RESUMO
Prostate adenocarcinoma (CaP) patients are classified into low-, intermediate-, and high-risk groups that reflect relative survival categories. While there are accepted treatment regimens for low- and high-risk patients, intermediate-risk patients pose a clinical dilemma, as treatment outcomes are highly variable for these individuals. A better understanding of the factors that regulate the progression of CaP is required to delineate risk. For example, aberrant activation of the Hedgehog (Hh) pathway is implicated in CaP progression. Here, we identify the serine protease inhibitor protease nexin 1 (PN1) as a negative regulator of Hh signaling in prostate. Using human CaP cell lines and a mouse xenograft model of CaP, we demonstrate that PN1 regulates Hh signaling by decreasing protein levels of the Hh ligand Sonic (SHH) and its downstream effectors. Furthermore, we show that SHH expression enhanced tumor growth while overexpression of PN1 inhibited tumor growth and angiogenesis in mice. Finally, using comparative genome hybridization, we found that genetic alterations in Hh pathway genes correlated with worse clinical outcomes in intermediate-risk CaP patients, indicating the importance of this pathway in CaP.
Assuntos
Adenocarcinoma/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteínas Hedgehog/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias da Próstata/metabolismo , Serpina E2/biossíntese , Transdução de Sinais , Adenocarcinoma/genética , Adenocarcinoma/patologia , Animais , Linhagem Celular Tumoral , Proteínas Hedgehog/genética , Humanos , Masculino , Camundongos , Camundongos Knockout , Proteínas de Neoplasias/genética , Transplante de Neoplasias , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Serpina E2/genética , Transplante HeterólogoRESUMO
PURPOSE: The purpose of this study was to assess the efficacy of a 2×2 Gy (total dose, 4 Gy) palliative radiation therapy (RT) regimen for treating patients with indolent non-Hodgkin lymphoma (NHL) in terms of response rate, response duration, and symptom relief. METHODS AND MATERIALS: A retrospective chart review was conducted. Between 2003 and 2007, 54 patients with NHL were treated to 85 anatomical sites with a 2×2 Gy palliative regimen. Local response was assessed by clinical and/or radiographic data. Symptoms before and after treatment for each site treated were obtained from clinical notes in patient medical records. Median follow-up time was 1.3 years. RESULTS: For the 54 patients, the median age at time of treatment was 71.1 years old, and 57% of them were male. Of the 85 disease sites treated, 56% of sites had indolent histology, 28% of sites were diagnosed with chronic lymphocytic leukemia (CLL), 13% of sites had aggressive histology, and 2% of sites were shown to have other histology. Overall response rate (ORR) was 81% (49% complete response [CR], 32% partial response [PR]). The 2-year rate for freedom from local progression was 50% (95% CI, 37%-61%). The ORR for follicular lymphoma, Mucosa associated lymphoid tissue (MALT), and marginal zone lymphoma (MZL) histology was 88%, compared with a 59% rate for CLL histology (p=0.005). While the ORR was similar for tumors of different sizes, the CR rate for patients with tumors<5 cm tended to be higher than those with tumors>10 cm (CR rate of 57% vs. 27%, respectively; p=0.06). For the 48 sites with clearly documented symptoms at pretreatment, 92% of sites improved after low-dose RT. CONCLUSIONS: Short-course low-dose palliative radiotherapy (2×2 Gy) is an effective treatment that results in high response rates for indolent non-Hodgkin lymphoma. This treatment regimen provides effective symptomatic relief for tumor bulk of all sizes.
