Approximately one-half of advanced (unresectable or metastatic) melanomas harbor a mutation in the BRAF gene, with V600E being the most common mutation. Targeted therapy with BRAF and MEK inhibitors ...is associated with significant long-term treatment benefit in patients with BRAF V600-mutated melanoma. Therefore, molecular testing for BRAF mutations is a priority in determining the course of therapy. A literature search was performed using MEDLINE/PubMed and scientific congress databases using the terms 'BRAF,' 'mutation,' and 'cancer/tumor.' These results were filtered to include manuscripts that focused on diagnostic tests for determining BRAF mutation status. Numerous BRAF testing methods were identified, including DNA-based companion diagnostic tests and DNA- and protein-based laboratory-developed tests. Herein we review the characteristics of each method and highlight the strengths and weaknesses that should be considered before use and when interpreting results for each patient. Molecular profiling has shown that mutation load increases with melanoma tumor progression and that unique patterns of genetic changes and evolutionary trajectories for different melanoma subtypes can occur. Discordance in the BRAF mutational status between primary and metastatic lesions, as well as intratumoral heterogeneity, is known to occur. Additionally, the development of acquired resistance to combination BRAF and MEK inhibitor therapy is still a formidable obstacle. Therefore, tumor heterogeneity and the development of acquired resistance have important implications for molecular testing and ultimately the treatment of patients with advanced-stage melanoma. Overall, this information may help community oncologists more accurately and effectively interpret results of diagnostic tests within the context of recent data characterizing melanoma tumor progression.
Aberrant Nuclear Factor-κappaB (NF-κB) activation due to rapid IκBα turnover and high basal IκBα kinase (IKK) activity has been frequently observed in prostate cancer. Apigenin, a naturally occurring ...plant flavone, exhibits anti-proliferative, anti-inflammatory and anti-carcinogenic activities by inhibiting NF-κB pathway, through a mechanism not fully understood. We found that apigenin feeding in microgram doses (bioavailable in humans) inhibited prostate tumorigenesis in TRAMP mice by interfering with NF-κB signaling. Apigenin feeding to TRAMP mice (20 and 50 μg/mouse/day, 6 days/week for 20 weeks) exhibited significant decrease in tumor volumes of the prostate and completely abolished metastasis, which correlated with inhibition of NF-κB activation and binding to the DNA. Apigenin intake blocked phosphorylation and degradation of IκBα by inhibiting IKK activation, which in turn led to suppression of NF-κB activation. The expression of NF-κB-regulated gene products involved in proliferation (cyclin D1, and COX-2), anti-apoptosis (Bcl-2 and Bcl-xL), and angiogenesis (vascular endothelial growth factor) were also downregulated after apigenin feeding. These events correlated with the induction of apoptosis in tumor cells, as evident by increased cleaved caspase-3 labeling index in the dorsolateral prostate. Our results provide convincing evidence that apigenin inhibits IKK activation and restores the expression of IκBα, preventing it's phosphorylation in a fashion similar to that elicited by IKK and proteasomal inhibitors through suppression of NF-κB signaling pathway.
Urinary bladder specimens are frequently encountered in the daily practice of surgical pathologists. The spectrum of pathologic entities encountered in bladder specimens is extraordinarily broad, and ...in some instances, immunohistochemical stains are used to help characterize challenging bladder lesions. Cost-effective biomarker selection tailored to the differential diagnosis facilitates an accurate diagnosis. This comprehensive review is prepared as a reference guide for the use of immunohistochemistry to categorize primary and secondary bladder neoplasms and to evaluate metastatic cancers for possible bladder origin.
Those who are knowledgeable in cosmology inform us that the expansion of the universe is such that the velocity at which a distant galaxy is receding from the observer is continually increasing with ...time. We humbly paraphrase that as “The bigger the universe gets, the faster it gets bigger.” This is an interesting analogy for the expansion of knowledge in the field of renal tumor pathology over the past 30 to 50 years. It is clear that a multitude of dedicated investigators have devoted incalculable amounts of time and effort to the pursuit of knowledge about renal epithelial neoplasms. As a consequence of the contributions of numerous investigators over many decades, the most recent World Health Organization classification of renal neoplasms includes about 50 well defined and distinctive renal tumors, as well as various miscellaneous and metastatic tumors. In addition, a number of emerging or provisional new entities are under active investigation and may be included in future classifications. In this review, we will focus on a number of these tumors, tracing as accurately as we can the origins of their discovery, relating relevant additions to the overall knowledge base surrounding them, and in some instances addressing changes in nomenclature.
Forkhead box O (FoxO) transcription factors play an important role as tumor suppressor in several human malignancies. Disruption of FoxO activity due to loss of phosphatase and tensin homolog and ...activation of phosphatidylinositol-3 kinase (PI3K)/Akt are frequently observed in prostate cancer. Apigenin, a naturally occurring plant flavone, exhibits antiproliferative and anticarcinogenic activities through mechanisms, which are not fully defined. In the present study, we show that apigenin suppressed prostate tumorigenesis in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice through the PI3K/Akt/FoxO-signaling pathway. Apigenin-treated TRAMP mice (20 and 50 μg/mouse/day, 6 days/week for 20 weeks) exhibited significant decrease in tumor volumes of the prostate as well as completely abolished distant organ metastasis. Apigenin treatment resulted in significant decrease in the weight of genitourinary apparatus (P < 0.0001), dorsolateral (P < 0.0001) and ventral prostate (P < 0.028), compared with the control group. Apigenin-treated mice showed reduced phosphorylation of Akt (Ser473) and FoxO3a (Ser253), which correlated with its increased nuclear retention and decreased binding of FoxO3a with 14-3-3. These events lead to reduced proliferation as assessed by Ki-67 and cyclin D1, along with upregulation of FoxO-responsive proteins BIM and p27/Kip1. Complementing in vivo results, similar observations were noted in human prostate cancer LNCaP and PC-3 cells after apigenin treatment. Furthermore, binding of FoxO3a with p27/Kip1 was markedly increased after 10 and 20 μM apigenin treatment resulting in G0/G1-phase cell cycle arrest, which was consistent with the effects elicited by PI3K/Akt inhibitor, LY294002. These results provide convincing evidence that apigenin effectively suppressed prostate cancer progression, at least in part, by targeting the PI3K/Akt/FoxO-signaling pathway.
Enzalutamide, an antiandrogen, is approved for therapy of castration resistant prostate cancer. Clinical applications have shown that approximately 30% of patients acquire resistance after a short ...period of treatment. However, the molecular mechanisms underlying this resistance is not completely understood. To identify transcriptomic signatures associated with acquisition of drug resistance we profiled gene expression of paired enzalutamide sensitive and resistant human prostate cancer LNCaP (lymph node carcinoma of the prostate) and C4-2B cells. Overlapping genes differentially regulated in the enzalutamide resistant cells were ranked by Ingenuity Pathway Analysis and their functional validation was performed using ingenuity knowledge database followed by confirmation to correlate transcript with protein expression. Analysis revealed that genes associated with cancer stem cells, such as
(OCT4),
,
,
,
,
,
, and
were markedly upregulated in enzalutamide resistant cells. Amongst the pathways enriched in the enzalutamide-resistant cells were those associated with RUNX2, hedgehog, integrin signaling, and molecules associated with elastic fibers. Further examination of a patient cohort undergoing ADT and its comparison with no-ADT group demonstrated high expression of POU5F1 (OCT4), ALDH1, and SOX2 in ADT specimens, suggesting that they may be clinically relevant therapeutic targets. Altogether, our approach exhibits the potential of integrative transcriptomic analyses to identify critical genes and pathways of antiandrogen resistance as a promising approach for designing novel therapeutic strategies to circumvent drug resistance.
Summary Transitional cell (urothelial) carcinoma of the bladder is the second most common urologic malignancy and is one of the best understood neoplasms, with relatively well-defined pathogenetic ...pathways, natural history, and tumor biology. Conventional clinical and pathologic parameters are widely used to grade and stage tumors and to predict clinical outcome of transitional cell carcinoma; but the predictive ability of these parameters is limited, and there is a lack of indices that could allow prospective assessment of risk for individual patients. In the last decade, a wide range of candidate biomarkers representing key pathways in carcinogenesis have been reported to be clinically relevant and potentially useful as diagnostic and prognostic molecular markers, and as potential therapeutic targets. The use of molecular markers has facilitated the development of novel and more accurate diagnostic, prognostic, and therapeutic strategies. FGFR3 and TP53 mutations have been recognized as key genetic pathways in the carcinogenesis of transitional cell carcinoma. FGFR3 appears to be the most frequently mutated oncogene in transitional cell carcinoma; its mutation is strongly associated with low tumor grade, early stage, and low recurrence rate, which confer a better overall prognosis. In contrast, TP53 mutations are associated with higher tumor grade, more advanced stage, and more frequent tumor recurrences. These molecular markers offer the potential to characterize individual urothelial neoplasms more completely than is possible by histologic evaluation alone. Areas in which molecular markers may prove valuable include prediction of tumor recurrence, molecular staging of transitional cell carcinoma, detection of lymph node metastasis and circulating cancer cells, identification of therapeutic targets, and prediction of response to therapy. With accumulating molecular knowledge of transitional cell carcinoma, we are closer to the goal of bridging the gap between molecular findings and clinical outcomes. Assessment of key genetic pathways and expression profiles could ultimately establish a set of molecular markers to predict the biological nature of tumors and to establish new standards for molecular tumor grading, classification, and prognostication. The main focus of this review is to discuss clinically relevant biomarkers that might be useful in the management of transitional cell carcinoma and to provide approaches in the analysis of molecular pathways that influence the clinical course of bladder cancer.
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