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Adenoviral Transduction of MRP-1/CD9 and KAI1/CD82 Inhibits Lymph Node Metastasis in Orthotopic Lung Cancer Model

¹ Department V of Oncology, Kitano Hospital, Tazuke Kofukai Medical Research Institute, Osaka, Japan and ² Division of Cardiovascular and Respiratory Medicine, Kobe University Graduate School of Medicine, Kobe, Japan

Requests for reprints: Masayuki Miyake, Kitano Hospital, Tazuke Kofukai Medical Research Institute, 2-4-20, Ohgimachi, Kita-ku, Osaka 530-8480, Japan. Phone: 81-6-6312-8816; Fax: 81-6-6312-8816; E-mail: miyakem{at}kitano-hp.or.jp.

Conventional therapies still remain less effective for metastasis of lung cancer, thus leading to a poor prognosis for this disorder. Although the processes involved in metastasis have not yet been clearly elucidated, our previous studies have shown that higher expression levels of MRP-1/CD9 and KAI1/CD82 in cancer cells are significantly correlated with less metastatic potency. To determine whether the gene transfer of these tetraspanins into lung tumor cells may be a useful strategy to regulate metastasis, we adopted an orthotopic lung cancer model produced by the intrapulmonary implantation of Lewis lung carcinoma (LLC) cells and evaluated the metastatic growth in the mediastinal lymph nodes using two different methods of gene delivery as follows: (a) the implantation of LLC cells preinfected with adenovirus encoding either MRP-1/CD9 cDNA, KAI1/CD82 cDNA, or LacZ gene into the mouse lung and (b) the intratracheal administration of these adenoviruses into the mice orthotopically preimplanted with LLC cells. In both cases, we found that the delivery of either MRP-1/CD9 or KAI1/CD82 cDNA dramatically reduced the metastases to the mediastinal lymph nodes in comparison with those of LacZ gene delivery, without affecting the primary tumor growth at the implanted site. These results reemphasize the important role of MRP-1/CD9 and KAI1/CD82 in the suppression of the metastatic process and also show the feasibility of gene therapy when using these tetraspanins for lung cancer to prevent metastasis to the regional lymph nodes. This strategy may therefore be clinically applicable as a prophylactic treatment to suppress the occurrence of lymph node metastasis. [Cancer Res 2007;67(4):1744–9]

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