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D.M. Jablons



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    O12 - Lung Cancer Biology II (ID 87)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Biology
    • Presentations: 1
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      O12.06 - Hedgehog/Gli Promotes Epithelial-Mesenchymal Transition in Non-Small Cell Lung Cancer (ID 2091)

      11:25 - 11:35  |  Author(s): D.M. Jablons

      • Abstract
      • Presentation
      • Slides

      Background
      A majority of non-small cell lung cancer (NSCLC) patients are diagnosed with metastatic phenotypes. Epithelial-to-Mesenchymal Transition (EMT), characterized by loss of epithelial markers, such as E-cadherin, is suggested to be involved in the metastatic process. In addition, aberrant activation of the Hedgehog-Gli(Hh/Gli) signaling pathway is implicated in various cancers, including NSCLC. We hypothesize that the Hh/Gli signaling pathway may regulate EMT in NSCLC, and inhibition of Hh/Gli pathway may provide a novel strategy to treat NSCLC and prevent metastasis.

      Methods
      Tumor tissues of 324 NSCLC patients were analyzed by immunohistochemistry for Gli and E-cadherin expression. Mechanistic studies were carried out in four NSCLC cell lines, A549, H1666, H2170 and H1703. Our lab has developed a novel small molecule Gli inhibitor (Gli-I )that effectively suppresses lung cancer in vitro and in vivo. Gli-I and a Smoothened inhibitor vismodegib were applied to suppress Hh/Gli signaling, while Hh protein was utilized to stimulate the pathway. Upon different treatments, EMT phenotypes were evaluated by wound healing assays and 3D cell invasion assays. Expression of EMT markers was measured by immunofluorescent staining and western blot at protein levels, as well as quantitative RT-PCR at mRNA levels.

      Results
      Our results demonstrated elevated Gli expression in 78% of NSCLC patient tissues. Gli expression was reversely correlated with E-Cadherin in patient tissues and culture cell lines. Inhibition of Hh signaling reduced cell migration and invasion, while stimulation of Hh signaling promoted EMT phenotypes. Specifically, Gli-I significantly suppressed cell proliferation, migration and invasion more effectively than vismodegib. Furthermore, mechanistic studied showed Hh/Gli signaling may regulate EMT through suppressing E-Cadherin.

      Conclusion
      Our results suggested that SHh/Gli signaling promotes cell proliferation and EMT, leading to NSCLC cell invasion and metastasis. Inhibition of Hh/Gli signaling by a novel Gli inhibitor Gli-I suppresses cell proliferation and invasion. Our novel Gli inhibitor holds the promise to provide an effective therapeutics to treat NSCLC and prevent metastasis.

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    P1.02 - Poster Session 1 - Novel Cancer Genes and Pathways (ID 144)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.02-009 - KCTD11 methylation in non-adenocarcinoma lung cancer (ID 2582)

      09:30 - 09:30  |  Author(s): D.M. Jablons

      • Abstract

      Background
      Lung cancer is the leading cause of cancer-related death worldwide. Nowdays, the histological subtypes of lung cancer and corresponding genetic polymorphisms play an important role in deciding the treatment options. KCTD11, a novel tumor suppressor, acts on antagonizing Hedgehog (Hh) signaling pathway . The deregulation of KCTD11 might activate glioma-associated oncogene homolog 1(Gli) transcription factors and lead to tumorigenesis. The present study was designed to analyze expression of the KCTD11 in different pathological lung cancer cell lines and lung cancer tissues, also the mechanism of KCTD11 inactivation and the possible affected downstream signal pathway.

      Methods
      Lung cancer cell lines and tissues were used to detect the expression of KCTD11. The clinical significance was analysed.Methylation detection was completed. KCTD11 vectors were transfected to squamous cell lung cancer cell lines to detect the Gli1 expression.

      Results
      The expression of KCTD11 was detected in Small airway epithelial cell (SAEC) and 14 lung cancer cell lines. RT-PCR showed reduced expression in lung cancer cell lines, especially in small cell lung cancer cell (SCLC) lines and squamous cell lung cancer cell (SCC) lines compared with SAEC. In all 14 tested cell lines (5 adenocarcinoma, 2 large cell, 3 SCC and 4 SCLC), we found these CpG islands were densely methylated in 3 of 4 SCLC cell lines, 2 of 3 SCC cell lines and 1 of 2 large cell lung cancer (LCC) cell linesbut none of the 5 adenomacarcinoma cell lines and SAEC. TMA staining showed significantly lower expression of KCTD11 in SCC lung cancer tissues than in normal tissues (24.2% vs 87.5%, p=0.000) .Also 5 of 10 SCC tissues compared with 1 of 12 adenocarcinoma showed methylation status. IHC analysis showed that there was 44.1% (55/118) positive Gli1 expression in group of negative KCTD11 expression. Correlation analysis showed they might exist marginally negative correlation (r=-0.165, p=0.052). H2170 cell lines with KCTD11 plasmid transfection showed significantly reduced Gli-1 expression compared with control plasmid transfection. (picture 1) Figure 1

      Conclusion
      In summary, we found the reduced KCTD11 expression in lung cancer. Hypermethylation was the important mechanism of KCTD11 epigenetic change in non-adenocarcinoma lung cancer cell lines and tissues. KCTD11 silencing resulted in the high expression of Gli1, a downstream mediator of Hh signaling pathway, and might affected the tumorigenesis and development in lung cancer. Targeting the KCTD11 treatment and thus controlling the Hh pathway might a new treatment target in non-adenocarcinoma lung cancer.

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    P3.07 - Poster Session 3 - Surgery (ID 193)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Surgery
    • Presentations: 1
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      P3.07-021 - Pulmonary Metastasis, Particularly of Sarcomas, Amenable to Aggressive Surgical Management (ID 1787)

      09:30 - 09:30  |  Author(s): D.M. Jablons

      • Abstract

      Background
      Background: Metastatic lesions are the most common malignancy of the lungs. In the past, pulmonary metastatectomy was reserved for cases of solitary or oligo-metastasis. Over the past decade, however, indications for surgical treatment of pulmonary metastasis have broadened for many cancers. Sarcomas have a predilection for spread to the lungs, often in the absence of metastasis to other organs. We examined our experience with an increasingly aggressive approach to pulmonary metastasis, to help define evolving parameters and expectations for clinical outcomes, exploring the perceived differences in the clinical patterns between sarcoma and other cancers.

      Methods
      Methods: We identified 262 patients who underwent a total of 361 R0 pulmonary metastatectomies, 336 of which were performed at UCSF Medical Center between 1996 and 2009. Sarcoma was the primary tumor in 118 patients undergoing 180 of these operations. Survival estimates were based on Kaplan-Meier analysis and compared using either a log-rank or Wilcoxon test. Predictors included surgical procedure; number/size of lesions; repeat resection; intervals to metastasis (DFI) and to recurrent metastasis; chemotherapy; cancer type; distribution of pulmonary and extra-pulmonary metastasis; patient age/sex. These predictors were compared using univariate and multivariate Cox proportional hazards modeling; multiple-predictor modeling started with a set of predictors based on historical/clinical significance, and stepwise forward selection determined which additional predictors were included until all p-values in the model were less than 0.1.

      Results
      Results: Despite an increasingly aggressive surgical approach, reflected in an increase in number of lesions, the percentage of patients with > 8 lesions, the number of patients with lesions < 1 cm, and in a decrease in DFI, the overall 5-year survival was 48% (median survival 4.7 years, 95%CI 3.5-5.5), and did not differ between the early and late periods of the study. Sarcoma patients, however, tended to be significantly younger (46 ± 16 yrs vs. 59 ± 14, P<0.001), and to have more lesions (4.0 ± 4.3 vs. 2.3 ± 2.3, P<0.001), a shorter DFI (2.5 ± 3.3 yrs vs. 3.6 ± 3.9, P = 0.004), more diffuse pulmonary involvement (43% bilateral disease vs. 29%, P = 0.02), and more frequent recurrence rate (80% vs. 51%, <0.001) than the non-sarcoma patients. Whereas lesion size (HR 1.2, P=0.004), age (HR 1.4, P<0.001), DFI (HR 2.1, P=0.008), and extra-pulmonary disease (HR 1.9, P=0.04) were all independent predictors of survival for non-sarcomas, only metastasis synchronous to the primary tumor (HR 2.7, P=0.007) and a need for anatomic resection (HR 2.5, P=0.006) independently predicted a higher mortality among sarcomas. Furthermore, a need for repeat resection did not impact the survival of sarcoma patients as long as complete resection remained feasible, whereas the 5-year survival of patients even with resectable recurrent non-sarcoma metastases dropped from 76% to 43% (P = 0.003).

      Conclusion
      Conclusion: Encouraging long-term survival can be achieved even with an increasingly aggressive surgical approach to pulmonary metastasis. Although sarcoma patients tend to present with rapidly progressive and extensive pulmonary disease, a tendency toward confinement of metastasis to the lungs may justify an even more aggressive surgical strategy for these patients.