Vascular endothelial growth factor-C and -D are involved in lymphangiogenesis in mouse unilateral ureteral obstruction.

Lymphatic remodeling in inflammation has been found in tracheal mycoplasma infection, human kidney transplant, skin inflammation, peritonitis, and corneal inflammation. Here we investigated lymphangiogenesis in fibrotic area in unilateral ureteral obstruction, a model of progressive renal fibrosis, and evaluated the roles of vascular endothelial growth factor (VEGF)-C and -D in the obstructed kidney. Compared to sham-operated mice, the number of LYVE-1-positive lymphatic vessels, the proliferation of LYVE-1-positive lymphatic endothelial cells, along with VEGF-C and -D mRNA expression were all significantly increased following ureteral obstruction. Depletion of macrophages with clodronate decreased lymphangiogenesis in the obstructed kidney. VEGF-C expression was higher in M2- than in M1-polarized macrophages from bone marrow-derived macrophages, and also increased in Raw 264.7 or renal proximal tubule cells by stimulation with TGF-ß1 or TNF-α. VEGF-D reversed the inhibitory effect of TGF-ß1 on VEGF-C-induced migration, capillary-like tube formation, and proliferation of human lymphatic endothelial cells. Additionally, the blockade of VEGF-C and VEGF-D signaling decreased obstruction-induced lymphangiogenesis. Thus, VEGF-C and VEGF-D are associated with lymphangiogenesis in the fibrotic kidney in a mouse model of ureteral obstruction.

A novel patient-derived intra-femoral xenograft model of bone metastatic prostate cancer that recapitulates mixed osteolytic and osteoblastic lesions.

UNLABELLED: Prostate cancer metastasizes to bone in the majority of patients with advanced disease leading to painfully debilitating fractures, spinal compression and rapid decline. In addition, prostate cancer bone metastases often become resistant to standard therapies including androgen deprivation, radiation and chemotherapy. There are currently few models to elucidate mechanisms of interaction between the bone microenvironment and prostate cancer. It is, thus, essential to develop new patient-derived, orthotopic models. Here we report the development and characterization of PCSD1 (Prostate Cancer San Diego 1), a novel patient-derived intra-femoral xenograft model of prostate bone metastatic cancer that recapitulates mixed osteolytic and osteoblastic lesions. METHODS: A femoral bone metastasis of prostate cancer was removed during hemiarthroplasty and transplanted into Rag2(-/-);γc(-/-) mice either intra-femorally or sub-cutaneously. Xenograft tumors that developed were analyzed for prostate cancer biomarker expression using RT-PCR and immunohistochemistry. Osteoblastic, osteolytic and mixed lesion formation was measured using micro-computed tomography (microCT). RESULTS: PCSD1 cells isolated directly from the patient formed tumors in all mice that were transplanted intra-femorally or sub-cutaneously into Rag2(-/-);γc(-/-) mice. Xenograft tumors expressed human prostate specific antigen (PSA) in RT-PCR and immunohistochemical analyses. PCSD1 tumors also expressed AR, NKX3.1, Keratins 8 and 18, and AMACR. Histologic and microCT analyses revealed that intra-femoral PCSD1 xenograft tumors formed mixed osteolytic and osteoblastic lesions. PCSD1 tumors have been serially passaged in mice as xenografts intra-femorally or sub-cutaneously as well as grown in culture. CONCLUSIONS: PCSD1 xenografts tumors were characterized as advanced, luminal epithelial prostate cancer from a bone metastasis using RT-PCR and immunohistochemical biomarker analyses. PCSD1 intra-femoral xenografts formed mixed osteoblastic/osteolytic lesions that closely resembled the bone lesions in the patient. PCSD1 is a new primary prostate cancer bone metastasis-derived xenograft model to study metastatic disease in the bone and to develop novel therapies for inhibiting prostate cancer growth in the bone-niche.

Comparison of laparoscopic radical nephrectomy and open radical nephrectomy for pathologic stage T1 and T2 renal cell carcinoma with clear cell histologic features: a multi-institutional study.

OBJECTIVES: To assess the oncologic efficacy of laparoscopic radical nephrectomy (LRN) compared with open radical nephrectomy (ORN) in patients with clear cell renal cell carcinoma (RCC). METHODS: We analyzed the data from 2561 patients who had undergone radical nephrectomy for RCC at 26 institutions in Korea from June 1998 to December 2007. The clinical data of 631 patients with clear cell RCC in the LRN group were compared with the clinical data of 924 patients in the ORN group. The patients with Stage pT3 or greater and those with lymph node or distant metastases were excluded to avoid a selection bias. To evaluate the technical adequacy and oncologic outcome, we compared the perioperative parameters and 5-year overall and disease-free survival rates. RESULTS: The operative time was significantly longer in the LRN group than in the ORN group (219 ± 77 vs 182 ± 62 minutes, P < .001), but the estimated blood loss and complication rate were significantly lower in the LRN group than in the ORN group (P < .001 and P < .001, respectively). On univariate analysis, the LRN group had 5-year overall (93.5% vs 89.8%, P = .120) and recurrence-free (94.0% vs 92.8%, P = .082) survival rates equivalent to those of the ORN group. Even after adjusting for age, sex, T stage, tumor grade, and body mass index in a Cox proportional hazards model, statistically significant differences between the 2 groups were not found for the 5-year overall (hazard ratio 1.523, P = .157) and recurrence-free (hazard ratio 0.917, P = .773) survival rates. CONCLUSIONS: Our large multi-institutional data have shown that LRN provides survival outcomes equivalent to those of ORN in patients with Stage pT1-T2 clear cell RCC.