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A. Ochiai



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    MO04 - Lung Cancer Biology I (ID 86)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
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      MO04.10 - Identification of biological properties of intralymphatic tumor related to the development of lymph node metastasis in lung adenocarcinoma (ID 1724)

      16:15 - 17:45  |  Author(s): A. Ochiai

      • Abstract
      • Presentation
      • Slides

      Background
      Intralymphatic tumors in the extratumoral area are considered to represent the preceding phase of lymph node (LN) metastasis. The aim of this study was to clarify the biological properties of intralymphatic tumors susceptible to the development of LN metastasis, with special reference to the expression of cancer initiating/stem cell (CIC/CSC) markers in cancer cells and the number of infiltrating stromal cells.

      Methods
      A total of 2087 consecutive adenocarcinoma patients underwent complete resections and systematic LN dissections between May 1998 and December 2012 were identified. Among these cases, we selected those that had been diagnosed as having lymphatic permeation in the extratumoral area (n = 107). We examined the expression levels of CIC/CSC related markers including ALDH1, OCT4, NANOG, SOX2 and Caveolin-1 in the intralymphatic and primary tumor cells to evaluate their relationship to LN metastasis. The number of infiltrating stromal cells expressing CD34, α-smooth muscle actin, and CD204 were also evaluated. Moreover, we measured E-cadherin expression to identify a correlation between CIC/CSC related molecules and epithelial - mesenchymal transition (EMT) process.

      Results
      Intrathoracic LN metastases were detected in specimens from 86 patients (80%). Among the intralymphatic tissues, low ALDH1 expression in cancer cells, high SOX2 expression in cancer cells, and a high number of CD204(+) macrophages were independent predictive factors for LN metastasis (odds ratio [95%CI] = 3.25 [1.11 – 9.82], P = 0.031 for ALDH1; 4.09 [1.38 – 13.4], P = 0.011 for SOX2; and 3.45 [1.16 – 11.4], P = 0.026 for CD204(+) macrophages). However, in the primary tumors, only a high SOX2 expression level in the cancer cells within the primary tumor was significantly correlated with LN metastasis (p=0.008); ALDH1 expression in the cancer cells and the number of CD204(+) macrophages were not correlated with LN metastasis (P = 0.230 and P = 0.088, respectively). Among these factors, only low ALDH1 expression in intralymphatic cancer cells was significantly correlated with the farther spreading of LN metastasis (mediastinal LN, pN2) (P = 0.046) and higher metastatic LN ratio (metastatic/resected) (P = 0.028). Intralymphatic cancer cells expressing low ALDH1 levels exhibited lower E-cadherin expression levels than cancer cells with high levels of ALDH1 expression (P = 0.015). The expressions of other CIC/CSC related markers, including OCT4, NANOG, SOX2, and Caveolin-1, were not correlated with the E-cadherin expression.

      Conclusion
      Intralymphatic cancer cells expressing low levels of ALDH1 and infiltrating macrophages expressing CD204 have a critical impact on LN metastasis. Especially, intralymphatic cancer cells expressing low levels of ALDH1 might acquire a metastatic aggressiveness by the EMT process. Our study highlighted the significance of evaluating the biological properties of intralymphatic tumors for tumor metastasis and suggested the possibility of usefulness as a new molecular target, especially as an adjuvant therapy.

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    P3.06 - Poster Session 3 - Prognostic and Predictive Biomarkers (ID 178)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 2
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      P3.06-016 - Aldehyde dehydrogenase 1 expression in cancer cells could have prognostic value for patients with non-small cell lung cancer who are treated with neoadjuvant therapy: identification of prognostic microenvironmental factors after chemoradiation (ID 1726)

      09:30 - 16:30  |  Author(s): A. Ochiai

      • Abstract

      Background
      Prognostic biomarkers for patients with non-small cell lung cancer (NSCLC) who have been treated with neoadjuvant therapy have not been fully assessed. Identifying biological prognostic markers may help to distinguish patients who are likely to benefit from additional postoperative chemotherapy. The purpose of this study was to analyze prognostic biomarkers in surgically resected NSCLC after treatment with neoadjuvant therapy, with special reference to the immunophenotypes of both the cancer cells and the stromal cells.

      Methods
      A series of 66 patients with NSCLC who were treated with neoadjuvant chemotherapy, chemoradiotherapy, or radiotherapy followed by complete resection at our hospital between April 1992 and December 2009 were reviewed. Among the 66 surgically resected specimens, case with viable tumor cells remained in the specimens were included in this study (n =52). We examined the expressions of geminin and cleaved caspase 3 (proliferation and apoptosis markers), E-cadherin and vimentin (epithelial mesenchymal transition related molecules), ALDH1 and CD44v6 (Stem cells related molecules) in the cancer cells. Furthermore in the stromal cells, the expressions of podoplanin and CD90 in cancer associated fibroblasts (CAFs) and CD204 in tumor associated macrophages (TAMs) were also examined.

      Results
      The 5-year disease-free survival rate of patients with high ALDH1 expression levels in their cancer cells was significantly lower than those with a low ALDH1 level (47.3% vs. 21.5%, respectively; P =0.023). The expression statuses of geminin, cleaved caspase 3, E-cadherin, vimentin, and CD44v6 in the cancer cells had no prognostic impact. The 5-year disease-free survival rate of patients with low or high podoplanin and CD90 levels in CAFs and CD204 levels in TAMs expression levels were not any prognostic impact in the stromal cells (37.9% vs. 29.1%, 33.8% vs. 37.5%, 38.4% vs. 29.0%, P =0.90, P = 0.75, P =0.98). In NSCLC without neoadjuvant therapy matching for clinical stage and histopathology (case control, n =104), the 5-year DFS rate of the patients with a high ALDH1 expression level was 48.3%, while that of the cases with a low ALDH1 expression level was 59.8%. The expression of ALDH1 in cancer cells was not correlated with the prognosis in NSCLC without neoadjuvant therapy (P =0.507). A multivariate analysis identified ALDH1 expression in cancer cells as significantly independent prognostic factors for disease-free survival in patients who received neoadjuvant therapy (P =0.045).

      Conclusion
      The presence of ALDH1-positive cancer cells was an independent recurrence predictor in patients who received neoadjuvant therapy, while CAFs and TAMs did not provide any predictors. Although prospective studies with a larger number of patients are required to confirm the prognostic significance of ALDH1 expression in cancer cells in validation populations with neoadjuvant therapy, our results suggest that the immunophenotypes of ALDH1 expression can serve as a guide to additional treatment after surgical resection in patients who received neoadjuvant therapy.

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      P3.06-050 - Characteristic Immunophenotype of Solid Subtype Component<br /> in Lung Adenocarcinoma (ID 3289)

      09:30 - 16:30  |  Author(s): A. Ochiai

      • Abstract

      Background
      Lung adenocarcinomas represent a morphologically heterogeneous tumor composed of an admixture of different histologic subtypes (lepidic, papillary, acinar, and solid subtype). The presence of a solid subtype component is reported to be associated with a poorer prognosis. The aim of this study was to evaluate the characteristic immunophenotype of the solid subtype component compared with the immunophenotypes of other components.

      Methods
      We analyzed the clinicopathological characteristics of stage I adenocarcinoma patients with predominant solid subtype disease. Furthermore, we immunostained adenocarcinomas with predominant lepidic, papillary, acinar, and solid subtype components (n = 23 each) for 10 molecular markers of tumor invasiveness and scored the results.

      Results
      Patients showing predominance of the solid subtype component (solid subtype adenocarcinoma) had a poorer prognosis than those showing predominance of the lepidic, papillary, or acinar component. Lymphovascular invasion was more often detected in solid subtype tumors than in others. The solid subtype component showed a significantly stronger staining intensity of laminin-5 expression than the lepidic, papillary, and acinar components (P\\0.001, P\\0.001, and P = 0.016, respectively). The fibronectin and vimentin expression levels were also significantly higher in the solid subtype component than in other components. This immunostaining character was validated by using mixed-subtype adenocarcinomas containing all four components in the same tumor.

      Conclusion
      This study concluded that the solid subtype component in lung adenocarcinomas exhibit the invasive immunophenotype, including increased laminin-5 expression, compared with the other components, which may be associated with a poorer prognosis.