PTK6 Activation at the Membrane Regulates Epithelial–Mesenchymal Transition in Prostate Cancer

Urology news  september.06.2013

Yu Zheng1, Zebin Wang1, Wenjun Bie1, Patrick M. Brauer1, Bethany E. Perez White2, Jing Li1,

Veronique Nogueira1, Pradip Raychaudhuri1,4, Nissim Hay1,4, Debra A. Tonetti2, Virgilia Macias3,

André Kajdacsy-Balla3, and Angela L. Tyner1

Departments of ¹Biochemistry and Molecular Genetics, ²Biopharmaceutical Sciences, and ³Pathology, University of Illinois at Chicago; and ⁴Research & Development Section, Jesse Brown VA Medical Center, Chicago, Illinois  

The intracellular tyrosine kinase protein tyrosine kinase 6 (PTK6) lacks a membrane-targeting SH4 domain and localizes to the nuclei of normal prostate epithelial cells. However, PTK6 translocates from the nucleus to the cytoplasm in human prostate tumor cells. Here, we show that while PTK6 is located primarily within the cytoplasm, the pool of active PTK6 in prostate cancer cells localizes to membranes.

Ectopic expression of membrane-targeted active PTK6 promoted epithelial–mesenchymal transition in part by enhancing activation of AKT, thereby stimulating cancer cell migration and metastases in xenograft models of prostate cancer. Conversely, siRNA-mediated silencing of endogenous PTK6 promoted an epithelial phenotype and impaired tumor xenograft growth. In mice, PTEN deficiency caused endogenous active PTK6 to localize at membranes in association with decreased E-cadherin expression.

Active PTK6 was detected at membranes in some high-grade human prostate tumors, and PTK6 and E-cadherin expression levels were inversely correlated in human prostate cancers. In addition, high levels of PTK6 expression predicted poor prognosis in patients with prostate cancer. Our findings reveal novel functions for PTK6 in the pathophysiology of prostate cancer, and they define this kinase as a candidate therapeutic target.

Cancer Res; 73(17); 5426–37. ©2013 AACR. ©2013 American Association for Cancer Research 

Transition Zone Prostate Cancer: Detection and Localization with 3-T Multiparametric MR Imaging

Urology news  September.06.2013

C. M. Hoeks, T. Hambrock, D. Yakar, C. A. Hulsbergen-van de Kaa, T. Feuth, J. A. Witjes, J. J. Fütterer and J. O. Barentsz /Department of Radiology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

Radiology 2013; 266: 207-217.  

 

Figure:

Illustration demonstrates neighboring approach used for MR imaging and whole-mount step-section histopathologic correlation among regions of prostate (1–30). Region 14 at left mid PZ neighbors with regions 7, 8, 13, 19, and 20, which are also localized at consecutive ipsilateral PZs, whereas region 11 at right apex to mid TZ neighbors with regions 5, 6, 12, 17, and 18, which are localized at consecutive TZs.

PURPOSE: To retrospectively compare transition zone (TZ) cancer detection and localization accuracy of 3-T T2-weighted magnetic resonance (MR) imaging with that of multiparametric (MP) MR imaging, with radical prostatectomy specimens as the reference standard.  

MATERIALS AND METHODS: The informed consent requirement was waived by the institutional review board. Inclusion criteria were radical prostatectomy specimen TZ cancer larger than 0.5 cm3 and 3-T endorectal presurgery MP MR imaging (T2-weighted imaging, diffusion-weighted [DW] imaging apparent diffusion coefficient [ADC] maps [b < 1000 sec/mm2], and dynamic contrast material-enhanced [DCE] MR imaging).  

From 197 patients with radical prostatectomy specimens, 28 patients with TZ cancer were included. Thirty-five patients without TZ cancer were randomly selected as a control group. Four radiologists randomly scored T2-weighted and DW ADC images, T2-weighted and DCE MR images, and T2-weighted, DW ADC, and DCE MR images. TZ cancer suspicion was rated on a five-point scale in six TZ regions of interest (ROIs).

A score of 4-5 was considered a positive finding. A score of 4 or higher for any ROI containing TZ cancer was considered a positive detection result at the patient level. Generalized estimating equations were used to analyze detection and localization accuracy by using ROI-receiver operating characteristics (ROC) curve analyses for the latter. Gleason grade (GG) 4-5 and GG 2-3 cancers were analyzed separately.  

RESULTS: Detection accuracy did not differ between T2-weighted and MP MR imaging for all TZ cancers (68% vs 66%, P = .85), GG 4-5 TZ cancers (79% vs 72%-75%, P = .13), and GG 2-3 TZ cancers (66% vs 62%-65%, P = .47). MP MR imaging (area under the ROC curve, 0.70-0.77) did not improve T2-weighted imaging localization accuracy (AUC = 0.72) (P > .05).  

CONCLUSION: Use of 3-T MP MR imaging, consisting of T2-weighted imaging, DW imaging ADC maps (b values, 50, 500, and 800 sec/mm2), and DCE MR imaging may not improve TZ cancer detection and localization accuracy compared with T2-weighted imaging.

Source: The Journal of Urology/Volume 190, Issue 3 , Page 881, September 2013

Figure selection by:M.Hezarkhani MD.Urologist

Hypogonadism Linked to Anabolic Steroid Use

Renal&Urology news   September 06, 2013

Jaime Landman, MD

Prior use of anabolic androgenic steroids (AAS) is common among young men seeking treatment for symptomatic hypogonadism, according to study findings reported online in The Journal of Urology. The study also found that anabolic steroid-induced hypogonadism is the most common etiology of profound hypogonadism

Larry Lipshultz, MD, and colleagues at the Baylor College of Medicine in Houston, reviewed data on 6,033 patients seeking treatment for hypogonadism from 2005 to 2010. They identified profound hypogonadism (testosterone level of 50 ng/dL or less) in 97 patients (1.6%). The most common etiology was prior use to AAS, which the investigators identified in 42 (43%) patients. 

Dr. Lipshultz's group conducted a follow-up anonymous survey of their current hypogonadal patient population (383 patients with a mean age of 49 years) undergoing testosterone replacement therapy. 

Of these patients, 80 (20.9%) had prior AAS exposure. These men had a mean age of 40 years. Hypogonadal men younger than 50 years were more than 10 times as likely as men older than 50 to have prior AAS exposure.

“These findings suggest a necessary refocused approach in the evaluation and treatment paradigms of young hypogonadal men,” the authors concluded.

Epigenetic susceptibility factors for prostate cancer with aging

 

N. A. Damaschke¹, B. Yang¹, S. Bhusari¹, J. P. Svaren^2,3, D.F. Jarrard^1,3,4,*

2 SEP 2013/DOI: 10.1002/pros.2271

Increasing age is a significant risk factor for prostate cancer. The prostate is exposed to environmental and endogenous stress that may underlie this remarkable incidence.

 DNA methylation, genomic imprinting, and histone modifications are examples of epigenetic factors known to undergo change in the aging and cancerous prostate. In this review we examine the data linking epigenetic alterations in the prostate with aging to cancer development.

Epigenetic changes are responsible for modifying expression of oncogenes and tumor suppressors. Several of these changes may represent a field defect that predisposes to cancer development. Focal hypermethylation occurs at CpG islands in the promoters of certain genes including GSTP1, RARβ2, and RASSF1A with both age and cancer, while global hypomethylation is seen in prostate cancer and known to occur in the colon and other organs.

A loss of genomic imprinting is responsible for biallelic expression of the well-known Insulin-like Growth Factor 2 (IGF2) gene. Loss of imprinting (LOI) at IGF2 has been documented in cancer and is also known to occur in benign aging prostate tissue marking the presence of cancer. Histone modifications have the ability to dictate chromatin structure and direct gene expression.

Discovery of genetic mutation in CRPC/development of biomarkers and new targeted therapies

Urology  news   September.6.2013

Discovery of genetic The mutation occurs in the androgen-synthesizing enzyme 3βHSD1 in castration-resistant prostate cancer (CRPC), according to research published online in Cell. This mutation enables the tumor to make its own supply of androgens, a hormone that fuels the growth of the prostate cancer.

Prostate cancer requires a constant supply of androgens in order to sustain itself. The current standard of care for patients with metastatic prostate cancer is medical castration, the ability to interfere with the body's production of testosterone (androgens) using medications that disrupt the process.

Oftentimes, metastatic prostate cancer flourishes despite the lack of testosterone in the bloodstream, creating CRPC. These tumors are able to exist without the body's supply of testosterone by creating androgens within the tumor cell; however, increased androgen synthesis has not yet been attributable to any known mutations. The Cleveland Clinic discovery shows that the 3βHSD1 mutation makes this enzyme hyperactive to create androgens.

"This discovery gives us the ability to identify molecular subtypes of prostate cancer known to resist treatment. By finding the mutated enzyme, we can now investigate treatments that block it. This kind of strategy is the crux of personalized medicine which is currently used as the standard of care for some forms of lung cancer and melanoma," said Nima Sharifi, M.D., Kendrick Family Chair for Prostate Cancer Research at Cleveland Clinic, who led the research.

The 3βHSD1 mutation can occur within CRPC tumors and it can also come from germline DNA, which is inherited from maternal and paternal sources.

The research found that laboratory models of human prostate cancer fall into two categories of androgen synthesis: those that make androgens slowly and those that do so rapidly. Next, they found that the 3βHSD1 mutation explains the difference between these two categories and that DNA from some patient tumors also contains this mutation. The mutation works by opening the floodgates to androgen synthesis, essentially throwing fuel on the fire that promotes tumor progression.

In an era of personalized cancer care, there is increased focus on defining and treating cancer by its genetic abnormalities. Tumor-promoting enzyme mutations in several cancers have been identified and, subsequently, have led to the development of targeted drug therapies, improving outcomes for patients.

"The past decade has seen an explosion of molecularly targeted therapies that are matched to specific mutations in a given patient's tumor," says Dr. Sharifi. "However, no drug-targeting based on enzyme mutations exists for the standard treatment of metastatic CRPC. With this finding, we have the opportunity for matching a mutant disease-driving biomarker with a pharmacologic inhibitor."

Prostate cancer is the most common cancer in men, with nearly 240,000 new cases diagnosed each year in the United States. According to the American Cancer Society, there will be an estimated 30,000 deaths due to prostate cancer in 2013. Almost every man who dies of prostate cancer dies with castration-resistant prostate cancer.

BTNL2 Gene and prostate cancer susceptibility

Edited by:Mohammad  Hezarkhani  MD,Urologist

Board-Certified of Urology,Tehran  University ,The Member  of  Iranian  Urological  Association

Madaen Hospital  Tehran Iran

[e-mail]

www.Hezarkhani.blogfa.com  hosted in Washington DC, United States

september,6 , 2013

Background: Location : 6p21.3

Sequence : Chromosome: 6; NC_000006.11 (32362513..32374900, complement)

GeneRIFs: Gene References Into Functions

1.Results show that single nucleotide polymorphism associated with BTNL2 gene is a risk factor for predisposition pulmonary sarcoidosis

2.Upon stratification analysis in search for a synergistic effect in sarcoidosis given the extensive linkage disequilibrium between BTNL2 rs2076530_A and HLA-DRB1*08:03; the risk-bearing allele of these two loci interact negatively.

3.We unravel the role of unexplored immunologically important genes, BAT1 and BTNL2, and the haplotypes of the significantly associated SNPs therein, to understand susceptibility to the disease, leprosy and its differential severity.

4.The rs10947262 and rs7775228 variants are not associated with risk of knee osteoarthritis in European descent populations.

5.The BTNL2 A allele variant occurs with a high frequency in Danish patients with sarcoidosis

6.The presence of a BTNL2G16071A variant allele almost doubles the risk of progressing to persistent pulmonary sarcoidosis in addition to increasing the risk of developing sarcoidosis.

7.preliminary data suggest that BTNL2 polymorphism may be associated with susceptibility to Kawasaki disease and coronary artery lesions in Taiwanese children

8.This genetic study reveals a significant association between the rs3763313, rs9268494, rs9268492 SNPs in the BTNL2 gene and tuberculosis.

9.the absence of a membrane anchored BTNL2 protein may increase genetic susceptibility to sarcoidosis and familial occurrence of the disease.

10.Single-nucleotide polymorphism in the BTNL2 gene is associated with ulcerative colitis.

Rare, inherited mutations account for 5% to 10% of all prostate cancer cases. However, to date, few causative mutations have been identified.Results indicate that rare BTNL2 variants play a role in susceptibility to both familial and sporadic prostate cancer.

References:

1- Germline Missense Variants/ BTNL2 Gene/Associated with Prostate Cancer Susceptibility  

Liesel M. FitzGerald1, Akash Kumar2, Evan A. Boyle2, Yuzheng Zhang1,1, Suzanne Kolb1,

Marni Stott-Miller1, Tiffany Smith4, Danielle M. Karyadi4, Elaine A. Ostrander4Li Hsu1,

Jay Shendure2, and Janet L. Stanford1,3/Authors' Affiliations: ¹Division of Public Health Sciences, Fred Hutchinson Cancer Research Center; ²Department of Genome Sciences, School of Medicine, ³Department of Epidemiology, School of Public Health, University of Washington, Seattle, Washington; and ⁴Cancer Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland  June 23, 2013. ©2013 American Association for Cancer Research.

2- National Center for Biotechnology Information, U.S. National Library of Medicine 8600 Rockville Pike, Bethesda MD, 20894 USA/August.21.2013

New Treatment Reduces Bone Pain, Extends Survival in Prostate Cancer Patients

Science News/ Sep.6.2013

Loyola University Medical Center is among the first hospitals in Chicago to offer a new targeted radiation treatment that can reduce bone pain and the incidence of fractures -- and also extend patients' lives.The treatment, recently approved by the Food and Drug Administration, is called Xofigo®.  

A radioactive substance, radium-223, is injected into the patient. Because it is similar to calcium, radium-223 binds to the bone. Radium-223 delivers high-energy radiation over a short distance, providing a targeted treatment that is less damaging to other structures or tissues, said Robert Wagner, MD, medical director of Nuclear Medicine in Loyola's Department of Radiology. 

Radium-223 is rapidly cleared from the blood stream. Fifteen minutes after injection, about 20 percent of the injected radioactivity remains in the blood. By 24 hours, less than 1 percent of radioactivity remains. 

Xofigo is indicated for prostate cancer patients in which:

- the cancer has spread to the bones, but not to other organs

-- the cancer is not responding to hormone therapy or surgery that blocks production of testosterone, and

-- the cancer spread to the bones is causing other serious symptoms.

Radium-223 is injected into an IV line in a patient's vein, in a procedure that takes less than 5 minutes. The patient receives a series of six injections, given once every four to six weeks.

Side effects can include upset stomach, diarrhea, swelling in the hands and feet and decreased counts of red blood cells, white blood cells and platelets. 

 

Story Source:Loyola University Health System.

Figure selection:Mohammad Hezarkhani  MD,Urologist