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M. Minami



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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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      O12.07 - Pulmonary fibroblasts increase EMT signaling and decrease sensitivity to chemotherapy in non-small cell lung cancer cells via TGF-beta and IL-6 signaling (ID 265)

      11:35 - 11:45  |  Author(s): M. Minami

      • Abstract
      • Presentation
      • Slides

      Background
      The tumor microenvironment is a key factor in tumor progression. A specific subset of stromal cells, termed cancer associated fibroblasts (CAFs), modulate the behavior of adjacent cancer cells by secreting various growth factors and cytokines. The purpose of this study was to clarify the roles of transforming growth factor (TGF)-β and interleukin (IL)-6 in the communication between CAFs and non-small-cell lung cancer (NSCLC) cells.

      Methods
      Fibroblasts obtained during surgical exploration were co-cultured with human lung adenocarcinoma cell lines. We defined fibroblasts obtained from tumors as CAFs and those from normal lung tissue as lung normal fibroblasts (LNFs). Immunohistochemistry was used to examine the fibroblast distribution, as well as TGF-β and IL-6 expression in 60 tumor specimens obtained from patients with NSCLC after undergoing induction chemotherapy or chemoradiotherapy (ITx).

      Results
      The expression levels of myofibroblast markers were higher in CAFs than LNFs after 5 passages in the absence of continuing interaction with carcinoma cells, and we used at least 2 pairs of those CAFs and LNFs in the following experiments. Conditioned medium (CM) from both types of fibroblasts induced epithelial mesenchymal transition (EMT) and acquisition of cancer stemness in lung cancer cells (A549 and NCI-H358), indicating it to be biologically active. Phenotypic changes of cancer cells by CM from CAFs were greater than those induced by CM from LNFs. These CAF-induced changes were inhibited by addition of the TGF-β inhibitor SB431542 or IL-6 receptor neutralizing antibody (IL6-R-Ab). The concentrations of TGF-β1 and IL-6 were higher in CM from CAFs as compared to that from LNFs. Subcutaneous co-injection of lung cancer cells and CAFs in mice enhanced tumor growth when compared with cancer cells alone, which was attenuated by administration of SB431542 or IL-6R-Ab. These findings suggested that CAFs may be more activated in our experimental system as compared to LNFs, and stimulate tumor progression via TGF-β and IL-6 signaling. In addition, decreased expression of epithelial markers and upregulation of mesenchymal markers were detected in surgically resected specimens after ITx as compared with biopsy specimens obtained before treatment. The disease-free survival rate of patients with EMT marker-positive tumors was significantly lower than that of those with EMT marker-negative tumors, indicating that EMT changes are associated with insensitivity to ITx. Furthermore, an increased diffuse distribution pattern of SMA-positive activated fibroblasts was significantly correlated with the expression of EMT markers. Also, though SMA-stained fibroblasts expressed IL-6 in the surgical specimens, TGF-β was expressed in cancer cells as well as CAFs after ITx. Together, our results suggest that tumor stromatic tissues including CAFs increase in response to ITx, while CAFs secrete TGF-β and IL-6, inducing EMT in cancer cells.

      Conclusion
      The TGF-β and IL-6 axis induces EMT and stimulates tumor progression, while TGF-β and IL-6 may play roles to contribute to communication between CAFs and NSCLC cells for tumor progression. Targeting CAFs as a therapeutic strategy against cancer is an intriguing concept that would benefit from further study.

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    P1.15 - Poster Session 1 - Thymoma (ID 189)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Thymoma & Other Thoracic Malignancies
    • Presentations: 1
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      P1.15-004 - Relationship of therapeutic results with immunohistochemical findings in thymic carcinoma cases (ID 1016)

      09:30 - 09:30  |  Author(s): M. Minami

      • Abstract

      Background
      A thymic carcinoma is a thymic epithelial neoplasm that has a large number of malignant features as compared to a thymoma. Since a thymic carcinoma is presented with locally advanced disease or distant metastasis, unresectable cases are frequently encountered at diagnosis, thus systemic chemotherapy is a key treatment strategy. Although cisplatin-based chemotherapy is usually administered for such cases, an optimal regimen has not been established. To determine a prognostic indicator for chemotherapy in patients with thymic cancer we evaluated the expressions of excision repair cross complementing-1 (ERCC1), class III β-Tubulin (TubIII), ribonucleotide reductase M1 (RRM1), and thymidylate synthase (TS)/orotate phosphoribosyltransferase (OPRT), which have been reported as possible indicators of the anticancer activity of cisplatin, taxanes, gemcitabine, and 5-fluorouracil drugs such as S-1, respectively.

      Methods
      Thymic carcinoma tissue samples obtained from 15 patients who underwent surgery or core-needle biopsy procedures between 1996 and 2007 at Osaka University Hospital were used. Immunohistochemical analysis was utilized to determine the expressions of ERCC1, TubIII, RRM1, TS, and OPRT in thymic cancer specimens, then the relationship between expression levels and clinical course were examined in a retrospective manner.

      Results
      Twelve males and 3 females (median age, 60.3 years) were studied. The histological subtype was squamous cell carcinoma in 10, small cell carcinoma in 2, large-cell neuroendocrine carcinoma in 2, and carcinoid in 1, while Masaoka classification was stage III in 4, IVa in 4, and IVb in 7. Surgical resection was performed as initial treatment in 8 patients. Chemotherapy, mainly platinum-based combinations, was administered in 12, including 6 who received combined radiotherapy. The median number of administered regimens and cycles were 2 (range, 1-9) and 7 (range, 2-44), respectively, for each patient. The response rate/disease-control rates following first- and second-line treatments were 83%/92% and 56%/78%, respectively. In 6 patients treated with gemcitabine, 3 tumors with a low expression of RRM1 showed a good response, whereas 2 of 3 tumors with a high expression of RRM1 showed a progressive disease response. S-1 was administered to 1 patient, which successfully suppressed tumor progression, and the specimen from that case demonstrated a low expression of TS and high expression of OPRT. We were able to obtain biopsy specimens before and resected tumors after treatment from 5 patients, in which the expressions of ERCC1, Tub III, and RRM1 were increased after treatment in 4, 3, and 4, respectively. Our results suggest that sensitivity to chemotherapy is lowered with additional courses in thymic carcinoma patients. The median survival was 36 months, while the 1-, 3-, and 5-year survival rates were 81.9%, 55.5%, and 23.1%, respectively.

      Conclusion
      First-line chemotherapy with platinum compounds may be effective treatment for patients with thymic cancer, while new drugs such as gemcitabine and S-1 might be useful in some cases. Prospective multi-institutional studies are required to ascertain the effectiveness of immunohistochemical evaluation used as a screening test for selecting the optimum chemotherapy regimen for thymic cancer patients.