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Field cancerization in non-small cell lung cancer: implications in disease pathogenesis.

ABSTRACT: Lung cancer, of which non-small cell lung cancer (NSCLC) composes the majority, is the leading cause of cancer-related deaths in the United States and worldwide. NSCLCs are tumors with complex biology that we have recently started to understand with the advent of various histological, transcriptomic, genomic, and proteomic technologies. However, the histological and molecular pathogenesis of this malignancy, in particular of adenocarcinomas, is still largely unknown. Earlier studies have highlighted a field cancerization phenomenon in which histologically normal-appearing tissue adjacent to neoplastic and pre-neoplastic lesions display molecular abnormalities, some of which are in common with those in the tumors. This review will summarize advances in understanding the field cancerization phenomenon and the potential relevance of this knowledge to gain important and novel insights into the molecular pathogenesis of NSCLC as well as to subsequent development of biomarkers for early detection of lung cancers and possibly personalized prevention.

SUBMITTER: Kadara H

PROVIDER: S-EPMC5821032 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Field cancerization in non-small cell lung cancer: implications in disease pathogenesis.

Kadara Humam H Wistuba Ignacio I II

Proceedings of the American Thoracic Society 20120501 2

Lung cancer, of which non-small cell lung cancer (NSCLC) composes the majority, is the leading cause of cancer-related deaths in the United States and worldwide. NSCLCs are tumors with complex biology that we have recently started to understand with the advent of various histological, transcriptomic, genomic, and proteomic technologies. However, the histological and molecular pathogenesis of this malignancy, in particular of adenocarcinomas, is still largely unknown. Earlier studies have highlig ...[more]

PMID: 22550239

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Project description:BackgroundEarlier work identified specific tumor-promoting abnormalities that are shared between lung cancers and adjacent normal bronchial epithelia. We sought to characterize the yet unknown global molecular and adjacent airway field cancerization (FC) in early-stage non-small cell lung cancer (NSCLC).MethodsWhole-transcriptome expression profiling of resected early-stage (I-IIIA) NSCLC specimens (n = 20) with matched tumors, multiple cytologically controlled normal airways with varying distances from tumors, and uninvolved normal lung tissues (n = 194 samples) was performed using the Affymetrix Human Gene 1.0 ST platform. Mixed-effects models were used to identify differentially expressed genes among groups. Ordinal regression analysis was performed to characterize site-dependent airway expression profiles. All statistical tests were two-sided, except where noted.ResultsWe identified differentially expressed gene features (n = 1661) between NSCLCs and airways compared with normal lung tissues, a subset of which (n = 299), after gene set enrichment analysis, statistically significantly (P < .001) distinguished large airways in lung cancer patients from airways in cancer-free smokers. In addition, we identified genes (n = 422) statistically significantly and progressively differentially expressed in airways by distance from tumors that were found to be congruently modulated between NSCLCs and normal lung tissues. Furthermore, LAPTM4B, with statistically significantly increased expression (P < .05) in airways with shorter distance from tumors, was upregulated in human immortalized cells compared with normal bronchial epithelial cells (P < .001) and promoted anchorage-dependent and -independent lung cancer cell growth.ConclusionsThe adjacent airway FC comprises both site-independent profiles as well as gradient and localized airway expression patterns. Profiling of the airway FC may provide new insights into NSCLC oncogenesis and molecular tools for detection of the disease.

Project description:BackgroundThe PD-1-blocking antibody nivolumab persists in patients several weeks after the last infusion. However, no study has systematically evaluated the maximum duration that the antibody persists on T cells or the association between this duration and residual therapeutic efficacy or potential adverse events.MethodsTo define the duration of binding and residual efficacy of nivolumab after discontinuation, we developed a simplified strategy for T cell monitoring and used it to analyze T cells from peripheral blood from 11 non-small cell lung cancer patients previously treated with nivolumab. To determine the suitability of our method for other applications, we compared transcriptome profiles between nivolumab-bound and nivolumab-unbound CD8 T cells. We also applied T cell monitoring in 2 nivolumab-treated patients who developed progressive lung tumors during long-term follow-up.ResultsProlonged nivolumab binding was detected more than 20 weeks after the last infusion, regardless of the total number of nivolumab infusions (2-15 doses) or type of subsequent treatment, in 9 of the 11 cases in which long-term monitoring was possible. Ki-67 positivity, a proliferation marker, in T cells decreased in patients with progressive disease. Transcriptome profiling identified the signals regulating activation of nivolumab-bound T cells, which may contribute to nivolumab resistance. In 2 patients who restarted nivolumab, T cell proliferation markers exhibited the opposite trend and correlated with clinical response.ConclusionsAlthough only a few samples were analyzed, our strategy of monitoring both nivolumab binding and Ki-67 in T cells might help determine residual efficacy under various types of concurrent or subsequent treatment.Trial registrationUniversity Hospital Medical Information Network Clinical Trials Registry, UMIN000024623.FundingThis work was supported by Japan Society for the Promotion of Science KAKENHI (JP17K16045, JP18H05282, and JP15K09220), Japan Agency for Medical Research and Development (JP17cm0106310, JP18cm0106335 and JP18cm059042), and Core Research for Evolutional Science and Technology (JPMJCR16G2).

Project description:Chronic ultraviolet B (UV-B) irradiation is known to be one of the most important hazards acting on the skin and poses a risk of developing photoaging, skin with cutaneous field cancerization (CFC), actinic keratosis (AKs), and squamous cell carcinomas (SCCs). Most of the UV-B light is absorbed in the epidermis, affecting the outermost cell layers, the stratum corneum, and the stratum granulosum, which protects against this radiation and tries to maintain the permeability barrier. In the present work, we show an impairment in the transepidermal water loss, stratum corneum hydration, and surface pH after chronic UV-B light exposure in an immunologically intact mouse model (SKH1 aged mice) of skin with CFC. Macroscopic lesions of AKs and SCCs may develop synchronically or over time on the same cutaneous surface due to both the presence of subclinical AKs and in situ SCC, but also the accumulation of different mutations in keratinocytes. Focusing on skin with CFC, yet without the pathological criteria of AKs or SCC, the presence of p53 immunopositive patches (PIPs) within the epidermis is associated with these UV-B-induced mutations. Reactive epidermis to chronic UV-B exposure correlated with a marked hyperkeratotic hyperplasia, hypergranulosis, and induction of keratinocyte hyperproliferation, while expressing an upregulation of filaggrin, loricrin, and involucrin immunostaining. However, incidental AKs and in situ SCC might show neither hypergranulosis nor upregulation of differentiation markers in the upper epidermis. Despite the overexpression of filaggrin, loricrin, involucrin, lipid enzymes, and ATP-binding cassette subfamily A member 12 (ABCA12) after chronic UV-B irradiation, the permeability barrier, stratum corneum hydration, and surface pH were severely compromised in the skin with CFC. We interpret these results as an attempt to restore the permeability barrier homeostasis by the reactive epidermis, which fails due to ultrastructural losses in stratum corneum integrity, higher pH on skin surface, abundant mast cells in the dermis, and the common presence of incidental AKs and in situ SCC. As far as we know, this is the first time that the permeability barrier has been studied in the skin with CFC in a murine model of SCC induced after chronic UV-B irradiation at high doses. The impairment in the permeability barrier and the consequent keratinocyte hyperproliferation in the skin of CFC might play a role in the physiopathology of AKs and SCCs.

Project description:It is known that disorders in apoptosis function play an important role in the pathogenesis of many types of cancer, including lung cancer. Tumor necrosis factor related apoptosis inducing ligand (TRAIL), a type II transmembrane protein, is a death ligand capable of inducing apoptosis by activating distinctive death receptor. Our purpose in this study is to investigate the gene polymorphisms in TRAIL molecular pathway and TRAIL gene expression levels in non-small cell lung cancer (NSCLC) patients in terms of pathogenesis and prognosis of the disease. In this study, TRAIL C1595T polymorphism was genotyped using polymerase chain reaction-restriction fragment length polymorphism analysis in 158 patients with NSCLC and 98 healthy individuals. Surgically resected tissues were examined and classified histopathologically. In addition, TRAIL gene expression levels in tumor tissue and tumor surrounding tissue samples of 48 patients with NSCLC were determined using real-time polymerase chain reaction. TRAIL gene expression levels of NSCLC patients were detected significantly 28.8 fold decrease in the tumor tissue group compared to the control group (p=0.026). When patients were compared to tumor stage, expression of TRAIL gene in advanced tumor stage was found to be significantly 7.86 fold higher than early tumor stage [p=0.028]. No significant relationship was found between NSCLC predisposition and prognostic parameters of NSCLC with TRAIL genotypes, but the frequency of TRAIL gene 1595 CT genotype was observed to be lower in the patients compared to the other genotypes, and the difference was found to be very close to statistical significance (p=0.07). It can be suggested that TRAIL may play an important role in the development of NSCLC and may be an effective prognostic factor in tumor progression.: It is known that disorders in apoptosis function play an important role in the pathogenesis of many types of cancer, including lung cancer. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a type II transmembrane protein, is a death ligand capable of inducing apoptosis by activating distinctive death receptor. Our purpose in this study is to investigate the gene polymorphisms in TRAIL molecular pathway and TRAIL gene expression levels in non-small cell lung cancer (NSCLC) patients in terms of pathogenesis and prognosis of the disease.

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Field cancerization in non-small cell lung cancer: implications in disease pathogenesis.

Publications

Field cancerization in non-small cell lung cancer: implications in disease pathogenesis.

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