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Hideyuki Saya



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    MS 26 - Re-Modeling Microenvironment Mimicking Human Cancer (ID 548)

    • Event: WCLC 2017
    • Type: Mini Symposium
    • Track: Biology/Pathology
    • Presentations: 1
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      MS 26.01 - Cancer Stem Cell (ID 7764)

      14:30 - 14:50  |  Presenting Author(s): Hideyuki Saya

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Cancer stem cells (CSCs) are a subset of tumor cells that are responsible for initiating and maintaining the disease. In the clinical point of view, the most important characteristics of CSCs include their resistance to various therapeutic interventions[1)]. However, the underlying mechanisms of the resistance remain unclear. CD44 has been identified as a cell surface marker associated with cancer stem cells (CSCs) in several types of epithelial tumor. We have recently found that expression of CD44, in particular variant forms of CD44 (CD44v), contributes to the defense against reactive oxygen species (ROS) by promoting the synthesis of reduced gluathione (GSH), a primary intracellular antioxidant. CD44v interacts with and stabilizes xCT, a subunit of a glutamate-cystine transporter, and thereby promotes the uptake of cystine for GSH synthesis[2)]. Therefore, ablation of CD44 reduced GSH levels and increased ROS levels, leading to suppression of tumor growth and metastasis in both transgenic and xenograft tumor models[3,4)]. Our findings reveal a novel function for CD44v in protection of CSCs from high levels of ROS in the tumor microenvironment[5)]. Expression of CD44v and xCT is associated with tumorigenesis and therapeutic resistance[6,7)]. Based on these preclinical findings, we conducted clinical trials using an xCT inhibitor, sulfasalazine, for cancer patients having advanced gastric cancer and lung cancer. The clinical trials for gastric cancers revealed that sulfasalazine treatment reduceed the number of CD44v-positive cells in post-treatment tumor tissue[8,9)]. In terms of the clinical trial for lung cancer, chemotherapy-naive patients with advanced non-squamous nonsmall cell lung cancer were enrolled in a dose-escalation study (standard 3 + 3 design) of SASP in combination with cisplatin and pemetrexed[10)]. Fifteen patients were enrolled in the study and dose-limiting toxicity was observed in one of six patients at a SASP dose of 1.5 g/day, two of five patients at 3 g/day, and two of three patients at 4.5 g/day. The maximum tolerated dose was thus 3 g/day, and the recommended dose was 1.5 g/day. The overall response rate was 26.7% and median progression-free survival (PFS) was 11.7 months, much longer than that for cisplatin–pemetrexed alone in previous studies. It is possible that the prolonged PFS was due to a sulfasalazine-induced reduction in the number of CD44v-positive CSCs that are the origin of disease recurrence. References: 1) Sugihara E and Saya H: Complexity of cancer stem cells (Review article). Int J Cancer 132:1249-1259, 2013 2) Ishimoto T, Nagano O, Yae T, Tamada M, Motohara T, Oshima H, Oshima M, Ikeda T, Asaba R, Yagi H, Masuko T, Shimizu T, Ishikawa T, Kai K, Takahashi E, Imamura Y, Baba Y, Ohmura M, Suematsu M, Baba H and Saya H: CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc- and thereby promotes tumor growth. Cancer Cell 19: 387-400, 2011 3) Yae T, Tsuchihashi K, Ishimoto T, Motohara T, Yoshikawa M, Yoshida GJ, Wada T, Masuko T, Mogushi K, Tanaka H, Osawa T, Kanki Y, Minami T, Aburatani H, Ohmura M, Kubo A, Suematsu M, Takahashi K, Saya H and Nagano O: Alternative splicing of CD44 mRNA by ESRP1 enhances lung colonization of metastatic cancer cell. Nat Commun 3: 883, 2012 4) Yoshikawa M, Tsuchihashi K, Ishimoto T, Yae T, Motohara T, Sugihara E, Onishi N, Masuko T, Yoshizawa K, Kawashiri S, Mukai M, Asoda S, Kawana H, Nakagawa T, Saya H and Nagano O: xCT inhibition depletes CD44v-expressing tumor cells that are resistant to EGFR-targeted therapy in head and neck squamous cell carcinoma. Cancer Res 73: 1855-1866, 2013 5) Nagano O, Okazaki S and Saya H: Redox regulation in stem-like cancer cells by CD44 variant isoforms (Review article). Oncogene 32: 5191-5198, 2013 6) Seishima R, Wada T, Tsuchihashi K, Okazaki S, Yoshikawa M, Oshima H, Oshima M, Sato T, Hasegawa H, Kitagawa Y, Goldenring JR, Saya H and Nagano O: Ink4a/Arf-dependent loss of parietal cells induced by oxidative stress promotes CD44-dependent gastric tumorigenesis. Cancer Prev Res 8: 492-501, 2015 7) Tsuchihashi K, Okazaki S, Ohmura M, Ishikawa M, Sampetrean O, Onishi N, Wakimoto H, Yoshikawa M, Seishima R, Iwasaki Y, Morikawa T, Abe S, Takao A, Shimizu M, Masuko T, Nagane M, Furnari FB, Akiyama T, Suematsu M, Baba E, Akashi K, Saya H and Nagano O: The EGF receptor promotes the malignant potential of glioma by regulating amino acid transport system xc(-). Cancer Res 76: 2954-2963, 2016 8) Shitara K, Doi T, Nagano O, Imamura CK, Ozeki T, Ishii Y, Tsuchihashi K, Takahashi S, Nakajima TE, Hironaka S, Fukutani M, Hasegawa H, Nomura S, Sato A, Einaga Y, Kuwata T, Saya H and Ohtsu A: Dose-escalation study for the targeting of CD44v[+] cancer stem cells by sulfasalazine in patients with advanced gastric cancer (EPOC1205). Gastric Cancer 20: 341-349, 2017 9) Shitara K, Doi T, Nagano O, Fukutani M, Hasegawa H, Nomura S, Sato A, Kuwata T, Asai K, Einaga Y, Tsuchihashi K, Suina K, Maeda Y, Saya H and Ohtsu A: Phase 1 study of sulfasalazine and cisplatin for patients with CD44v-positive gastric cancer refractory to cisplatin (EPOC1407). Gastric Cancer 2017 (in press) 10) Otsubo K, Nosaki K, Imamura CK, Ogata H, Fujita A, Sakata S, Hirai F, Toyokawa G, Iwama E, Harada T, Seto T, Takenoyama M, Ozeki T, Mushiroda T, Inada M, Kishimoto J, Tsuchihashi K, Suina K, Nagano O, Saya H, Nakanishi Y and Okamoto I: Phase I study of salazosulfapyridine in combination with cisplatin and pemetrexed for advanced non-small cell lung cancer. Cancer Sci 108: 1843-1849, 2017

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    P1.02 - Biology/Pathology (ID 614)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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      P1.02-023 - TGF-β Signaling Mediated by Fibroblasts is Associated with the Histological Subtypes of Lung Adenocarcinoma (ID 8068)

      09:30 - 09:30  |  Author(s): Hideyuki Saya

      • Abstract

      Background:
      About 90% of invasive lung adenocarcinoma cases contain several histologic subtypes and demonstrate heterogenous histologic patterns. How such histological heterogeneity is formed remains unclear. The histological subtypes are associated with the prognosis in lung adenocarcinoma patients. Understanding the molecular mechanisms contributing to the pathological subtypes may provide a basis for developing new therapeutic strategies. Tumor microenvironments (TME) including endothelial cells, immune cells, and fibroblasts, have all been recognized as key components regulating cancer progression. TME influences tumor cells via direct cell-cell contact or their products, such as cytokines and extracellular matrixes. In this study, we determined the role of TME in the histological heterogeneity of lung adenocarcinoma.

      Method:
      We inoculated GFP-labeled A549 human lung adenocarcinoma cells into tissues in four different sites of immunodeficient mice including; the pleural cavity, subcutaneous region, intracardial, and the renal capsule. We then compared the histopathological features of those xenograft tumors. We established immortalized αSMA-positive cancer associated fibroblasts (CAFs) from the xenograft tumors, and co-cultured them with A549 cells in 3D culture conditions so as to analyze the interaction between the tumor cells and the stromal cells.

      Result:
      We found that the xenografted A549 cells developed distinct histological types of tumors; solid types and acinar types, depending on the inoculated sites. The solid type tumors contained an abundance of acidic mucins stained with Alcian blue, and they expressed MUC5AC, which is one of the common mucin core proteins. The acinar type tumors showed gland-like structures encircled by stromal cells. We found that the phosphorylation of Smad3 were upregulated in the acinar type tumors, especially αSMA-positive CAFs. Smad3 is the downstream of the transforming growth factor-β (TGF-β) signal. These data indicate that the TGF-β/Smad pathway is activated in acinar type tumors. CAFs derived from acinar type tumors induced acinar formations of A549 cells under in vitro 3D culture conditions. We also found that the inhibitor of TGF-β receptor I suppressed such acinar formations, suggesting that TGF-β signaling is associated with the histological subtypes of lung adenocarcinoma.

      Conclusion:
      Our data show that the histological heterogeneity of lung adenocarcinoma is dependent on TGF-β signaling mediated by the αSMA-positive CAFs. Inhibition of TGF-β signaling might block interactions between cancer cells and αSMA-positive CAFs, and TGF-β signaling inhibitors might suppress tumor heterogeneity in lung adenocarcinoma.