Stepwise progression of pulmonary adenocarcinoma is described from the viewpoint of both pathology and molecular biology. Pulmonary adenocarcinoma develops to invasive carcinoma through atypical ...adenomatous hyperplasia, adenocarcinoma
in situ
and minimally invasive adenocarcinoma. The Noguchi classification is well correlated with this sequential histological progression. On the other hand, in terms of molecular biology,
p16
gene inactivation,
EGFR
mutation and
KRAS
mutation are early events, and tumors progress to invasive adenocarcinoma as a result of
p53
mutation, loss of various chromosomes and other genetic abnormalities.
The balance between cell death and survival is a critical parameter in the regulation of cells and the maintenance of homeostasis in vivo. Three major mechanisms for cell death have been identified ...in mammalian cells: apoptosis (type I), autophagic cell death (type II), and necrosis (type III). These three mechanisms have been suggested to engage in cross talk with each other. Among them, autophagy was originally characterized as a cell survival mechanism for amino acid recycling during starvation. Whether autophagy functions primarily in cell survival or cell death is a critical question yet to be answered. Here, we present a comprehensive review of the cell death-related events that take place during autophagy and their underlying mechanisms in cancer and autoimmune disease development.
The 2021 WHO Classification of Thoracic Tumours was published earlier this year, with classification of lung tumors being one of the chapters. The principles remain those of using morphology first, ...supported by immunohistochemistry, and then molecular techniques. In 2015, there was particular emphasis on using immunohistochemistry to make classification more accurate. In 2021, there is greater emphasis throughout the book on advances in molecular pathology across all tumor types. Major features within this edition are (1) broader emphasis on genetic testing than in the 2015 WHO Classification; (2) a section entirely dedicated to the classification of small diagnostic samples; (3) continued recommendation to document percentages of histologic patterns in invasive nonmucinous adenocarcinomas, with utilization of these features to apply a formal grading system, and using only invasive size for T-factor size determination in part lepidic nonmucinous lung adenocarcinomas as recommended by the eighth edition TNM classification; (4) recognition of spread through airspaces as a histologic feature with prognostic significance; (5) moving lymphoepithelial carcinoma to squamous cell carcinomas; (6) update on evolving concepts in lung neuroendocrine neoplasm classification; (7) recognition of bronchiolar adenoma/ciliated muconodular papillary tumor as a new entity within the adenoma subgroup; (8) recognition of thoracic SMARCA4-deficient undifferentiated tumor; and (9) inclusion of essential and desirable diagnostic criteria for each tumor.
Respiratory epithelial cell death by influenza virus infection is responsible for the induction of inflammatory responses, but the exact cell death mechanism is not understood. Here we showed that ...influenza virus infection induces apoptosis and pyroptosis in normal or precancerous human bronchial epithelial cells. Apoptosis was induced only in malignant tumor cells infected with influenza virus. In human precancerous respiratory epithelial cells (PL16T), the number of apoptotic cells increased at early phases of infection, but pyroptotic cells were observed at late phases of infection. These findings suggest that apoptosis is induced at early phases of infection but the cell death pathway is shifted to pyroptosis at late phases of infection. We also found that the type I interferon (IFN)-mediated JAK-STAT signaling pathway promotes the switch from apoptosis to pyroptosis by inhibiting apoptosis possibly through the induced expression of the
anti-apoptotic gene. Further, the inhibition of JAK-STAT signaling repressed pyroptosis but enhanced apoptosis in infected PL16T cells. Collectively, we propose that type I IFN signaling pathway triggers pyroptosis but not apoptosis in the respiratory epithelial cells in a mutually exclusive manner to initiate proinflammatory responses against influenza virus infection.
Respiratory epithelium functions as a sensor of infectious agents to initiate inflammatory responses along with cell death. However, the exact cell death mechanism responsible for inflammatory responses by influenza virus infection is still unclear. We showed that influenza virus infection induced apoptosis and pyroptosis in normal or precancerous human bronchial epithelial cells. Apoptosis was induced at early phases of infection, but the cell death pathway was shifted to pyroptosis at late phases of infection under the regulation of type I IFN signaling to promote proinflammatory cytokine production. Taken together, our results indicate that the type I IFN signaling pathway plays an important role to induce pyroptosis but represses apoptosis in the respiratory epithelial cells to initiate proinflammatory responses against influenza virus infection.
The serine threonine kinase AKT plays a central role in the regulation of cell survival in a variety of human neoplastic diseases. A series of studies have revealed a connection between AKT signaling ...and two important protein degradation pathways in mammalian cells: the ubiquitin–proteasome system and autophagy. Two distinct ubiquitination systems have been reported to regulate AKT signaling: K63-linked ubiquitination, which promotes the oncogenic activation of AKT, and K48-linked ubiquitination, which triggers the proteasomal degradation of phosphorylated AKT. Autophagy is an evolutionarily conserved mechanism for the gross disposal and recycling of intracellular proteins in mammalian cells. AKT signaling may play a regulatory role in autophagy; however, the underlying mechanisms have not been fully clarified. Recently, AKT was shown to phosphorylate key molecules involved in the regulation of autophagy. Furthermore, lysosomal co-localization of the AKT–Phafin2 complex is reportedly critical for the induction of autophagy. In this review, we will discuss the connection between AKT, a core intracellular survival regulator, and two major intracellular proteolytic signaling pathways in mammalian cells.
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•The serine threonine kinase AKT is a core intracellular survival regulator.•Links between AKT and the ubiquitin-proteasome system were emerged.•Moreover, connection between AKT signal with autophagy has also been elucidated.•We will discuss connection between AKT and the two major proteolytic pathways.
The Blueprint (BP) Programmed Death Ligand 1 (PD-L1) Immunohistochemistry Comparability Project is a pivotal academic/professional society and industrial collaboration to assess the feasibility of ...harmonizing the clinical use of five independently developed commercial PD-L1 immunohistochemistry assays. The goal of BP phase 2 (BP2) was to validate the results obtained in BP phase 1 by using real-world clinical lung cancer samples.
BP2 were conducted using 81 lung cancer specimens of various histological and sample types, stained with all five trial-validated PD-L1 assays (22C3, 28-8, SP142, SP263, and 73-10); the slides were evaluated by an international panel of pathologists. BP2 also assessed the reliability of PD-L1 scoring by using digital images, and samples prepared for cytological examination. PD-L1 expression was assessed for percentage (tumor proportional score) of tumor cell (TC) and immune cell areas showing PD-L1 staining, with TCs scored continuously or categorically with the cutoffs used in checkpoint inhibitor trials.
The BP2 results showed highly comparable staining by the 22C3, 28-8 and SP263 assays; less sensitivity with the SP142 assay; and higher sensitivity with the 73-10 assay to detect PD-L1 expression on TCs. Glass slide and digital image scorings were highly concordant (Pearson correlation >0.96). There was very strong reliability among pathologists in TC PD-L1 scoring with all assays (overall intraclass correlation coefficient ICC = 0.86–0.93), poor reliability in IC PD-L1 scoring (overall ICC = 0.18–0.19), and good agreement in assessing PD-L1 status on cytological cell block materials (ICC = 0.78–0.85).
BP2 consolidates the analytical evidence for interchangeability of the 22C3, 28-8, and SP263 assays and lower sensitivity of the SP142 assay for determining tumor proportion score on TCs and demonstrates greater sensitivity of the 73-10 assay compared with that of the other assays.
A grading system for pulmonary adenocarcinoma has not been established. The International Association for the Study of Lung Cancer pathology panel evaluated a set of histologic criteria associated ...with prognosis aimed at establishing a grading system for invasive pulmonary adenocarcinoma.
A multi-institutional study involving multiple cohorts of invasive pulmonary adenocarcinomas was conducted. A cohort of 284 stage I pulmonary adenocarcinomas was used as a training set to identify histologic features associated with patient outcomes (recurrence-free survival RFS and overall survival OS). Receiver operating characteristic curve analysis was used to select the best model, which was validated (n = 212) and tested (n = 300, including stage I–III) in independent cohorts. Reproducibility of the model was assessed using kappa statistics.
The best model (area under the receiver operating characteristic curve AUC = 0.749 for RFS and 0.787 for OS) was composed of a combination of predominant plus high-grade histologic pattern with a cutoff of 20% for the latter. The model consists of the following: grade 1, lepidic predominant tumor; grade 2, acinar or papillary predominant tumor, both with no or less than 20% of high-grade patterns; and grade 3, any tumor with 20% or more of high-grade patterns (solid, micropapillary, or complex gland). Similar results were seen in the validation (AUC = 0.732 for RFS and 0.787 for OS) and test cohorts (AUC = 0.690 for RFS and 0.743 for OS), confirming the predictive value of the model. Interobserver reproducibility revealed good agreement (k = 0.617).
A grading system based on the predominant and high-grade patterns is practical and prognostic for invasive pulmonary adenocarcinoma.
Peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) is a diagnosis of exclusion, being the most common entity in mature T-cell neoplasms, and its molecular pathogenesis remains ...significantly understudied. Here, combining whole-exome and targeted-capture sequencing, gene-expression profiling, and immunohistochemical analysis of tumor samples from 133 cases, we have delineated the entire landscape of somatic alterations, and discovered frequently affected driver pathways in PTCL, NOS, with and without a T-follicular helper (TFH) cell phenotype. In addition to previously reported mutational targets, we identified a number of novel recurrently altered genes, such as KMT2C, SETD1B, YTHDF2, and PDCD1. We integrated these genetic drivers using hierarchical clustering and identified a previously undescribed molecular subtype characterized by TP53 and/or CDKN2A mutations and deletions in non-TFH PTCL, NOS. This subtype exhibited different prognosis and unique genetic features associated with extensive chromosomal instability, which preferentially affected molecules involved in immune escape and transcriptional regulation, such as HLA-A/B and IKZF2. Taken together, our findings provide novel insights into the molecular pathogenesis of PTCL, NOS by highlighting their genetic heterogeneity. These results should help to devise a novel molecular classification of PTCLs and to exploit a new therapeutic strategy for this group of aggressive malignancies.
Lung adenocarcinoma (LAC) is the most prevalent form of lung cancer. Epithelial cell transforming sequence 2 (ECT2) is a guanine nucleotide exchange factor that has been implicated in oncogenic and ...malignant phenotypes of LAC. Here, we identified an oncogenic role of ECT2 in the extracellular matrix (ECM) dynamics of LAC cells. We showed that suppression of ECT2 decreased adhesion and spreading of LAC cells on ECM components. Morphologically, ECT2‐depleted cells exhibited a rounded shape and cytoskeletal changes. Examination of transcriptional changes by RNA sequencing revealed a total of 1569 and 828 genes whose expressions were altered (absolute fold change and a difference of >2 fold) in response to suppression of ECT2 in two LAC cells (Calu‐3 and NCI‐H2342), respectively, along with 298 genes that were common to both cell lines. Functional enrichment analysis of common genes demonstrated a significant enrichment of focal adhesions. In accord with this observation, we found that ECT2 suppression decreased the expression level of proteins involved in focal adhesion signaling including focal adhesion kinase (FAK), Crk, integrin β1, paxillin, and p130Cas. FAK knockdown leads to impaired cell proliferation, adhesion, and spreading of LAC cells. Moreover, in LAC cells, ECT2 binds to and stabilizes FAK and is associated with the formation of the focal adhesions. Our findings provide new insights into the underlying role of ECT2 in cell‐ECM dynamics during LAC progression and suggest that ECT2 could be a promising therapeutic avenue for lung cancer.
In this study, we demonstrated that epithelial cell transforming sequence 2 (ECT2) is an essential mediator of cell‐extracellular matrix (ECM) dynamics in the malignant progression of lung adenocarcinoma. We found that suppression of ECT2 decreased adhesion and spreading of lung adenocarcinoma cells on the ECM and demonstrated that ECT2 has a regulatory role in focal adhesion signaling, being associated with the focal adhesion formation that contains both focal adhesion kinase (FAK) and ECT2.
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