Phone: (212) 746-5788
Fax: (212) 746-0975
Urology
- Adrenal Cancer
- Kidney Cancer
- Bladder Cancer
- Prostate Cancer
- Ureteral Cancer
- Testicular Cancer
- Urologic Sarcoma
Procedures
- Adrenalectomy
- Nephrectomy
- Robotic Cystectomy
- Robotic Prostatectomy
- Ureteral Cancer Treatment
- Testicular Cancer Treatment
- Urologic Sarcoma Treatment
Inhibition of Lymphangiogenesis: A Novel Mechanism of Imidazoquinoline-Induced Tumor Suppression in Bladder Cancer.
Huixian Liu, Michael J. Schwartz, Eric Kauffman, and Douglas S. Scherr
Department of Urology, The New York-Presbyterian Hospital, Weill Medical College of Cornell University, New York, NY, 10021
Introduction and objective: Progression of malignant tumors of epithelial origin often involves metastasis to regional lymph nodes. Activation of vascular endothelial growth factor receptor-3 (VEGFR-3) on tumor-associated lymphatic endothelium results in lymphangiogenesis and, thus, enhanced rates of lymph node metastasis. We investigate the potential role of imidazoquinolines, Toll-like receptor 7/8 (TLR 7/8) agonists, in inhibition of lymphangiogenesis in lymphatic endothelial cells and suppression of bladder cancer cell invasion.
Experimental Design: The murine bladder cancer cell line (MBT-2), lymphatic endothelial cell line (LEC), and macrophage cell line (RAW264.7) were cultured in RPMI-1640 medium. In vitro effects of imidazoquinolines on gene transcription, cell proliferation, invasion and lymphangiogenesis were evaluated by RT-PCR, methylthiazoletetrazolium (MTT) assay, trans-well migration assay and lymphatic tube formation assay, respectively. Effects of an imidazoquinoline on in vivo lymphangiogenesis related gene expression were investigated by immunohistochemistry in a mouse model of orthotopic bladder cancer.
Results: VEGFR-3 transcription was downregulated both in LEC and RAW264.7 cell lines treated with imidazoquinoline. Furthermore, transcription of VEGFR-3 was downregulated in RAW264.7 cells by supernatants of MBT-2 cells pretreated with imidazoquinoline while transcription of selected macrophage activation factors was upregulated. In vitro proliferation of LEC cells was reduced by 44% at a concentration of 100 ?g/ml imidazoquinoline, and lymphatic tube formation by LEC cells was suppressed. Migration of MBT-2 cells was suppressed up to 91% with imidazoquinoline treatment relative to control. VEGFR-3 expression was consistently inhibited in bladder tumor-associated macrophages and peritumoral lymphatics in vivo.
Conclusions: Imidazoquinolines are efficient inhibitors of VEGFR-3 expression in macrophage and LEC cells in vitro and in vivo. As a suppressor of lymphangiogenesis, imidazoquinolines may reduce the invasive potential of bladder cancer cells. Suppression of in vitro lymphangiogenesis may occur through either a direct inhibitory effect or a paracrine mechanism from bladder tumor cells pretreated with imidazoquinolines. Our findings may help further understanding of anti-tumor effects of Toll-like receptor agonists and broaden potential applications of imidazoquinolines in tumor therapy.