K. Tabata

Adenoviral vector-mediated RTVP-1 gene-modified tumor cell-based vaccine suppresses the development of experimental prostate cancer

We previously identified a novel p53 target gene, RTVP-1, that possesses unique cytotoxic and immunostimulatory activities which make it potentially useful for cancer gene therapy. To test the therapeutic potential of RTVP-1 in a gene-modified tumor cell-based vaccine model, we used an adenoviral vector capable of efficient transduction and expression of RTVP-1 (AdRTVP-1), together with a highly metastatic mouse prostate cancer cell line (178-2 BMA). A vaccine was prepared with 178-2 BMA cells transduced with AdRTVP-1 or a control adenoviral vector expressing β-galactosidase (Adβgal). After irradiation of the cells, syngeneic 129/Sv mice were vaccinated three times at weekly intervals. After 3 weeks, they were challenged with orthotopic 178-2 BMA cells. After 21 days, fewer than 60% of the RTVP-1-cell-vaccinated mice developed tumors compared to 100% of the control mice. The RTVP-1-cell vaccine significantly reduced primary tumor wet weight compared with control Adβgal-cell vaccine (P<0.0001 at 7 and 14 days). Experimental metastasis to lung was also significantly reduced (P=0.0377), and survival significantly increased (P=0.0002). In addition, significantly increased NK and CTL activities were demonstrated in the AdRTVP-1-cell-vaccinated mice. These findings indicate that RTVP-1 gene-modified cell-based vaccines may be useful in the prevention of recurrent prostate cancer.

Cooperative effects of adenoviral vector-mediated interleukin 12 gene therapy with radiotherapy in a preclinical model of metastatic prostate cancer

We investigated the potential benefits of combining adenoviral vector mediated in situ interleukin-12 (AdmIL-12) gene therapy with radiation therapy (XRT) to enhance therapeutic efficacy. In a metastatic mouse prostate cancer cell line, 178-2 BMA, AdmIL-12+XRT demonstrated enhanced therapeutic activities in vitro as determined by clonogenic survival, apoptosis, and mIL-12 levels. At the molecular level, increased expression of tumor necrosis factor-α mRNA was specific for the combined therapy. In a subcutaneous 178-2 BMA in vivo model, the combination of AdmIL-12+XRT produced statistically significant tumor growth suppression compared to control vector Adβgal, Adβgal XRT, or AdmIL-12 as monotherapy. In addition, significant prolongation of survival was demonstrated for the combination of AdmIL-12+XRT. The combination of AdmIL-12+XRT significantly suppressed both spontaneous and pre-established lung metastases, and led to a prolonged elevation of serum IL-12 and significantly increased natural killer (NK) activities. Importantly, in vivo depletion of NK cells resulted in significant attenuation of the antimetastatic activities of AdmIL-12 alone or AdmIL-12+XRT. These combined effects suggest that AdIL-12 gene therapy together with radiotherapy may achieve maximal tumor control (both local and systemic) in selected prostate cancer patients via radio-gene therapy induced local cytotoxicity and local and systemic antitumor immunity.

Tumor growth and metastasis suppression by Glipr1 gene-modified macrophages in a metastatic prostate cancer model

We previously identified the mouse and human Glipr1 and GLIPR1/RTVP-1 genes, respectively, as direct p53 targets with proapoptotic activities in various cancer cell lines, including prostate cancer (PCa). Intratumoral injection of an adenoviral vector capable of efficient transduction and expression of Glipr1 (AdGlipr1) yielded promising therapeutic results in an orthotopic, metastatic mouse model of PCa. AdGlipr1-transduced macrophages (Mφ/Glipr1) generated greater surface expression of CD40, CD80 and major histocompatibility complex class II molecules and greater production of interleukin 12 (IL-12) and IL-6 in vitro than control macrophages did. Mechanistic analysis indicated that increased production of IL-12 in Mφ/Glipr1 depends on activation of the p38 signaling cascade. Mφ/Glipr1 injected into orthotopic 178-2BMA tumors in vivo resulted in significantly suppressed prostate tumor growth and spontaneous lung metastases and longer survival relative to those observed in control-treated mice. Furthermore, these preclinical data indicate the generation of systemic natural killer cell activity and tumor-specific cytotoxic T lymphocyte responses. Trafficking studies confirmed that intratumorally injected Mφ/Glipr1 could migrate to draining lymph nodes. Overall, our data suggest that this novel gene-modified cell approach is an effective treatment avenue that induces antitumor immune responses in preclinical studies.

Therapeutic effects of gelatin matrix-embedded IL-12 gene-modified macrophages in a mouse model of residual prostate cancer

We evaluated the potential use of intraoperative gelatin matrix hemostatic sealant (GMHS; FloSeal; Baxter Healthcare) embedded with macrophages (Mφ) transduced with murine interleukin (IL)-12 recombinant adenoviral vector (G/Mφ/AdmIL-12) for prevention of recurrence of prostate cancer following radical prostatectomy. Application of G/Mφ/AdmIL-12 resulted in significant suppression of tumor growth and spontaneous lung metastases, a statistically significant survival advantage of the G/Mφ/AdmIL-12-treated animals, more efficient trafficking of Mφ to lymph nodes draining from the prostate and generation of systemic natural killer cell activity and tumor-specific cytolytic T lymphocyte responses compared to the controls in a preclinical mouse model of residual prostate cancer. Our data recommend this treatment as a novel adjuvant for prevention of local recurrence of prostate cancer following radical prostatectomy.

Dynamics of Cancer-Related Proteins in Patients with Bladder Cancer

Bladder cancer (BC) is the second most common malignancy in the urologic field. Preoperative predictive biomarkers of cancer progression and prognosis are impera‐ tive for optimizing appropriate treatment for patients with BC. The prediction of patient outcomes before initial treatment would enable physicians to choose better modalities and avoid unnecessary aggressive treatments. In addition, preoperative molecular markers are expected to be a minimally invasive tool for predicting precise prognosis and progression in patients with BC. The proteins secreted from the tumor cells reflect various states of tumors in real time and at given conditions, and those expression patterns are different from normal cell components. Approximately 20–25% of cellular proteins are in extracellular spaces, and these proteins have important roles in invasion, angiogenesis, regulation of cell-to-cell interactions, and metastasis. It has been suggested that tumor-secreting proteins are a promising source for tumor diagnostic biomarkers. Proteomic analysis was utilized to identify the secreted proteins in sera from patients with BC. Several biomarkers associated with BC are reviewed here.

Prognostic Impact of Perirenal Fat or Adrenal Gland Involvement in Renal Cell Carcinoma Exhibiting Venous Vascular Extension

Venous vascular extension is one of the aggressive tumor behaviors especially for renal cell carcinoma (RCC). It has been reported that 4% to 10% have tumor thrombus extending into the venous system among patients with newly diagnosed RCC (Marshall et al., 1970; Hoehn & Hermanek, 1983; Casanova & Zingg, 1991; Hatcher et al., 1991; Pagano et al., 1992). Compared with conservative treatment regimens, surgical resection remains the most effective treatment for these patients (Staehler & Brkovic, 2000). The mean 5-year survival rates of such patients with inferior vena cava involvement undergoing radical surgery for RCC have been reported as 32% to 64% (Neves & Zincke, 1987; Skinner et al., 1989; Montie et al., 1991; Swierzewski et al., 1994; Glazer & Novick, 1996).