 5-year survival rate for non-small cell lung cancer (NSCLC) patients remains low, demonstrating the necessity for novel treatments. One strategy to improve translational research is the development of surrogate models reflecting somatic mutations identified in lung cancer patients as these impact treatment responses. With the advent of CRISPR-mediated genome editing, gene deletion as well as site-directed integration of point mutations enabled us to model human malignancies in more detail than ever before. Here, we report that by using CRISPR/Cas9-mediated targeting of Trp53 and KRas, we recapitulated the classic murine NSCLC model Trp53fl/fl:lsl-KRasG12D/wt. Developing tumors were indistinguishable from Trp53fl/fl:lsl-KRasG12D/wt-derived tumors with regard to morphology, marker expression, and transcriptional profiles. We demonstrate the applicability of CRISPR for tumor modeling in vivo and ameliorating the need to use conventional genetically engineered mouse models. Furthermore, tumor onset was not only achieved in constitutive Cas9 expression but also in wild-type animals via infection of lung epithelial cells with two discrete AAVs encoding different parts of the CRISPR machinery. While conventional mouse models require extensive husbandry to integrate new genetic features allowing for gene targeting, basic molecular methods suffice to inflict the desired genetic alterations in vivo. Utilizing the CRISPR toolbox, in vivo cancer research and modeling is rapidly evolving and enables researchers to swiftly develop new, clinically relevant surrogate models for translational research.
Hintergrund der Studie ist die Untersuchung der Auswirkung systematischer Lymphadenektomie bei chirurgischer Sanierung von Bronchial-Carcinomen auf die 5-Jahres-Überlebensrate der Patienten und der Vergleich zwischen dem präoperativ diagnostiziertem Tumorstadium und dem histologischem Befund. In der Studie werden die Daten von insgesamt 95 Patienten, die sich von 1996 bis 2001 einer Thorakotomie aufgrund eines Bronchial-Carcinoms unterziehen mussten, retrospektiv untersucht. Die 5-Jahres-Überlebensrate wurde nach Kaplan-Meier Methode errechnet. Es zeigte sich, dass der intra- sowie postoperative Verlauf durch die Lymphknotendissektion nicht beeinträchtigt wurde. Trotz der größeren Wundfläche, bedingt durch die Lymphknotenentfernung, benötigen 65% der Patienten keine Erythrozytenkonzentrate, 25% der Patienten benötigen 1-2 Konserven und bei den verbleibenden 10% war die Transfusion von 3 oder mehr Erythrozytenkonzentraten notwendig. Die Operationszeit betrug im Durchschnitt 4.6 Stunden vom Hautschnitt bis zum Wundverschluss. Der Vergleich zwischen dem radiologischem und dem histologischem Tumorstadium zeigte bei N0-Stadium eine 64%ige, bei N1-Stadium eine 91%ige und bei N2-Stadium eine 35%ige Übereinstimmung. Bezüglich der Lymphknotenmetastasierung wurde bei den Patienten ein regelmäßiges Überspringen von Lymphknotenlevel beobachtet. Dies ist am ehesten durch Querverbindungen zwischen den einzelnen Stationen zu erklären. Es muss daher immer eine komplette Lymphknotendisektion durchgeführt werden. Es zeigte sich kein Zusammenhang zwischen der Tumorlokalisation und einem bestimmten Befallmuster von Lymphknotenlevel. Die 5-Jahres-Überlebensrate lag bei 50,4 %. Die 5-Jahres-Überlebensrate ist signifikant abhängig vom Lymphknotenstatium und in geringem Maße vom Tumorstadium. Patienten mit N2-Stadium erzielten eine 5-Jahres-Überlebensrate von 15%, während Patienten mit N0-Stadium eine 5-Jahres-Überlebensrate von 57% zeigten. Patienten mit linksseitigem Tumorbefall hatten eine 5-Jahres-Überlebensrate von 47,56 %, Patienten mit rechtsseitigem Tumorbefall 51,9 %. Somit konnte eine seitenunterschiedliche Prognose in unserer Untersuchung nicht bestätigt werden. Die vorliegende Studie konnte die Hypothese der Verschlechterung der Langzeitprognose durch die intraoperative Gabe von Erythrozytenkonzentraten bestätigen. Wenn möglich, sollte daher auf eine Blutgabe intraoperativ verzichtet werden.
MicroRNAs are well-known strong RNA regulators modulating whole functional units in complex signaling networks. Regarding clinical application, they have potential as biomarkers for prognosis, diagnosis, and therapy. In this review, we focus on two microRNAs centrally involved in lung cancer progression. MicroRNA-21 promotes and microRNA-34 inhibits cancer progression. We elucidate here involved pathways and imbed these antagonistic microRNAs in a network of interactions, stressing their cancer microRNA biology, followed by experimental and bioinformatics analysis of such microRNAs and their targets. This background is then illuminated from a clinical perspective on microRNA-21 and microRNA-34 as general examples for the complex microRNA biology in lung cancer and its diagnostic value. Moreover, we discuss the immense potential that microRNAs such as microRNA-21 and microRNA-34 imply by their broad regulatory effects. These should be explored for novel therapeutic strategies in the clinic.
Lung cancer is currently the leading cause of cancer related mortality due to late diagnosis and limited treatment intervention. Non-coding RNAs are not translated into proteins and have emerged as fundamental regulators of gene expression. Recent studies reported that microRNAs and long non-coding RNAs are involved in lung cancer development and progression. Moreover, they appear as new promising non-invasive biomarkers for early lung cancer diagnosis. Here, we highlight their potential as biomarker in lung cancer and present how bioinformatics can contribute to the development of non-invasive diagnostic tools. For this, we discuss several bioinformatics algorithms and software tools for a comprehensive understanding and functional characterization of microRNAs and long non-coding RNAs.
Small cell lung cancers (SCLCs) and extrapulmonary small cell cancers (SCCs) are very aggressive tumors arising de novo as primary small cell cancer with characteristic genetic lesions in RB1 and TP53. Based on murine models, neuroendocrine stem cells of the terminal bronchioli have been postulated as the cellular origin of primary SCLC. However, both in lung and many other organs, combined small cell/non-small cell tumors and secondary transitions from non-small cell carcinomas upon cancer therapy to neuroendocrine and small cell tumors occur. We define features of "small cell-ness" based on neuroendocrine markers, characteristic RB1 and TP53 mutations and small cell morphology. Furthermore, here we identify a pathway driving the pathogenesis of secondary SCLC involving inactivating NOTCH mutations, activation of the NOTCH target ASCL1 and canonical WNT-signaling in the context of mutual bi-allelic RB1 and TP53 lesions. Additionaly, we explored ASCL1 dependent RB inactivation by phosphorylation, which is reversible by CDK5 inhibition. We experimentally verify the NOTCH-ASCL1-RB-p53 signaling axis in vitro and validate its activation by genetic alterations in vivo. We analyzed clinical tumor samples including SCLC, SCC and pulmonary large cell neuroendocrine carcinomas and adenocarcinomas using amplicon-based Next Generation Sequencing, immunohistochemistry and fluorescence in situ hybridization. In conclusion, we identified a novel pathway underlying rare secondary SCLC which may drive small cell carcinomas in organs other than lung, as well.