The Ron receptor promotes prostate tumor growth in the TRAMP mouse model.

The Ron receptor tyrosine kinase (TK) is overexpressed in many cancers, including prostate cancer. To examine the significance of Ron in prostate cancer in vivo, we utilized a genetically engineered mouse model, referred to as TRAMP mice, that is predisposed to develop prostate tumors. In this model, we show that prostate tumors from 30-week-old TRAMP mice have increased Ron expression compared with age-matched wild-type prostates. Based on the upregulation of Ron in human prostate cancers and in this murine model of prostate tumorigenesis, we hypothesized that this receptor has a functional role in the development of prostate tumors. To test this hypothesis, we crossed TRAMP mice with mice that are deficient in Ron signaling (TK-/-). Interestingly, TK-/- TRAMP+ mice show a significant decrease in prostate tumor mass relative to TRAMP mice containing functional Ron. Moreover, TK-/- TRAMP+ prostate tumors exhibited decreased tumor vascularization relative to TK+/+ TRAMP+ prostate tumors, which correlated with reduced levels of the angiogenic molecules vascular endothelial growth factor and CXCL2. Although Ron loss did not alter tumor cell proliferation, a significant decrease in cell survival was observed. Similarly, murine prostate cancer cell lines containing a Ron deficiency exhibited decreased levels of active nuclear factor-κB, suggesting that Ron may be important in regulating prostate cell survival at least partly through this pathway. In total, our data show for the first time that Ron promotes prostate tumor growth, prostate tumor angiogenesis and prostate cancer cell survival in vivo.

The Ron receptor tyrosine kinase positively regulates angiogenic chemokine production in prostate cancer cells.

Overexpression of the Ron receptor tyrosine kinase has recently been shown in a wide variety of human cancers. However, no studies have examined Ron receptor expression or function during prostate tumorigenesis. In this study we report that Ron is highly expressed in human prostate adenocarcinoma and metastatic lymph nodes when compared with normal prostate or benign prostate hyperplasia. Furthermore, we show that Ron is overexpressed in PC-3 and DU145 prostate cancer cell lines, and that the levels of angiogenic chemokines produced by prostate cancer cells positively correlate with Ron expression. The knockdown of Ron in PC-3 or DU145 cells results in a significant decrease in angiogenic chemokine production and is associated with a decreased activation of the transcription factor nuclear factor-kappaB (NF-kappaB). Moreover, exogenous overexpression of Ron in LNCaP cells is sufficient to induce a significant increase in angiogenic chemokines that can be abrogated by inhibition of NF-kappaB signaling. Given that the function of angiogenic chemokines is important in the development of new blood vessels, we also examined the ability of Ron to modulate endothelial cell migration. Our data show that knockdown of Ron in prostate cancer cells results in significantly less endothelial cell chemotaxis when compared with Ron-expressing cells in vitro as well as in reduced tumor growth and decreased microvessel density after orthotopic transplantation into the prostate in vivo. In total, our data suggest that the Ron receptor is important in modulating prostate tumor growth by modulating angiogenic chemokine production and subsequent endothelial cell recruitment.

Dengue fever outbreaks in two villages of Dharmapuri district in Tamil Nadu.

BACKGROUND & OBJECTIVES: Dengue fever is an important public health problem in India. In recent years this disease has extended to rural areas also due to rapid urbanization. In Tamil Nadu, fever outbreaks were reported in two villages of Dharmapuri district during May and September 2001 with clinical symptoms suggestive of dengue fever. Epidemiological, virological and entomological investigations were carried out in these two villages to ascertain the etiology of the outbreaks. METHODS: Paired serum samples were collected from febrile patients clinically suspected to have dengue and were tested for the presence of IgM antibodies to dengue virus by MAC ELISA. Samples were also tested by Dengue Duo IgM/IgG rapid strip. Surveys of larval and adult Aedes mosquitoes were carried out before and after anti-larval and anti-adult measures were implemented. Female Ae. aegypti mosquitoes collected in Mampatti village were tested individually for the presence of dengue-2 viral antigen by indirect immunofluorescence assay (IIFA). In addition, two pools of female Ae. aegypti mosquitoes were tested for the presence of dengue viral antigen by ELISA and then subjected to Toxo-IFA system for demonstration of dengue virus. RESULTS: A total of 124 and 267 fever cases with clinical symptoms and signs suggestive of dengue were reported in Kadumuchandiram and Mampatti villages of Dharmapuri district, respectively. Serodiagnosis revealed that 13 of 31 and 14 of 52 patients tested were positive for dengue-2 virus by MAC ELISA in Kadumuchandiram and Mampatti villages respectively. Dengue Duo rapid strip test also detected 14 (of 31 tested) patients positive for dengue virus specific IgM antibodies in Kadumuchandiram village and 8 (of 12 tested) in Mampatti village. Application of temephos and fogging with pyrethrum 2 per cent extract were found to be effective against immatures and adults respectively. Both the pools of Ae. aegypti tested for the presence of dengue viral antigen were positive by ELISA and one mosquito (tested individually) was positive by IIFA. Supernatants of two pools were found to be positive for dengue-2 virus by Toxo-IFA. INTERPRETATION & CONCLUSION: Virological and serological investigations confirmed that the outbreaks of fever were due to dengue virus infection. High breeding of Ae. aegypti in the study villages, detection of dengue-2 viral antigen and isolation of dengue-2 virus in Ae. aegypti mosquitoes confirmed the etiology.