Overexpressed HSF1 cancer signature genes cluster in human chromosome 8q.

BACKGROUND: HSF1 (heat shock factor 1) is a transcription factor that is found to facilitate malignant cancer development and proliferation. In cancer cells, HSF1 mediates a set of genes distinct from heat shock that contributes to malignancy. This set of genes is known as the HSF1 Cancer Signature genes or simply HSF1-CanSig genes. HSF1-CanSig genes function and operate differently than typical cancer-causing genes, yet it is involved in fundamental oncogenic processes. RESULTS: By utilizing expression data from 9241 cancer patients, we identified that human chromosome 8q21-24 is a location hotspot for the most frequently overexpressed HSF1-CanSig genes. Intriguingly, the strength of the HSF1 cancer program correlates with the number of overexpressed HSF1-CanSig genes in 8q, illuminating the essential role of HSF1 in mediating gene expression in different cancers. Chromosome 8q21-24 is found under selective pressure in preserving gene order as it exhibits strong synteny among human, mouse, rat, and bovine, although the biological significance remains unknown. Statistical modeling, hierarchical clustering, and gene ontology-based pathway analyses indicate crosstalk between HSF1-mediated responses and pre-mRNA 3' processing in cancers. CONCLUSIONS: Our results confirm the unique role of chromosome 8q mediated by the master regulator HSF1 in cancer cases. Additionally, this study highlights the connection between cellular processes triggered by HSF1 and pre-mRNA 3' processing in cancers.

Metastatic seminoma to the ureter.

We present a case report of testicular seminoma with intraluminal metastasis to the ureter causing obstruction and hydronephrosis. To our knowledge, this is the fourth case to be reported in the world literature of metastatic tumor to the ureter from a primary testicular seminoma.

Emerging genomic biomarkers for improving kidney, prostate, and bladder cancer health disparities outcomes.

BACKGROUND: Recent advances in genomic and genetic technologies have facilitated better health outcomes for urologic cancer patients. Genomic and genetic heterogeneity may contribute to differences in tumor biology and urologic cancer burden across various populations. OBJECTIVE: To examine how emerging genomic and genetic biomarkers, self-reported race, and ancestry-informative markers are associated with kidney, prostate, and bladder cancer outcomes. RESULTS: Genomic and genetic alterations found in African American kidney cancer patients included distinct somatic mutations, somatic copy number alterations, chromosomal instability, germ-line risk alleles, and germ-line genetic variants. These changes correlated with improved risk prediction, prognosis, and survival; and a predicted decrease in response to targeted therapies. SNP risk alleles and ancestry-informative markers were associated with improved risk prediction in prostate cancer patients of both African and European descent. AKT activation suggest differential response to AKT-targeted therapies in African American, Asian American, and Tunisian bladder cancer patients. Both self-reported race and genetic ancestry predicted urologic cancer risk prediction. CONCLUSION: Precision medicine approaches that integrate population-specific genomic and genetic information with other known urologic cancer-specific characteristics can improve outcomes and be leveraged to reduce cancer health disparities. Further investigations are necessary to identify novel genomic biomarkers with clinical utility.

Epidemiology, pathology, and genetics of prostate cancer among African Americans compared with other ethnicities.

Prostate cancer is the most common cancer affecting men in the Western world. In the United States, it is the second leading cause of cancer related deaths after lung and bronchus carcinoma. No definitive causes of prostate cancer (PCa) have been identified to date but, increasing age, a positive family history, and sub-Saharan African ancestry are strongly linked to its development. African American men (AAM) have the highest reported incidence rates in the United States and their mortality from the disease is markedly higher than that of European American men (EAM). Conversely, Asian American men and Pacific Islanders (API), American Indian and Alaskan Native (AI/AN) men, and Hispanic men all have lower incidence and mortality rates as compared with EAM. The reasons for these differences are unclear. However, it is clear that AAM have more advanced PCa when diagnosed. Several other reasons have been suggested and these include differences in treatments and health seeking behavior among the ethnic groups, cultural beliefs, environmental/lifestyle factors, dietary and genetic factors. In conclusion, there are multiple factors that impact prostate cancer outcome and that may be responsible for ethnic disparity. These factors are discussed in this chapter.

Primary small cell carcinoma of the upper urinary tract: A case report.

Small cell carcinoma of the urinary tract is an aggressive malignancy that comprises less than 1% of urinary bladder cancers. The renal pelvis and ureter, also lined by urothelium, are rare sites for small cell carcinoma. The diagnosis and staging of upper tract cancer are difficult due to the need for small, atraumatic instrument to access the upper tract. There are fewer than 40 reported cases of upper urinary tract small cell carcinoma. These include both pure and variant histologies. We present the management of a 72 year old male with small cell carcinoma of the upper urinary tract.

Application of Urinary Volatile Organic Compounds (VOCs) for the Diagnosis of Prostate Cancer.

BACKGROUND: Prostate cancer (PCa) screening using serum prostate-specific antigen (PSA) testing has caused unnecessary biopsies and overdiagnosis owing to its low accuracy and reliability. Therefore, there is an increased interest in identifying better PCa biomarkers. Studies showed that trained dogs can discriminate patients with PCa from unaffected men by sniffing urine. We hypothesized that urinary volatile organic compounds (VOCs) may be the source of that odor and could be used to develop urinary VOC PCa diagnosis models. PATIENTS AND METHODS: Urine samples from 55 and 53 biopsy proven PCa-positive and -negative patients respectively were initially obtained for diagnostic model development. Urinary metabolites were analyzed by gas chromatography-mass spectrometry. A PCa diagnosis model was developed and validated using innovative statistical machine-learning techniques. A second set of samples (53 PCa-positive and 22 PCa-negative patients) were used to evaluate the previously developed PCa diagnosis model. RESULTS: The analysis resulted in 254 and 282 VOCs for their significant association (P < .05) with either PCa-positive or -negative samples respectively. Regularized logistic regression analysis and the Firth method were then applied to predict PCa prevalence, resulting in a final model that contains 11 VOCs. Under cross-validation, the area under the receiver operating characteristic curve (AUC) for the final model was 0.92 (sensitivity, 0.96; specificity, 0.80). Further evaluation of the developed model using a testing cohort yielded an AUC of 0.86. As a comparison, the PSA-based diagnosis model only rendered an AUC of 0.54. CONCLUSION: The study describes the development of a urinary VOC-based model for PCa detection.

Dual targeting of HSP70 does not induce the heat shock response and synergistically reduces cell viability in muscle invasive bladder cancer.

Muscle invasive bladder cancer (MIBC) is a common malignancy and major cause of morbidity worldwide. Over the last decade mortality rates for MIBC have not decreased as compared to other cancers indicating a need for novel strategies. The molecular chaperones HSP70 and HSP90 fold and maintain the 3-dimensional structures of numerous client proteins that signal for cancer cell growth and survival. Inhibition of HSP70 or HSP90 results in client protein degradation and associated oncogenic signaling. Here we targeted HSP70 and HSP90 with small molecule inhibitors that trap or block each chaperone in a low client-affinity "open" conformation. HSP70 inhibitors, VER155008 (VER) and MAL3-101 (MAL), along with HSP90 inhibitor, STA-9090 (STA), were tested alone and in combination for their ability to reduce cell viability and alter protein levels in 4 MIBC cell lines. When combined, VER+MAL synergistically reduced cell viability in each MIBC cell line while not inducing expression of heat shock proteins (HSPs). STA+MAL also synergistically reduced cell viability in each cell line but induced expression of cytoprotective HSPs indicating the merits of targeting HSP70 with VER+MAL. Additionally, we observed that STA induced the expression of the stress-related transcription factor HSF2 while reducing levels of the co-chaperone TTI1.

HSP90 inhibitors disrupt a transient HSP90-HSF1 interaction and identify a noncanonical model of HSP90-mediated HSF1 regulation.

Heat shock factor 1 (HSF1) initiates a broad transcriptional response to proteotoxic stress while also mediating a cancer-specific transcriptional program. HSF1 is thought to be regulated by molecular chaperones, including Heat Shock Protein 90 (HSP90). HSP90 is proposed to sequester HSF1 in unstressed cells, but visualization of this interaction in vivo requires protein crosslinking. In this report, we show that HSP90 binding to HSF1 depends on HSP90 conformation and is only readily visualized for the ATP-dependent, N-domain dimerized chaperone, a conformation only rarely sampled by mammalian HSP90. We have used this mutationally fixed conformation to map HSP90 binding sites on HSF1. Further, we show that ATP-competitive, N-domain targeted HSP90 inhibitors disrupt this interaction, resulting in the increased duration of HSF1 occupancy of the hsp70 promoter and significant prolongation of both the constitutive and heat-induced HSF1 transcriptional activity. While our data do not support a role for HSP90 in sequestering HSF1 monomers to suppress HSF1 transcriptional activity, our findings do identify a noncanonical role for HSP90 in providing dynamic modulation of HSF1 activity by participating in removal of HSF1 trimers from heat shock elements in DNA, thus terminating the heat shock response.

Metastatic Mucinous Adenocarcinoma and Carcinoid Tumor Arising From a Mature Cystic Teratoma of a Horseshoe Kidney.

Concurrent primary carcinoid tumor and primary mucinous adenocarcinoma arising within a mature cystic teratoma of a horseshoe kidney is a rare event and has been reported once in the literature. We present the first case where this tumor subtype has metastasized to lymph nodes. Treatment included open partial nephrectomy, lymph node dissection, and adjuvant chemotherapy with temozolomide and capecitabine. Due to the rare combination of tumor histologies, it is unlikely that this cohort will ever be able to be adequately studied to determine a standard of care. Thus extrapolation of treatment methods of similar tumors will continue to guide treatment.

Combined inhibition of heat shock proteins 90 and 70 leads to simultaneous degradation of the oncogenic signaling proteins involved in muscle invasive bladder cancer.

Heat shock protein 90 (HSP90) plays a critical role in the survival of cancer cells including muscle invasive bladder cancer (MIBC). The addiction of tumor cells to HSP90 has promoted the development of numerous HSP90 inhibitors and their use in clinical trials. This study evaluated the role of inhibiting HSP90 using STA9090 (STA) alone or in combination with the HSP70 inhibitor VER155008 (VER) in several human MIBC cell lines. While both STA and VER inhibited MIBC cell growth and migration and promoted apoptosis, combination therapy was more effective. Therefore, the signaling pathways involved in MIBC were systematically interrogated following STA and/or VER treatments. STA and not VER reduced the expression of proteins in the p53/Rb, PI3K and SWI/SWF pathways. Interestingly, STA was not as effective as VER or combination therapy in degrading proteins involved in the histone modification pathway such as KDM6A (demethylase) and EP300 (acetyltransferase) as predicted by The Cancer Genome Atlas (TCGA) data. This data suggests that dual HSP90 and HSP70 inhibition can simultaneously disrupt the key signaling pathways in MIBC.

Effect of phytosterols on cholesterol metabolism and MAP kinase in MDA-MB-231 human breast cancer cells.

Epidemiological studies suggest that dietary phytosterols may offer protection form some types of cancer including breast cancer. In an attempt to investigate the mechanism by which phytosterols offer this protection, we investigated the effect of the two most common dietary phytosterols, beta-sitosterol and campesterol, on the mevalonate and MAP Kinase (MAPK) pathways in MDA-MB-231 cells. These pathways play a role in cell growth and apoptosis. MDA-MB-231 cell line was used in this study since it is a hormone-insensitive tumor cell line which represents the majority of advanced breast cancer cases. Cells grown in the presence of 16 microM beta-sitosterol or campesterol for 3 days exhibited a 70% and 6% reduction in cell growth, respectively, while cholesterol treatment had no effect on growth as compared to the control. Studies investigating the effect of sterol supplementation on the relative and total sterol composition of cells, showed that cells supplemented with cholesterol contained 23% more cholesterol than the control. Cells supplemented with campesterol had almost one-half the cholesterol of controls but accumulated campesterol to account for 40% of the total sterols. In the case of cells supplemented with beta-sitosterol, cells had only 25% of their sterols as cholesterol and the rest was in the form of beta-sitosterol. All sterols tested equally inhibited de novo cholesterol synthesis using 14C-acetate as substrate. beta-Sitosterol supplemented cells had reduced cholesterol synthesis when using 3H-mevalonolactone as substrate, which suggests that the inhibition in this pathway is downstream of mevalonate where processes such as isoprenylation of proteins may take place. Mevalonate supplementation to cells treated with beta-sitosterol did not completely correct the observed growth inhibition by beta-sitosterol. There was no effect of sterols on the concentrations of both low (21-26 kDa) or high (44-74 kDa) molecular weight isoprenylated proteins in these cells. On the other hand, both the quantity and activity of MAPK was elevated in the cells supplemented with beta-sitosterol. These data suggest that the down regulation of cholesterol synthesis from mevalonate and stimulation of the MAPK pathway may play roles in the inhibition of MDA-MB-231 cell growth by beta-sitosterol.

Vitamin D receptor gene polymorphisms and disease free survival after radical prostatectomy.

BACKGROUND: Vitamin D has been linked with prostate cancer risk in epidemiologic studies and has antiproliferative, prodifferentiation, and antimetastatic properties in experimental systems. Its hormonal activity is mediated by the vitamin D receptor. We investigated whether germ-line genetic variation in the vitamin D receptor impacts progression of prostate cancer after radical prostatectomy. METHODS: We analyzed BsmI and TaqI polymorphisms using archived specimens from a large series of radical prostatectomy patients at a single institution. Our series included 428 white men (WM) and 310 African-American men (AAM) who were carefully and uniformly staged and followed for 5-10 years. RESULTS: The distribution of polymorphisms varied between WM and AAM. There was little association between genotype and extent of disease at diagnosis, Gleason score, preoperative PSA, or recurrence overall. Among WM with locally advanced disease, however, the BsmI B allele protected against recurrence in models examining gene dose (P = 0.04) and dominant effects (P = 0.05). CONCLUSIONS: Overall vitamin D receptor polymorphisms did not predict pathologic features of prostate cancer but may impact on risk of recurrence among men in certain risk groups. Analysis of polymorphisms may provide clues about the mechanisms through which vitamin D exerts its inhibitory effects on prostate cancer in vivo in men.