Development Of Cystic Lesions Research Articles

Inactivation of Tsc2 in Abcg2 lineage-derived cells drives the appearance of polycystic lesions and fibrosis in the adult kidney.

Tuberous sclerosis complex 2 (TSC2), or tuberin, is a pivotal regulator of the mechanistic target of rapamycin signaling pathway that controls cell survival, proliferation, growth, and migration. Loss of Tsc2 function manifests in organ-specific consequences, the mechanisms of which remain incompletely understood. Recent single cell analysis of the kidney has identified ATP-binding cassette G2 (Abcg2) expression in renal proximal tubules of adult mice as well as a in a novel cell population. The impact in adult kidney of Tsc2 knockdown in the Abcg2-expressing lineage has not been evaluated. We engineered an inducible system in which expression of truncated Tsc2, lacking exons 36-37 with an intact 3' region and polycystin 1, is driven by Abcg2. Here, we demonstrate that selective expression of Tsc2fl36-37 in the Abcg2pos lineage drives recombination in proximal tubule epithelial and rare perivascular mesenchymal cells, which results in progressive proximal tubule injury, impaired kidney function, formation of cystic lesions, and fibrosis in adult mice. These data illustrate the critical importance of Tsc2 function in the Abcg2-expressing proximal tubule epithelium and mesenchyme during the development of cystic lesions and remodeling of kidney parenchyma.

Clinical-relevant model of intraductal papillary mucinous neoplasm induced by ARID1A loss.

e14696 Background: Intraductal papillary mucinous neoplasm (IPMN) constitutes a precursor lesion for malignancy of pancreas. Genes encoding subunits of SWI/SNF chromatin-remodeling complexes like ARID1A are collectively mutated in a significant proportion of patients with pancreatic neoplasm. In the present study, we characterize the role of ARID1A in pancreatic tumorigenesis using genetic engineering mouse models. Methods: Various mouse strains were interbred to obtain pancreas-specific Arid1aflox, KrasLSL-G12D/+; Arid1aflox, KrasLSL-G12D/+; Tgfbr2flox; Arid1aflox, and various littermate control animals. Tissue microarrays were used to determine the expression of ARID1A in human pancreatic ductal adenocarcinoma and IPMN. Results: Arid1a loss in pancreas of mice incurred pancreatic duct dilation and development of cystic lesions. Concomitant Kras mutation and Arid1a inactivation accelerated formation of cystic neoplasm resembling human IPMN. These lesions were reminiscent of specific subtype of IPMN given their morphology and expression pattern of mucin proteins. Histological examination further revealed the step-wise progression of these neoplasm from low-grade to high-grade dysplasia and even invasive carcinoma. TGFBR2 deletion promoted the malignant transformation of IPMN to invasive carcinoma in the background of Kras and Arid1a alterations. Analysis of human tissues consistently showed negative or low expression of ARID1A in over half of IPMN patients. Moreover, patients with pancreatic adenocarcinoma also exhibited downregulated ARID1A expression, and reduced expression correlated with worse prognosis. Conclusions: We have established a preclinical mouse model of pancreatic cystic tumor closely resembling human IPMN. This is helpful for the further understanding of biology of IPMN and highlight therapeutic niches for patient tailored treatment in those with altered SWI/SNF function.

Are Liver Cystic Lesions after Islet Transplantation Caused by Streptozotocine?

Introduction: Pancreatic islets (PI) transplanted (Tx) into the portal vein cause a permanent exposure of surrounding liver tissue to insulin in high concentration. There were published several papers pronouncing the hypothesis of a direct triggering effect of Tx PI on a development of focal morphological changes in liver tissue (tumors, cysts). At the same time, streptozotocine (STZ) was supposed to play a minor but not negligible role in this phenomenon. Methods: Syngeneic pancreatic islets were transplanted into the healthy or diabetic (50mg/kg STZ) Brown Norway rats. Group A (n=5)-healthy, Tx of 450 PI into the portal vein; Group B (n=17)-STZ diabetes, Tx of 450 PI into the portal vein; Group C (n=8)-STZ diabetes, Tx of 100 PI under the left kidney capsule; Group D (n=7)-STZ diabetes, human insulin pellet s.c. (changed each 6th week); All recipients were monitored for 10 months including MRI of liver. At the end of study each liver was examined by histology. The ultrastructure of liver was examined by electron microscopy (TEM) 3 hours after injection of STZ. Results: Tx of PI in suboptimal number normalized fasting blood glucose levels but did not normalize glucose assimilation during IVGTT in all diabetic animals. While liver of Group A recipients remained intact, in animals of Groups B and C multiple voluminous cystic complexes with cholangiocyte cubic epithelium lining were detected after 10 months irrespective of Tx site. In animals of Group D, blood glucose levels were nearly normalized six months after STZ injection and there was no need to replace pellets later on. There were simple, individual cystic lesions within liver in this group after 10 months. There were not any typical lesions in TEM examined samples. Conclusions: The injection of STZ and subsequent Tx of PI can cause cholagiogenic cystic lesions development in rats. The therapy by human insulin did not stimulate the development of cystic lesions by the equal efficiency. STZ itself cannot cause the cystic transformation of BN rat liver. Disclosure L. Kosinová: None. A. Patikova: None. E. Sticova: None. A. Vojtíšková: None. L. Bartonova: None. M. Cahova: None. J. Kriz: None.

Cystic brain metastasis is associated with poor prognosis in patients with advanced breast cancer

PurposeBrain metastasis (BM) with a cystic component from breast cancer is rare and largely uncharacterized. The purpose of this study was to identify the characteristics of cystic BM in a large cohort of breast cancer patients.ResultsA total of 35 eligible patients with cystic BM and 255 patients with solid BM were analyzed. Three factors were significantly associated with an increased probability of developing cystic lesions: age at diagnosis ≤ 40 years, age at BM ≤ 45 years, and poor histological grade (p < 0.05). Patients with cystic metastasis were also characterized by a larger metastasis volume, a shorter progression-free survival (PFS) following their first treatment for BM, and poor overall survival after BM (p < 0.05). Multivariate analysis further demonstrated that local control of cystic BM was only potentially achieved for HER2-negative primary tumors (p = 0.084).MethodsBreast cancer patients with parenchymal BM were reviewed from consecutive cases treated at our institution. Cystic BM was defined when the volume of a cystic lesion was greater than 50% of the aggregated volume of all lesions present. Clinicopathologic and radiographic variables were correlated with development of cystic lesions and with prognosis of cystic BM.ConclusionsThis study shows that cystic BM from breast cancer, a special morphological type of BM, had worse prognosis than the more commonly observed solid BM. Younger age and low tumor grade were associated with the development of cystic lesions. Further comprehensive research and management of cystic BM are warranted to improve its poor prognosis.

Combined deletion of Vhl, Trp53 and Kif3a causes cystic and neoplastic renal lesions.

The von Hippel-Lindau (VHL) tumour suppressor gene is bi-allelically inactivated in the majority of cases of clear cell renal cell carcinoma (ccRCC); however, Vhl knockout mouse models do not recapitulate human ccRCC, implying that additional mutations are required for tumour formation. Mutational inactivation of VHL sensitises renal epithelial cells to lose the primary cilium in response to other mutations or extracellular stimuli. Loss of cilia is believed to represent a second hit in VHL mutant cells that causes the development of cystic lesions that, in some cases, can progress to ccRCC. Supporting this idea, genetic ablation of the primary cilium by deletion of the kinesin family member 3A (Kif3a) gene cooperates with loss of Vhl to accelerate cyst formation in mouse kidneys. Additionally, aged Vhl/Trp53 double-mutant mice develop renal cysts and tumours at a relatively low incidence, suggesting that there is a genetic cooperation between VHL and TP53 mutation in the development of ccRCC. Here we generated renal epithelium-specific Kif3a/Trp53 and Vhl/Kif3a/Trp53 mutant mice to investigate whether primary cilium deletion would accelerate the development of cystic precursor lesions or cause their progression to ccRCC. Longitudinal microcomputed tomography (μCT) imaging and histopathological analyses revealed an increased rate of cyst formation, increased proportion of cysts with proliferating cells, higher frequency of atypical cysts as well as the development of neoplasms in Vhl/Kif3a/Trp53 mutant kidneys compared to Kif3a/Trp53 or Vhl/Kif3a mutant kidneys. These findings demonstrate that primary cilium loss, in addition to Vhl and Trp53 losses, promotes the transition towards malignancy and provide further evidence that the primary cilium functions as a tumour suppressor organelle in the kidney. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Tumor Suppressor VHL Functions in the Control of Mitotic Fidelity

The von Hippel-Lindau (VHL) tumor suppressor protein pVHL is commonly mutated in clear cell renal cell carcinoma (ccRCC) and has been implicated in the control of multiple cellular processes that might be linked to tumor suppression, including promoting proper spindle orientation and chromosomal stability. However, it is unclear whether pVHL exerts these mitotic regulatory functions in vivo as well. Here, we applied ischemic kidney injury to stimulate cell division in otherwise quiescent mouse adult kidneys. We show that in the short term (5.5 days after surgery), Vhl-deficient kidney cells demonstrate both spindle misorientation and aneuploidy. The spindle misorientation phenotype encompassed changes in directed cell division, which may manifest in the development of cystic lesions, whereas the aneuploidy phenotype involved the occurrence of lagging chromosomes but not chromosome bridges, indicative of mitotic checkpoint impairment. Intriguingly, in the long term (4 months after the ischemic insult), Vhl-deficient kidneys displayed a heterogeneous pattern of ccRCC precursor lesions, including cysts, clear cell-type cells, and dysplasia. Together, these data provide direct evidence for a key role of pVHL in mediating oriented cell division and faithful mitotic checkpoint function in the renal epithelium, emphasizing the importance of pVHL as a controller of mitotic fidelity in vivo.

Cystic Changes in Gastric Glands After Gastric Surgery and in the Intact Stomach

Cystic changes of gastric mucosal glands have been described mainly after gastric operations, and like intestinal metaplasia and dysplasia, they may represent a premalignant condition. Their association with gastritis raises the possibility of their being secondary to the inflammatory process. Enterogastric reflux of duodenal contents, local chronic ischemia, and inflammatory reaction as a result of gastric surgery and suture at gastroenterostomy have been considered responsible for this lesion. In 18 of 157 consecutive patients (11.5%) who underwent endoscopic gastric biopsy within a year we found cystic changes of gastric mucosal glands. Cystic changes were present in 43% of 30 patients after gastric operation for duodenal ulcer disease, within an average of 8.4 years in contrast to only 4% of patients with an intact stomach. This change is statistically significant (Z = 1.97, (p less than 0.05) and suggests that there is a cause-and-effect link between the operation and the development of cystic lesions. In three patients we traced the original operative specimen, and in none did we find cystic changes. All the cases were associated with chronic gastritis; mild dysplasia was found in four (22%). The cystic glands were shown (by alcian blue-periodic acid-schiff staining) to secrete neutral mucin like normal gastric glands, and unlike dysplastic glands or intestinal metaplasia where acid mucin is characteristic. Thus, our findings suggest an inflammatory cause for the cystic glandular change (reactive, hyperplastic change of glands), and suggest that it is probably not a preneoplastic state.