Birt–Hogg–Dubé syndrome (BHD) is an autosomal dominant inherited disorder characterised by fibrofolliculomas, renal tumours, pulmonary cysts and pneumothorax. The pulmonary cysts and repeated episodes of pneumothorax are the clinical hallmarks for discovering families affected by the syndrome. This disorder is caused by mutations in the gene coding for folliculin (FLCN). FLCN forms a complex with FLCN-interacting protein 1 (FNIP1) and FNIP2 (also known as FNIPL), and the complex cross-talks with signalling molecules such as 5′-AMP-activated protein kinase (AMPK) and the mammalian target of rapamycin (mTOR). Heterozygous Flcn knockout mice and rats with Flcn gene mutations develop renal cysts, adenomas and/or carcinomas. These findings suggest that FLCN functions as a tumour suppressor that inhibits renal carcinogenesis. However, the mechanisms of the formation of pulmonary cysts and pneumothorax associated with heterozygous mutations in FLCN are poorly understood. Resected lung specimens from patients with BHD are often misdiagnosed by pathologists as non-specific blebs or bullae or emphysema, and patients with BHD who have pulmonary cysts and repeated pneumothorax frequently do not receive appropriate medical investigations. This review discusses the clinical and pathological features of lungs of patients with BHD, focusing on the diagnostic pathology and possible mechanisms of cyst formation.

Renal cell carcinoma (RCC) associated with Xp11.2 translocation (TFE3-RCC) has been recently defined as a distinct subset of RCC classified by characteristic morphology and clinical presentation. The Xp11 translocations involve the TFE3 transcription factor and produce chimeric TFE3 proteins retaining the basic helix–loop–helix leucine zipper structure for dimerization and DNA binding suggesting that chimeric TFE3 proteins function as oncogenic transcription factors. Diagnostic biomarkers and effective forms of therapy for advanced cases of TFE3-RCC are as yet unavailable. To facilitate the development of molecular based diagnostic tools and targeted therapies for this aggressive kidney cancer, we generated a translocation RCC mouse model, in which the PRCC-TFE3 transgene is expressed specifically in kidneys leading to the development of RCC with characteristic histology. Expression of the receptor tyrosine kinase Ret was elevated in the kidneys of the TFE3-RCC mice, and treatment with RET inhibitor, vandetanib, significantly suppressed RCC growth. Moreover, we found that Gpnmb (Glycoprotein nonmetastatic B) expression was notably elevated in the TFE3-RCC mouse kidneys as seen in human TFE3-RCC tumors, and confirmed that GPNMB is the direct transcriptional target of TFE3 fusions. While GPNMB IHC staining was positive in 9/9 cases of TFE3-RCC, Cathepsin K, a conventional marker for TFE3-RCC, was positive in only 67% of cases. These data support RET as a potential target and GPNMB as a diagnostic marker for TFE3-RCC. The TFE3-RCC mouse provides a preclinical in vivo model for the development of new biomarkers and targeted therapeutics for patients affected with this aggressive form of RCC. Implications: Key findings from studies with this preclinical mouse model of TFE3-RCC underscore the potential for RET as a therapeutic target for treatment of patients with TFE3-RCC, and suggest that GPNMB may serve as diagnostic biomarker for TFE3 fusion RCC.

Pathophysiology of placentation abnormalities in pregnancy-induced hypertension Mitsuko Furuya1, Junji Ishida2,3, Ichiro Aoki1, Akiyoshi Fukamizu2,31Department of Pathology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; 2Graduate School of Life and Environmental Sciences; 3Center for Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba 305-8577, Japan During embryogenesis and development, the fetus obtains oxygen and nutrients from the mother through placental microcirculation. The placenta is a distinctive organ that develops and differentiates per se, and that organizes fetal growth and maternal condition in the entire course of gestation. Several life-threatening diseases during pregnancy, such as pregnancy-induced hypertension (PIH) and eclampsia, are closely associated with placental dysfunction. Genetic susceptibilities and poor placentation have been investigated intensively to understand the pathophysiology of PIH. It is currently thought that â??poor placentation hypothesisâ??, in which extravillous trophoblasts fail to invade sufficiently the placental bed, explains in part maternal predisposition to this disease. Cumulative studies have suggested that hypoxic micromilieu of fetoplacental site, shear stress of uteroplacental blood flow, and aberrantly secreted proinflammatory substances into maternal circulation synergistically contribute to the progression of PIH. For example, soluble form of vascular endothelial growth factor receptor-1 (sVEGFR-1) and soluble form of CD105 are elevated in circulation of PIH mothers. However, it remains to be poorly understood the pathological events in the placenta during the last half of gestation as maternal systemic disorders get worse. For better understanding and effective therapeutic approaches to PIH, it is important to clarify pathological course of PIH-associated changes in the placenta. In this review, current understanding of placental development and the pathophysiology of PIH placenta are summarized. In addition, recent findings of vasoactive signalings in PIH and rodent PIH models are discussed.Keywords: pregnancy-induced hypertension, preeclampsia, placenta, neovascularization, intrauterine growth restriction, transgenic mice, renin â?? angiotensin-system

The placenta plays a central role in governing local circulatory system that mediates maternal condition and fetal growth. In early gestational phases, the placenta exerts properties of invasion and neovascularization for successful placentation. Extravillous invasive trophoblasts replace uterine endometrial vasculature and establish local blood pathway to obtain oxygen and nutrients from the mother. In later phases, the placenta promotes villous angiogenesis and vascular maturation that are finely controlled by angiogenic and antiangiogenic molecules. Among various molecules involved in placental neovascularization, vascular endothelial growth factor receptors (VEGFRs) and angiotensin II receptor type 1 (AT1) mediate important signaling pathways for maternal circulatory system and fetal growth. VEGFR1 and VEGFR2 are functional receptors for placental growth factor (PlGF) and VEGF, respectively, and PlGF-VEGFR1 and VEGF-VEGFR2 interactions are disturbed in many preeclamptic patients by excess amount of soluble form of VEGFR1 (also named sFlt1), a natural PlGF/VEGF antagonist. Recent studies have disclosed that excessive sFlt1 production in the placenta and aberrant AT1 signaling in the mother are closely associated with the pathology of preeclampsia and intrauterine growth restriction (IUGR). In this paper, neovascularization of the placenta and pathological events associated with disrupted balance between angiogenic and antiangiogenic signaling in preeclampsia are discussed.