JunB promotes cell invasion and angiogenesis in VHL-defective renal cell carcinoma.

Inactivation of the von Hippel-Lindau (VHL) tumor-suppressor gene causes both hereditary and sporadic clear-cell renal-cell carcinoma (ccRCC). Although the best-characterized function of the VHL protein (pVHL) is regulation of hypoxia-inducible factor-α (HIFα), pVHL also controls the development of pheochromocytoma through HIF-independent pathways by regulating JunB. However, it is largely unknown how these pathways contribute to the development and progression of ccRCC. In the present study, we confirmed that JunB was upregulated in VHL-defective ccRCC specimens by immunostaining. Short-hairpin RNA (shRNA)-mediated knockdown of JunB in 786-O and A498 VHL null ccRCC cells suppressed their invasiveness. In addition, JunB knockdown significantly repressed tumor growth and microvessel density in xenograft tumor assays. Conversely, forced expression of wild-type, but not dimerization-defective, JunB in a VHL-restored 786-O subclone promoted invasion in vitro and tumor growth and vessel formation in vivo. Quantitative PCR array analysis revealed that JunB regulated multiple genes relating to tumor invasion and angiogenesis such as matrix metalloproteinase-2 (MMP-2), MMP-9 and chemokine (C-C motif) ligand-2 (CCL2) in 786-O cells. JunB knockdown in these cells reduced the proteolytic activity of both MMPs in gelatin zymography and the amount of CCL2 in the culture supernatant. Moreover, shRNA-mediated knockdown of MMP-2 or inhibition of CCL2 activity with a neutralizing antibody repressed xenograft tumor growth and angiogenesis. Collectively, these results suggest that JunB promotes tumor invasiveness and enhances angiogenesis in VHL-defective ccRCCs.

Mechanisms of adverse effects of anti-VEGF therapy for cancer.

Advances in understanding the role of vascular endothelial growth factor (VEGF) in normal physiology are giving insight into the basis of adverse effects attributed to the use of VEGF inhibitors in clinical oncology. These effects are typically downstream consequences of suppression of cellular signalling pathways important in the regulation and maintenance of the microvasculature. Downregulation of these pathways in normal organs can lead to vascular disturbances and even regression of blood vessels, which could be intensified by concurrent pathological conditions. These changes are generally manageable and pose less risk than the tumours being treated, but they highlight the properties shared by tumour vessels and the vasculature of normal organs.

Health-related quality-of-life after external beam radiation therapy for localized prostate cancer: intensity-modulated radiation therapy versus conformal radiation therapy.

We compared health-related quality-of-life (HRQL) after intensity-modulated radiotherapy (IMRT) with statuses obtained after old and new protocols of three-dimensional conformal radiation therapy (3DCRT) for localized prostate cancer. We measured the general and disease specific HRQL using the MOS 36-Item Health Survey (SF-36), and the University of California, Los Angeles Prostate Cancer Index (UCLA PCI), respectively. IMRT resulted in similar profiles of general and disease-specific HRQL to two other methods within the first year after treatment. Moreover, IMRT gave rise to comparable urinary, intestinal and sexual side effects despite the high dose of radiation applied.

Failure of ureteric bud invasion: a new model of renal agenesis in mice.

FUBI (failure of ureteric bud invasion) is a highly inbred strain of mouse with a high spontaneous incidence of uni- or bilateral renal agenesis (60%). Bilateral renal agenesis is lethal within 2 days after birth. The primary defect of FUBI is failure of the ureteric bud to penetrate into the metanephric mesenchyme at around embryonic day 11, resulting in apoptosis of metanephric cells and leading to renal agenesis on the affected side. The metanephros seemed to be normal because co-culturing of the FUBI metanephros with homologous spinal cord induced differentiation of the rudiment, but co-culturing with the homologous ureteric bud frequently did not. Genetic analysis revealed that more than two genes were involved in this malformation and we mapped one of the modifier loci, fubi1, on chromosome 2, at approximately 65 cM from the centromere. In this region, there are two possible candidate genes, Wilms' tumor 1 and formin, that play important roles in kidney development. Some of formin mutants shared a similar phenotype with FUBI; however, there was no difference in the expression of formin in embryonic kidneys between FUBI and control NFS/N mice. Studies of fubi1 congenic mice indicated that interaction of two or more loci is essential for the FUBI phenotype.

[Neoadjuvant CYVADIC (cyclophosphamide, vincristine, adriamycin and dacarbazine) therapy for retroperitoneal leiomyosarcoma: a case report].

Retroperitoneal leiomyosarcoma is often too large to be completely removed. We report a 67-year-old woman successfully treated with neoadjuvant CYVADIC (cyclosphosphamide, vincristine, adriamycin and dacarbazine). The tumor was removed with the right kidney and ureter and a part of the vena cava after 2 courses of CYVADIC. The tumor recurred at the duodenum 7 years later and was completely removed following neoadjuvant CYVADIC. Neoadjuvant chemotherapy could be helpful for the complete resection of advanced leiomyosarcoma.