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M. Noguchi
Moderator of
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ES 01 - New TNM and WHO Classification (ID 510)
- Event: WCLC 2017
- Type: Educational Session
- Track: Radiology/Staging/Screening
- Presentations: 4
- Moderators:M. Noguchi, Peter Goldstraw
- Coordinates: 10/16/2017, 11:00 - 12:30, Room 301 + 302
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ES 01.01 - New TNM Classification (ID 7583)
11:00 - 11:20 | Presenting Author(s): Ramon Rami-Porta
- Abstract
- Presentation
Abstract:
Introduction The new tumor, node and metastasis (TNM) classification of lung cancer –the 8[th] edition– has already been discussed in the two previous World Conferences of Lung Cancer. (J Thorac Oncol 2015; 10 (Supp 2): s69; J Thorac Oncol 2017; 12 (Supp 1): s2-s3.) The purpose of this educational session is to revise the innovations of the 8[th] edition, to point out its lights and shadows, and to highlight how they can affect our clinical practice. The innovations introduced in the 8[th] edition were based on sound statistical analyses of 70,189 patients with non-small cell lung cancer and 6,189 with small cell lung cancer diagnosed from 1999 to 2010. (1) Although a large number of patients was registered in the International Association for the Study of Lung Cancer database, data originated mainly from Asia and Europe and the other geographic regions of the world were scarcely represented. The innovations are applicable to both types of carcinomas (2) and also to bronchopulmonary carcinoids. (3) Rules to classify lung cancers with multiple lesions were provided based on data where data were available or on multidisciplinary consensus. (4) Primary tumor (T component) New T categories were introduced based on tumor size: T1a 1-2cm, T1c >2-3cm, T2a >3-4cm, T2b >4-5cm, T3 >5-7cm and T4 >7cm. In addition, endobronchial location less than 2 cm from the carina and total atelectasis /pneumonitis were reclassified as T2, while invasion of the diaphragm was reclassified as T4 and invasion of the mediastinal pleural was deleted as a T descriptor. The definition of visceral pleural invasion proposed for the 7[th] edition, i.e., the invasion of its elastic layer, was confirmed for the 8[th] edition and the recommendation to use elastic stains was reinforced. (5, 6) Codes for adenocarcinoma in situ –Tis(AIS) – and minimally invasive adenocarcinoma –T1mi– were defined, too. (7) Because tumor size has more prognostic relevance, its measurement must be as accurate as possible. The recommendation is to measure it on computed tomography with the lung window, because the mediastinal window may underestimate it. The registered size should be the greatest dimension in any of the available projections: axial, coronal or saggital. For part-solid non-mucinous adenocarcinomas, only does the size of the solid part on computed tomography at clinical staging or the size of the invasive part at pathologic examination count to assign a T category based on tumor size. (7) Nodal involvement (N component) The present N categories (NX, N0, N1, N2 and N3) and their descriptors remain unchanged. An important confirmation in the analyses of survival was that quantification of nodal disease at pathologic staging impacts prognosis: the more involved nodal stations, the worse the prognosis. (8) Therefore, identifying the number of involved nodal stations is important both at clinical and pathologic staging, although it is difficult to determine them accurately at clinical staging unless a lymphadenectomy is performed at the time of mediastinoscopy. The proposed subclassification of the N categories for prospective testing are: N1a – involvement of a single N1 station; N1b – involvement of multiple N1 stations; N2a1 – involvement of a single N2 station without N1; N2a2 – involvement of a single N2 station with N1; and N2b – involvement of multiple N2 stations. N1b and N2a1 have similar prognosis. Metastatic disease (M component) Intrathoracic metastases (M1a: malignant pleural and pericardial effusions and/or nodules, and contralateral separate tumor nodules) remain the same. Extrathoracic metastases were divided into single extrathoracic metastasis (the redefined M1b category) and multiple extrathoracic metastases in one or in several organs (the new M1c category). (9) These innovations imply that counting the number of metastases is important, at least from the prognostic point of view, but also from the therapeutic, because single extrathoracic metastasis can be the base to define oligometastatic disease, the treatment of which is aimed to be radical, with whatever therapeutic means are available, instead of palliative, as it usually is the case with polymetastatic disease. Stage grouping More stages have been created to accommodate the new T1 (T1a N0 M0 is stage IA1, T1b N0 M0 is stage IA2 and T1c N0 M0 is stage IA3) categories; to isolate locally advanced tumors (T3-T4 N3 M0 are now stage IIIC); or to separate metastatic disease (M1a and M1b are stage IVA and M1c is stage IVB). (10) Some tumors have shifted their positions. Tumors that are stage shifters should be treated according to evidence and not according to the treatment for those stages in which they now are based on prognosis, because a mere change in taxonomy does not imply a change in treatment. Clinical judgment in the multidisciplinary team discussions should led to the best therapeutic option for these patients whose tumors have moved from one stage to another. Conclusion The 8[th] edition facilitates the indication of prognosis and the stratification of tumors in future clinical trial, but requires more discipline from us when measuring tumor size, quantifying nodal disease and determining the number of extrathoracic metastasis. References 1. Rami-Porta R, Bolejack V, Giroux DJ et al. J Thorac Oncol 2014; 9: 1618-1624. 2. Nicholson AG, Chansky K, Crowley J et al. J Thorac Oncol 2016; 11: 300-311. 3. Travis WD, Giroux DJ, Chansky K, et al. J Thorac Oncol 2008; 3: 1213-1223. 4. Detterbeck FC, Nicholson AG, Franklin WA et al. J Thorac Oncol 2016; 11: 539-650. 5.Travis WD, Brombilla E, Rami-Porta R et al. J Thorac Oncol 2008; 3: 1384-1390. 6. Rami-Porta R, Bolejack V, Crowley J et al. J Thorac Oncol 2015; 10: 990-1003. 7. Travis WD, Asamura H, Bankier A et al. J Thorac Oncol 2016; 11: 1204-1223. 8. Asamura H, Chansky K, Crowley J et al. J Thorac Oncol 2015; 10: 1675-1684. 9. Eberhardt WEE, Mitchell A, Crowley J et al. J Thorac Oncol 2015; 10: 1515-1522. 10. Goldstraw P, Chansky K, Crowley J et al. J Thorac Oncol 2016; 11: 39-51.
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ES 01.02 - New Histological Classification (ID 7584)
11:20 - 11:40 | Presenting Author(s): William D Travis
- Abstract
- Presentation
Abstract:
The 2015 WHO Classification had a major impact on the new 8[th] Edition TNM Classification. Compared to the 2004 Classification, major changes include: 1) use of immunohistochemistry throughout; 2) New emphasis on genetic studies and personalized therapeutic strategies; 3) A new classification of lung cancer in small biopsy and cytology samples; 4) adoption of the 2011 IASLC/ATS/ERS lung adenocarcinoma classification; 5) reclassification of large cell carcinoma based upon immunohistochemistry and genetics. Since publication of the 2015 WHO Classification new advances include recognition of ciliated muconodular papillary tumors, SMARCA4 and SMARCB1 deficient neoplasms and digital image analysis as a novel way to assess lung cancer morphology. This presentation will primarily focus on the impact of the new WHO Classification on the 8[th] Edition TNM classification. First the new TNM classification incorporates the introduction of the concepts of adenocarcinoma in situ (AIS) which should be staged as Tis (AIS) and minimally invasive adenocarcinoma (MIA) which should be staged as T1mi. AIS is defined as a lung adenocarcinoma with pure lepidic growth measuring ≤3 cm. MIA is defined as a ≤3 cm lepidic predominant adenocarcinoma with an invasive component measuring 0.5 cm or less. Both AIS and MIA should lack stromal, vascular, or pleural invasion and spread through alveolar space invasion (STAS). Lepidic predominant adenocarcinomas are lung adenocarcinomas with a predominant lepidic component that measure > 3 cm in total size or that have an invasive component measuring >0.5 cm. It is recommended to use invasive size for T-descriptor size in nonmucinous adenocarcinomas with a lepidic component. This is in keeping with a recommendation made in three editions of the UICC TNM Supplement since 2003. It is also supported by a growing amount of evidence showing that invasive size is a better predictor of survival than total size in nonmucinous adenocarcinomas with a lepidic component. Both radiologists and pathologists should report the greatest dimension for tumor size for both clinical and pathologic staging. In addition for nonmucinous lung adenocarcinomas, both the total size and invasive size should be reported with invasive size used for T-factor size determination. By computed tomography (CT) in nonmucinous lung adenocarcinomas, the presence of ground glass versus solid opacities generally correspond to lepidic versus invasive patterns respectively seen pathologically. Since, this is not an absolute correlation, when CT features suggest nonmucinous AIS, MIA and LPA, reporting of the suspected diagnosis and clinical staging, should be made as a preliminary assessment that may need to be revised after evaluation of resected specimens pathologically. Since the mucinous variants of AIS, MIA and invasive mucinous adenocarcinomas usually present by CT as a solid or consolidated nodule, and due to the lack of proven correlation between ground glass/solid CT appearance with lepidic/invasive growth pathologically it is not recommended to apply the total vs solid size assessment by CT in suspected invasive mucinous adenocarcinomas. Furthermore there is insufficient data in invasive mucinous adenocarcinomas that invasive size is a better predictor of survival than total size. Pathologic assessment of total vs invasive tumor size in resected nonmucinous lung adenocarcinomas with a lepidic component can be improved by reviewing CT scans because the lepidic component is often poorly appreciated pathologically on gross exam and size is underestimated. In addition, tumor size can be more accurately assessed after radiologic pathologic correlation in the following settings: 1) Lepidic nonmucinous adenocarcinomas that do not fit onto a single slide, 2) Sausage or bilobed shaped tumors where the maximum single diameter may be better assessed using all three CT views (axial, coronal and sagittal) rather than just axial alone, 3) Tumors removed in multiple parts, 4) Intraoperative defects in tumors, 5) Marked non-neoplastic reactions, 6) Mistaken pathologic assessment. In neoadjuvant tumors, it can be difficult to measure tumor size because tumors that show considerable treatment effect often do not have a uniform response allowing a single focus of viable tumor to be measured. It has been shown that 90% or more treatment effect is the most important prognostic finding instead of tumor size in surgically resected nonsmall cell lung cancer patients following induction therapy. One way to estimate viable tumor size is to multiply the percent of viable tumor cells times the size of the total tumor bed. This can be utilized in the setting of a single focus or multiple foci of viable tumor. Recording the percentage of treatment effect is important in addition to estimating tumor size for T-factor determination. REFERENCES 1. Travis WD, et al The New IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification. JThoracic Oncol 2011;6:244-85. 2. Travis WD, et al WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. Lyon: International Agency for Research on Cancer; 2015. 3. Travis WD, et al The IASLC Lung Cancer Staging Project: Proposals for Coding T Categories for Subsolid Nodules and Assessment of Tumor Size in Part-Solid Tumors in the Forthcoming Eighth Edition of the TNM Classification of Lung Cancer. J Thorac Oncol 2016;11:1204-23. 4. Tsutani Y, et al Prognostic significance of using solid versus whole tumor size on high-resolution computed tomography for predicting pathologic malignant grade of tumors in clinical stage IA lung adenocarcinoma. JThoracCardiovascSurg 2012;143:607-12. 5. Maeyashiki T, et al The size of consolidation on thin-section computed tomography is a better predictor of survival than the maximum tumour dimension in resectable lung cancer. Eur J Cardiothorac Surg 2013;43:915-8. 6. Yoshida A, et al Clinicopathological and molecular characterization of SMARCA4-deficient thoracic sarcomas with comparison to potentially related entities. Modern pathology : 2017;30:797-809. 7. Luo X, et al Comprehensive Computational Pathological Image Analysis Predicts Lung Cancer Prognosis. J Thorac Oncol 2016;12:501-9. 8. Kamata T, et al . Ciliated Muconodular Papillary Tumors of the Lung: A Clinicopathologic Analysis of 10 Cases. The American journal of surgical pathology 2015;39:753-60. 9. MacMahon H, et al Guidelines for Management of Incidental Pulmonary Nodules Detected on CT Images: From the Fleischner Society 2017. Radiology 2017;284:228-43. 10. Kamata T, et al. Frequent BRAF or EGFR Mutations in Ciliated Muconodular Papillary Tumors of the Lung. J Thorac Oncol 2016;11:261-5.
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ES 01.03 - Immunohistochemistry, Chromosomal and DNA Analysis, and Molecular Testing (ID 7585)
11:40 - 12:00 | Presenting Author(s): Yasushi Yatabe
- Abstract
- Presentation
Abstract not provided
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ES 01.04 - Staging and Pathology of Multiple Nodules Presenting in the Lungs (ID 7586)
12:00 - 12:20 | Presenting Author(s): Andrew G Nicholson
- Abstract
- Presentation
Abstract:
Multiple tumor nodules arising in the lungs can be due either to separate primary lung cancers (SPLCs) or intrapulmonary metastases (IPM) (separate tumor nodules). The recently revised Union for International Cancer Control (UICC) and American Joint Committee on Cancer (AJCC) staging manuals (8th editions), based on proposals from work undertaken by the IASLC Staging and Prognostic Factors Committee (SPFC), include updates in T, N and M components, that reflect increased interest in staging of patients with multiple tumor nodules (1-4) due to increased frequency of presentation (1) and advances in classification of tumor subtypes (5). T categories for multiple tumor nodules are unchanged when compared to the 7[th] edition, with SPLCs continuing to be staged individually, with the recommendation that multiple lesions be grouped with the number of lesions in brackets (e.g. (2)), or (m) for multiple. Patients with IPM are staged as T3 (same lobe), T4 (different lobe in ipsilateral lung) and M1a (contralateral lung). However, although unchanged, these categories have been impacted by changes in the histologic classification of lung cancer (6), in particular adenocarcinomas (7). For the current edition, those tumors that present with multiple areas of pneumonic consolidation, these frequently corresponding to invasive mucinous adenocarcinomas, are viewed as a potential subgroup of IPM. There is also increased interest in those patients who present with multiple ground glass lesions, these typically corresponding to patients with non-mucinous adenocarcinomas with a lepidic component. These types of multiple tumor nodules are currently viewed as a potential subgroup of SPLCs. It is hoped that the next decade will see further research from within the lung cancer community that informs the 9[th] edition in relation to the staging of these types of tumor (3). In relation to pathologic staging, from 1975 until recently, distinction between SPLC and IPM was undertaken using criteria proposed by Martini and Melamed: tumors occurring in different lobes, having different major histologic types or being separated by a time interval of more than two years were to be classified as SPLCs (8). Recently, these criteria have been supplanted by the process of comprehensive histologic assessment (CHA) (9). CHA involves determination of major histologic type, assessment of predominant and minor histologic patterns according to histologic subtyping and evaluation of cytological features. CHA has been shown to significantly improve the pathologic distinction between SPLC and IPM to a level comparable to molecular analysis (9). Recent work undertaken by the IASLC Pathology Committee has also shown that usage of this methodology has good reproducibility amongst diagnostic pathologists. Furthermore, p staging status strongly correlated with nuclear pleomorphism, cell size, acinar formation, nucleolar size, and mitotic rate. In addition to the above, immunohistochemistry already has a role in refining the distinction between SPLC and IPM, and molecular techniques are also likely to be used increasingly in the situation. Studies have been published showing that comprehensive genotypic and morphological assessment is feasible, though they are not yet sufficient to establish clonal relationships between multiple tumour nodules (10). Ultimately, a multidisciplinary approach is likely to be the best methodology for distinction between SPLC and IPM, in particular the assessment of imaging data alongside histologic, immunohistochemical and molecular profiles, both in the context of biopsies and resections. 1. Detterbeck FC, Franklin WA, Nicholson AG, Girard N, Arenberg DA, Travis WD, et al. The IASLC Lung Cancer Staging Project: Background Data and Proposed Criteria to Distinguish Separate Primary Lung Cancers from Metastatic Foci in Patients with Two Lung Tumors in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer. J Thorac Oncol. 2016. 2. Detterbeck FC, Bolejack V, Arenberg DA, Crowley J, Donington JS, Franklin WA, et al. The IASLC Lung Cancer Staging Project: Background Data and Proposals for the Classification of Lung Cancer with Separate Tumor Nodules in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer. J Thorac Oncol. 2016. 3. Detterbeck FC, Nicholson AG, Franklin WA, Marom EM, Travis WD, Girard N, et al. The IASLC Lung Cancer Staging Project: Summary of Proposals for Revisions of the Classification of Lung Cancers with Multiple Pulmonary Sites of Involvement in the Forthcoming Eighth Edition of the TNM Classification. J Thorac Oncol. 2016. 4. Detterbeck FC, Marom EM, Arenberg DA, Franklin WA, Nicholson AG, Travis WD, et al. The IASLC Lung Cancer Staging Project: Background Data and Proposals for the Application of TNM Staging Rules to Lung Cancer Presenting as Multiple Nodules with Ground Glass or Lepidic Features or a Pneumonic-Type of Involvement in the Forthcoming Eighth Edition of the TNM Classification. J Thorac Oncol. 2016. 5. Travis WD, Asamura H, Bankier AA, Beasley MB, Detterbeck F, Flieder DB, et al. The IASLC Lung Cancer Staging Project: Proposals for Coding T Categories for Subsolid Nodules and Assessment of Tumor Size in Part-Solid Tumors in the Forthcoming Eighth Edition of the TNM Classification of Lung Cancer. J Thorac Oncol. 2016;11(8):1204-23. 6. Travis WD, Brambilla E, Burke AP, Marx A, Nicholson, AG WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. IARC Press, 2015. 7. Travis WD, Brambilla E, Noguchi M, Nicholson AG, Geisinger KR, Yatabe Y, et al. International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol. 2011;6(2):244-85. 8. Martini N, Melamed MR. Multiple primary lung cancers. J Thorac Cardiovasc Surg. 1975;60:606-12. 9. Girard N, Deshpande C, Lau C, Finley D, Rusch V, Pao W, et al. Comprehensive histologic assessment helps to differentiate multiple lung primary nonsmall cell carcinomas from metastases. Am J Surg Pathol. 2009;33(12):1752-64. 10. Schneider F, Derrick V, Davison JM, Strollo D, Incharoen P, Dacic S. Morphological and molecular approach to synchronous non-small cell lung carcinomas: impact on staging. Mod Pathol. 2016;29(7):735-42.
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P1.02 - Biology/Pathology (ID 614)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.02-071 - SFN Stabilizes Oncoproteins through Binding with SKP1 to Block SCF<Sup>FBW7</Sup> Ubiquiting Ligase (ID 9121)
09:30 - 09:30 | Author(s): M. Noguchi
- Abstract
Background:
Lung adenocarcinoma is the most common subtype of non-small cell lung cancer (NSCLC) and accounts for about 50% of them. Although EGFR or EML4-ALK has been identified as oncogenic driver mutation and translocation for advanced adenocarcinoma, trigger or mechanism of its early progression is still unclear. Previously, we revealed that stratifin (SFN, 14-3-3 sigma) has tissue-specific functions and regulate cell cycle progression in a positive manner in lung adenocarcinoma (Shiba-Ishii A et al. Mol Cancer 2015). Moreover, S-phase kinase-associated protein 1 (SKP 1) which is an adaptor part of SCF-type E3 ubiquitin ligase complex including SCF[FBW7], SCF[SKP2] and SCF[β][-TRCP] was identified as one of the SFN binding protein by pull-down assay and LC-MS/MS analysis. The aim of this study is to analyze the molecular mechanism of tumor progression in lung adenocarcinoma associated with SFN binding with SKP1. We have hypothesized that SFN binds with SKP1 among various SCF complexes and specifically blocks SCF[FBW7] function to ubiquitinate oncoproteins such as cyclin E1, c-Myc, c-Jun, and notch 1.
Method:
Endogenous interaction of SKP1 and SFN or FBW7 was examined by co-immunoprecipitation using A549, lung adenocarcinoma cells. We performed ubiquitination assay under the treatment of proteosome inhibitor, MG132 to induce accumulation of ubiquitinated oncoproteins after siRNA-SFN transfection. Moreover, to investigate whether SFN regulates the localization of SKP1, we performed immunofluorescence staining of A549 after siRNA-SFN treatment.
Result:
We found that SKP1 interacted with SFN and FBW7, respectively in lung adenocarcinoma cells. The binding activity of FBW7 with SKP1 increased after suppression of SFN, indicating that SFN and FBW7 might competitively bind with SKP1. Moreover, knockdown of SFN led to reduction of oncoproteins such as cyclin E1, c-Myc, c-Jun and notch 1 and showed accumulation of poly-ubiquitinated oncoproteins relative to the control by blocking proteosome degradation. However, p27[Kip1] (substrate of SCF[SKP2]) and IKB (substrate of SCF[β][-TRCP]) showed no expression change after knockdown of SFN. While SKP1 mainly localized in cytoplasm of A549, knockdown of SFN induced translocation of SKP1 to nucleus.
Conclusion:
SFN induces the stabilization of oncoproteins by blocking SCF[FBW7 ]ubiquitin ligase in lung adenocarcinoma and associated with its malignant progression. SFN will be a promising theraputic target for lung adenocarcinoma.
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P2.02 - Biology/Pathology (ID 616)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 3
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.02-025 - Histological Difference of Tumor-Infiltrate Lymphocytes in Non-Small Cell Lung Cancer (ID 7506)
09:30 - 09:30 | Author(s): M. Noguchi
- Abstract
Background:
Lymphocytes play important roles in cancer immunity. Tumor-infiltrate lymphocytes (TILs) are seen in non-small cell lung cancer (NSCLC) and generally classified according to their localization (epithelial area and stromal area). The distribution and the number of TILs are quite different. Cancer cells have an ability to evade from cancer immunity, and the several mechanisms of the ability have been reported; decreased expression of tumor antigen, inhibition of immune response, induction of immunosuppressive cells, and secretion of immunosuppressive cytokines. We hypothesized that the mechanisms of evasion from cancer immunity would influence TIL representation. In this study, we investigated the differences of TILs in histological differentiation, since we considered that histological difference could affect cancer immunity.
Method:
We retrospectively investigated surgical specimens between 2009 and 2015. Consecutive 20 cases with minimally invasive adenocarcinoma (MIA), lepidic adenocarcinoma (Ad lepidic), acinar or papillary adenocarcinoma (Ad aci/pap), solid adenocarcinoma (Ad solid) and squamous cell carcinoma (Sq) were selected (total 100 cases). We checked all fields of the tumors in the slice with maximum tumor-diameter microscopically at 100-fold magnification. TILs in the field were judged as positive when more than 10 lymphocytes flocking in tumor epithelial area or stromal area were observed. TILs of the tumors were assessed as the rate of the TIL positive fields in all, and separately evaluated in epithelial area and stromal area. Then, analysis of variance was used to assess the histological differences of TILs. Significant difference was considered as p-value was less than 0.05.
Result:
The average rates of TIL positive fields in epithelial area of MIA, Ad lepidic, Ad aci/pap, Ad solid and Sq were 11.2 ± 20.4%, 15.8 ± 20.4%, 26.9 ± 20.9%, 52.4 ± 30.0% and 27.8± 28.8%, respectively. The rate of Ad solid was significantly higher than those of MIA, Ad lepidic and Ad aci/pap, and the rate of Sq was also significantly higher than those of MIA and Ad lepidic. The average rates of TIL positive fields in stromal area of MIA, Ad lepidic, Ad aci/pap, Ad solid and Sq were 41.9 ± 26.1%, 51.2 ± 28.3%, 57.6 ± 23.2%, 67.7 ± 25.4% and 67.8 ± 30.0%, respectively. The rate of MIA was significantly lower than Ad solid and Sq.
Conclusion:
TILs were significantly different representation depending on the histology. Especially in adenocarcinoma, the TILs differed according to the grade of differentiation. These results might show that highly differentiated lung adenocarcinoma has low expression of tumor antigen.
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P2.02-055 - Stratifin Regulates Stabilization of Receptor Tyrosine Kinases via Activation of Ubiquitin-Specific Protease 8 in Lung Adenocarcinoma (ID 8354)
09:30 - 09:30 | Author(s): M. Noguchi
- Abstract
Background:
Receptor tyrosine kinases (RTKs) such as epidermal growth factor receptor (EGFR) and hepatocyte growth factor receptor (MET) are the best-known therapeutic targets in lung adenocarcinoma. Previously, we have revealed that stratifin (SFN, 14-3-3 sigma) acts as a novel oncogene, accelerating tumor initiation and progression of lung adenocarcinoma and interacts with ubiquitin-specific protease 8 (USP8) (IJC 2011, Mol Cancer 2015). USP8 is one of the deubiquitination enzymes that stabilize specific protein substrates by removing ubiquitin from the proteins, and is known to target receptor tyrosine kinases (RTKs). In this study, we investigated the molecular mechanism underlying the binding of SFN to USP8 in lung adenocarcinoma cells, as the role of this interaction in RTK stabilization was considered a promising avenue for identifying a useful therapeutic target for lung adenocarcinoma.
Method:
Expressions of USP8 and SFN in human lung adenocarcinoma tissues (n=193) were examined by immunohistochemistry and statistically analyzed with clinicopathological features of patients. Functional analysis of USP8 and SFN such as cellular proliferation assay, apoptosis assay, and wound healing assay was examined after siRNA-USP8 or SFN transfection. Regulation mechanism of USP8 and SFN on RTKs stabilization was demonstrated using co-immunoprecipitation, western blot analysis, and immunofluorescence.
Result:
USP8 specifically bound to SFN in lung adenocarcinoma cells. Both USP8 and SFN showed higher expression in human lung adenocarcinoma than in normal lung tissue, and their expression was mutually correlated. Expression of SFN, but not that of USP8, was significantly associated with histological subtype, pathological stage, and patient’s prognosis. In vitro, USP8 binds SFN at the early- and late-endosome in immortalized adenocarcinoma in situ (AIS) cells. Moreover, USP8 or SFN knockdown led to down-regulation of tumor cell proliferation, RTK expression, and expression of downstream factors including AKT and STAT3, as well as accumulation of ubiquitinated RTKs leading to lysosomal degradation. Additionally, transfection with mutant USP8 and mutant SFN, which are unable to interact each other, reduced the expression of RTKs and their downstream factors, indicating that interaction with SFN is important for USP8-mediated stabilization of RTKs via deubiquitination.
Conclusion:
RTKs are regulated by ubiquitin-lysosome system, and aberrant stabilization of RTKs contributes to the proliferative activity of many human cancers, including NSCLC. Here, we demonstrate SFN induces aberrant activation of USP8 and subsequently protects RTKs from lysosomal degradation, resulting in hyperactivation of these signaling pathways. SFN may be central to the development of a useful therapeutic strategy for both early and advanced lung adenocarcinomas.
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P2.02-073 - Cytoplasmic Mislocalization of ECT2 Protein Is Associated with Poor Prognosis in Lung Adenocarcinoma (ID 8430)
09:30 - 09:30 | Author(s): M. Noguchi
- Abstract
Background:
Lung cancer is the most lethal malignancy in worldwide. We have previously compared genetic abnormality profiles in early-stage lung adenocarcinoma using array-comparative genomic hybridization (CGH) and found that Epithelial cell transforming sequence 2 (ECT2) amplification and overexpression a new prognostic marker in early-stage lung adenocarcinoma (Cancer Science, 2014). ECT2 is an oncogene that is overexpressed in several types of human cancer and has tumorigenic activity. ECT2 is localized in the nucleus of normal cells, and its function is associated with cytokinesis. In cancer cells, ECT2 exists in not only nucleus but also cytoplasm. However, cytoplasmic ECT2 is thought to promote tumor growth and invasion. In the present study, we aimed to explore the expression of cytoplasmic ECT2 and to assess its functional and prognostic significance in lung adenocarcinoma. First, we examined the subcellular localization of the ECT2 protein in lung adenocarcinoma cells. Subsequently, we investigated the biological significance of cytoplasmic ECT2 that mediated its phosphorylation state. Finally, we examined the clinicopathological attributes of cytoplasmic ECT2 in terms of patient outcome.
Method:
ECT2 expression was evaluated in an immortalized lung epithelial cells (PL16B) and eight lung adenocarcinoma cell lines Calu-3, A549, RERF-LC-KJ, NCI-H1650, PC-9, NCI-H23, NCI-H1975, and HCC827 using Immunoblotting, RT-PCR, Immunofluorescence, and Immunohistochemistry. In order to assess the clinicopathologic characteristics of cytoplasmic ECT2, we examined 50 cases of surgical specimens lung adenocarcinoma by immunohistochemistry. Twenty fresh scraping samples of lung adenocarcinoma were also used to evaluate the expression of Phosho-ECT2 (T790). The Kaplan–Meier method and Cox regression analyses represent the prognostic significance of cytoplasmic ECT2 in lung adenocarcinoma.
Result:
We found that ECT2 expressed in eight lung adenocarcinoma at variable degree levels. In PL16B cells, ECT2 was localized in the nucleus, whereas in lung adenocarcinoma cell lines ECT2 distributed in both the cytosol and the nucleus. Importantly, overexpression of ECT2 leads to aberrant cytoplasmic localization in lung adenocarcinoma cells. We also found that cytoplasmic ECT2 was phosphorylated and accumulated at the cell membrane in lung adenocarcinoma cell lines and surgical specimens. The phosphorylated form of ECT2 was reported to correlate with malignant attributes of lung adenocarcinoma and our clinical analysis showed that cytoplasmic ECT2 expression was significantly associated with poor outcome (OS; P=0.002, DFS; P =0.001), and was an independent prognostic factor in lung adenocarcinoma.
Conclusion:
We demonstrate that aberrant localization of ECT2 to the cytoplasm is a specific feature of lung adenocarcinoma, and provide a new potential prognostic biomarker in lung adenocarcinoma.
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P3.16 - Surgery (ID 732)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Surgery
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.16-039 - Right Upper Lobectomy with SVC Reconstruction after Induction Chemoradiotherapy for a Patient with Bulky N2 NSCLC (ID 7522)
09:30 - 09:30 | Author(s): M. Noguchi
- Abstract
Background:
The treatment strategy for N2 IIIA non-small cell lung cancer (NSCLC) is still controversial. Some believe that patients with bulky N2 are not good candidates for trimodality treatment. In addition, with regard to the survival of patients underwent lung resection with SVC reconstruction, patients with SVC involvement due to direct invasion of the main tumor have longer survival compared to those with SVC involvement due to mediastinal lymph node (LN) metastasis. We encountered a patient with bulky N2 NSCLC with SVC involvement.
Method:
A 69-year-old man complaining of cough was referred to our hospital for examination of a chest abnormal shadow. Chest CT showed a 58-mm pulmonary mass lesion in the right upper lobe and mediastinal LN swelling (#4R: 31 mm, #2R: 15 mm), which resulted in stenosis of the SVC. Transbronchial biopsy of the mass and EBUS-TBNA of the #4R LN showed squamous cell carcinoma. Since distant metastasis was not apparent, the patient was diagnosed with locally advanced IIIA lung cancer with bulky N2. After induction of concurrent chemoradiotherapy (2 cycles CDDP+VNR + 45 Gy radiotherapy), the lesion showed 9.5% reduction and was defined as stable disease according to the RECIST criteria.
Result:
Since it would be difficult to dissect the SVC and #4R LN, and this procedure would require substantial time, we approached by median sternotomy and right fourth intercostal thoracotomy and established the shunt between the left brachiocephalic vein and the right atrial appendage prior to cross-clump of the SVC. The SVC was resected because of extensive firm adhesion of the #4R LN, and reconstructed with a 12-mm reinforced polytetrafluoroethylene graft. The anastomosis was performed using a 5-0 Plorene suture. The patient underwent right upper lobectomy with mediastinal dissection and combined resection of the SVC. The operation time was 494 min and blood loss was 700 g. The patient was discharged on postoperative day 16. Pathological examination revealed the effect of chemoradiotherapy was Ef2, and viable cells were present in the #4 LN (ypN2).
Conclusion:
While the long-term outcome of this patient is unknown, we believe the trimodality treatment is an option for bulky N2 NSCLC with SVC involvement.
