Faculty Profiles - CHEN-YOSHIKAWA Toyofumi

Papers - CHEN-YOSHIKAWA Toyofumi

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Loss of SMAD4 Promotes Lung Metastasis of Colorectal Cancer by Accumulation of CCR1(+) Tumor-Associated Neutrophils through CCL15-CCR1 Axis Reviewed

Takamasa Yamamoto, Kenji Kawada, Yoshiro Itatani, Susumu Inamoto, Ryosuke Okamura, Masayoshi Iwamoto, Ei Miyamoto, Toyofumi F. Chen-Yoshikawa, Hideyo Hirai, Suguru Hasegawa, Hiroshi Date, Makoto M. Taketo, Yoshiharu Sakai

CLINICAL CANCER RESEARCH Vol. 23 ( 3 ) page： 833 - 844 2017.2

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

Purpose: We have reported loss of SMAD4 promotes expression of CCL15 from colorectal cancer to recruit CCR1(+) myeloid cells through the CCL15-CCR1 axis, which contributes to invasion and liver metastasis. However, the molecular mechanism of lung metastasis is yet to be elucidated. Our purpose is to determine whether similar mechanism is involved in the lung metastasis of colorectal cancer.
Experimental Design: In a mouse model, we examined whether SMAD4 could affect the metastatic activity of colorectal cancer cells to the lung through the CCL15-CCR1 axis. We immunohistochemically analyzed expression of SMAD4, CCL15, and CCR1 with 107 clinical specimens of colorectal cancer lung metastases. We also characterized the CCR1(+) myeloid cells using several cell-type-specific markers.
Results: In a mouse model, CCL15 secreted from SMAD4-deficient colorectal cancer cells recruited CCR1(+) cells, promoting their metastatic activities to the lung. Immunohistochemical analysis of lung metastases from colorectal cancer patients revealed that CCL15 expression was significantly correlated with loss of SMAD4, and that CCL15-positive metastases recruited approximately 1.9 times more numbers of CCR1(+) cells than CCL15-negative metastases. Importantly, patients with CCL15-positive metastases showed a significantly shorter relapse-free survival (RFS) than those with CCL15-negative metastases, and multivariate analysis indicated that CCL15 expression was an independent predictor of shorter RFS. Immunofluorescent staining showed that most CCR1(+) cells around lung metastases were tumor-associated neutrophil, although a minor fraction was granulocytic myeloid-derived suppressor cell.
Conclusions: CCL15-CCR1 axis may be a therapeutic target to prevent colorectal cancer lung metastasis. CCL15 can be a bio-marker indicating poor prognosis of colorectal cancer patients with lung metastases. (C) 2016 AACR.

DOI： 10.1158/1078-0432.CCR-16-0520

Web of Science

PubMed

Protective Effect of Inhaled Rho-Kinase Inhibitor on Lung Ischemia- Reperfusion Injury Reviewed

Keiji Ohata, Toyofumi F. Chen-Yoshikawa, Toshi Menju, Ei Miyamoto, Satona Tanaka, Mamoru Takahashi, Hideki Motoyama, Kyoko Hijiya, Akihiro Aoyama, Hiroshi Date

ANNALS OF THORACIC SURGERY Vol. 103 ( 2 ) page： 476 - 483 2017.2

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

Background. Rho-kinase, an intracellular serine/threonine kinase, is a key regulator of cytoskeletal dynamics. Recent studies have demonstrated that Rho-kinase is involved in the ischemia-reperfusion injury (IRI) pathogenesis of many organs; however, its involvement with lung IRI remains unclear. This study assessed the association of Rho-kinase with lung IRI and evaluated the protective effect of inhaled Rho-kinase inhibitors in lung IRI.
Methods. The study included isolated rat lung perfusion models, divided into three groups: sham, Rho-kinase inhibitor, and warm ischemia (n = 6 each). The lungs were exposed to 60 minutes of warm ischemia by perfusion cessation. At the onset of ischemia, nebulized fasudil, a novel Rho-kinase inhibitor, and saline were inhaled in the Rho-kinase inhibitor and warm ischemia groups, respectively. Perfusion was restarted after the ischemic period, and physiologic data were collected for 90 minutes. Lungs in the sham group were continuously perfused without ischemia or drug administrations. Protein expression in tissue specimens related to the Rho-kinase pathway was evaluated by Western blotting.
Results. Warm ischemia and subsequent reperfusion enhanced Rho-kinase activity, and this was suppressed by fasudil inhalation. Fasudil inhalation significantly attenuated IRI pathophysiology, including pulmonary vascular contraction, dynamic compliance, lung edema, and oxygenation. Molecular analysis showed that Rho-kinase suppressed myosin phosphatase and endothelial nitric oxide synthase activities, suggesting these are downstream targets of Rho-kinase during lung IRI pathogenesis.
Conclusions. The present study suggests that Rho-kinase activation is involved in lung IRI pathogenesis and that inhaled Rho-kinase inhibitors may attenuate this pathogenesis. (Ann Thorac Surg 2017; 103: 476-83) (C) 2017 by The Society of Thoracic Surgeons

DOI： 10.1016/j.athoracsur.2016.07.067

Web of Science

PubMed

Hypoxia-inducible factor 1 promotes chemoresistance of lung cancer by inducing carbonic anhydrase IX expression Reviewed

Terumasa Sowa, Toshi Menju, Toyofumi F. Chen-Yoshikawa, Koji Takahashi, Shigeto Nishikawa, Takao Nakanishi, Kei Shikuma, Hideki Motoyama, Kyoko Hijiya, Akihiro Aoyama, Toshihiko Sato, Makoto Sonobe, Hiroshi Harada, Hiroshi Date

CANCER MEDICINE Vol. 6 ( 1 ) page： 288 - 297 2017.1

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Lung cancer treatment is difficult owing to chemoresistance. Hypoxia-inducible factor 1 (HIF-1) and HIF-1-induced glycolysis are correlated with chemoresistance; however, this is not evident in lung cancer. We investigated the effect of HIF-1 and carbonic anhydrase IX (CAIX), a transmembrane protein neutralizing intracellular acidosis, on chemoresistance and prognosis of lung cancer patients after induction chemoradiotherapy. Associations of HIF-1, glucose transporter 1 (GLUT1), and CAIX with chemoresistance of lung cancer were investigated using A549 lung cancer cells under normoxia or hypoxia in vitro. HIF-1-induced reprogramming of glucose metabolic pathway in A549 cells and the effects of HIF-1 and CAIX on the cytotoxicity of vinorelbine were investigated. Immunohistochemical analyses were performed to determine HIF-1, GLUT1, and CAIX expression levels in cancer specimens from lung cancer patients after induction chemoradiotherapy. Hypoxia induced HIF-1 expression in A549 cells. Moreover, hypoxia induced GLUT1 and CAIX expression in A549 cells in a HIF-1-dependent manner. Glucose metabolic pathway was shifted from oxidative phosphorylation to glycolysis by inducing HIF-1 in A549 cells. HIF-1 and CAIX induced chemoresistance under hypoxia, and their inhibition restored the chemosensitivity of A549 cells. The expression levels of HIF-1, GLUT1, and CAIX were associated with poor overall survival of lung cancer patients after induction chemoradiotherapy. HIF-1 and CAIX affected the chemosensitivity of A549 cells and prognosis of lung cancer patients. Therefore, inhibition of HIF-1 and CAIX might improve prognosis of lung cancer patients after induction chemoradiotherapy. Further analysis might be helpful in developing therapies for lung cancer.

DOI： 10.1002/cam4.991

Web of Science

PubMed

Barr virus-associated post-transplantation lymphoproliferative disorder as acomplication after cadaveric lung transplantation following allogenic hematopoietic stem cell transplantation. Reviewed

Hoshino T, Chen-Yoshikawa TF, Nagasaka I, Hatsumi N, Takada S, Date H, Sakura T

Journal of Hematopoietic Cell Transplantation Vol. 6 ( 2 ) page： 120 - 124 2017

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Papers - CHEN-YOSHIKAWA Toyofumi