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Hyaluronic Acid and Hyaluronidase: Promising Prognostic Indicators for Prostate Cancer
Posted November 10, 2004
Vinata B. Lokeshwar, Ph.D., University of Miami School of Medicine, Florida

Increased use of the PSA (prostate-specific antigen) test during the last decade has significantly increased the detection of localized disease, which has the potential to be cured by surgery or radiation. Even when treatment appears successful, prostate cancer recurs in many patients with localized disease, and current methods to predict prostate cancer progression are not accurate. Dr. Vinata Lokeshwar developed a test for bladder cancer based on measuring concentrations of hyaluronic acid (HA), a sugar polymer and component of the tissue matrix and fluids, and the enzyme that breaks it down, hyaluronidase (HAase). This work indicated the potential for HA/HAase as an effective tumor marker in bladder cancer. Dr. Lokeshwar's group further examined the possibility that elevated levels of HA/HAase could be a marker for prostate cancer progression based on their understanding that many tumors share similar characteristics of growth and metastasis. They compared the predictive value of HA and HAase with six other biochemical and structural markers of prostate cancer, including PSA and Gleason score. They found that measuring HA and HAase in combination was 85% accurate in predicting recurrence of prostate cancer. This was superior to any other marker. Predictive accuracy is increased when HA/HAase are combined with information about the tumor margins and extraprostatic extension. Use of these combined prognostic indicators shows great promise in improving doctors' ability to identify localized prostate cancers that are likely to progress and ensuring that these patients receive more aggressive treatment. This research was made possible with funding from an FY01 PCRP Idea Development Award.

Publications:

Ekici S, Cerwinka WH, Duncan RC, Gomez P, Civantos F, Soloway MS, Lokeshwar VB. 2004. Comparison of the prognostic potential of hyaluronic acid, hyaluronidase (HYAL-1), CD44v6 and microvessel density for prostate cancer. Int J Cancer 112: 121-129.

Lokeshwar VB, Cerwinka WH, Lokeshwar BL. HYAL1 hyaluronidase: a molecular determinant of bladder tumor growth and invasion. Cancer Res. (Accepted).

Posey JT, Soloway MS, Ekici S, et al. 2003. Evaluation of the prognostic potential of hyaluronic acid and hyaluronidase (HYAL1) for prostate cancer. Cancer Res. 63:2638-2644.

Lokeshwar VB, Schroeder GL, Carey RI, et al. 2002. Regulation of hyaluronidase activity by alternative mRNA splicing. J Biol Chem. 277:33654-33663.

Link:

Abstract: Hyaluronic Acid And Hyaluronidase In Prostate Cancer- Evaluation Of Their Therapeutic And Prognostic Potential

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Putting Prostate Cancer Genes on the Map
Posted September 21, 2004

Your father instilled in you a sense of familial pride. Summer vacations with grandma and grandpa resulted in your abiding love for baseball, picnics and jazz. Your freckles are from your great-grandmother. Ancestry defines us not only ethnically and culturally but also genetically. Family and ethnic groups, which are more similar genetically than the general population, are important resources in the hunt for genetic causes for diseases as diverse as Huntington's disease, cystic fibrosis, and breast cancer. Discovering which genes are important in the development of prostate cancer may lead to similar breakthroughs in our understanding of the causes and development of prostate cancer. The relative importance of the leading genetic variations has not been determined because studies with the general population have not been able to isolate those genes with the greatest impact on prostate cancer development. Several genetic variations identified initially in population-based studies have not demonstrated significance in prostate cancer development in subsequent studies. Dr. Isaacs and Dr. Xu are using families at greater risk for prostate cancer to identify specific regions of chromosomes and, ultimately, the genes, associated with prostate cancer development in studies funded by three awards from the Prostate Cancer Research Program. They are using microsatellite markers, small, unique sequences associated with specific locations on each of our 23 chromosomes, to rapidly screen a man's genome for locations that are similar among men with prostate cancer but differ from the "normal" population. Thus far, Dr. Isaacs and Dr. Xu have identified several potential prostate cancer-causing chromosomal regions that may be significant in prostate cancer. Analysis of a set of 36 Ashkenazi Jewish families found that family members with prostate cancer were more likely to have matching microsatellite markers on a portion of chromosome 7 than would be expected by c hance. In another study, genetic samples of 126 individuals from 33 African American families with high incidences of prostate cancer provided evidence for five prostate cancer susceptibility regions: three on chromosome 1, HPC1, PCAP, and CAPB; HPC20 on chromosome 20; and HPCX on the X chromosome. Finding the chromosomal region linked to inheriting an increased risk for prostate cancer is only the first step; the team is now trying to locate the actual cancer-causing gene(s). Once identified, these genes will be assessed for use in genetic tests to identify men who are at greater risk to develop prostate cancer than the general population.

Publications:

Brown WM, Lange EM, Chen H, et al. 2004. Hereditary prostate cancer in African American families: linkage analysis using markers that map to five candidate susceptibility loci. Br J Cancer, 90(2):510-514.

Friedrichsen DM, Stanford JL, Isaacs SD, et al. 2004. Identification of a prostate cancer susceptibility locus on chromosome 7q11-21 in Jewish families. Proc Natl Acad Sci USA, 101(7):1939-1944.

Link:

Abstract: Collection of Prostate Cancer Families and Mapping Additional Hereditary Prostate Cancer Genes (HPC2, HPC3,....)

Abstract: Mapping Hereditary Prostate Cancer Genes (HPC2, HPC3,...)

Abstract: Linkage Disequilibrium Mapping Of Hereditary Prostate Cancer Genes In The Ashkenazi Jewish Population

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Cholesterol and Prostate Cancer
Posted June 25, 2004
Michael R. Freeman, Ph.D., Children's Hospital Boston, Boston, Massachusetts

Diet is thought to play an important role in the development and pathogenesis of cancer. In studies funded through one of two fiscal year 2002 Prostate Cancer Research Program's Prostate Cancer Consortium Awards, Dr. Freeman and his associates are investigating the relationship between high levels of circulating cholesterol, which are often caused by eating foods high in saturated fat or cholesterol, and prostate cancer development and progression . The Emory University Consortium, led by Dr. Jonathan Simons of Emory University's Winship Cancer Center, involves researchers from multiple institutions working together on a variety of projects to identify new therapeutic targets and concepts for treating metastatic prostate cancer. Dr. Freeman's work in the Consortium focuses on "lipid rafts", which are portions of a cell's membrane that contain high concentrations of lipids such as cholesterol. These rafts can function as cell signaling centers allowing information to travel within the cell's environment and activate other genes and pathways in a step-by step fashion. It has long been known that prostate cancer cells accumulate cholesterol but the implications of this accrual have been unclear. Previously, Freeman and his colleagues showed that high levels of the cholesterol-rich lipid rafts help prostate cancer cells survive and multiply; survival of the cancer cells was reduced if the lipid rafts were disrupted. In his work in the Emory Consortium, Freeman is examining the relationship between circulating cholesterol and malignant prostate cancer and whether cholesterol-reducing agents such as the cholesterol-lowering "statin" drugs used for heart disease prevention can block the onset of prostate cancer or its divert its progression to malignant disease. The characterization of the components of cholesterol-rich lipid rafts found in prostate cancer cells may lead to the identification of new biomarkers for prostate cancer progression and to novel targets for therapeutic intervention.

Publications:

Zhuang L, Lin J, Lu ML, Solomon KR, and Freeman MR. 2002. Cholesterol-rich lipid rafts mediate akt-regulated survival in prostate cancer cells. Cancer Research, 62(8):2227-2231.

Freeman MR and Solomon KR. 2004. Cholesterol and prostate cancer. Journal of Cell Biochemistry, 91(1):54-69.

Link:

Abstract: A Synergy Consortium Targeting the Lethal Phenotypes of Prostate Cancer

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From Cosmetic Concerns to Quality of Life: The Journey of Laser Technology in Prostate Cancer Treatment
Posted January 26, 2004
Nathaniel M. Fried, Ph.D., Johns Hopkins School of Medicine, Baltimore, MD

Following prostate cancer surgery, many patients (5%-20%) suffer from urethral and bladder neck strictures. The scarring from the surgery leads to stenosis or a narrowing of the urethra and/or bladder neck and this, in turn, causes urinary incontinence. Traditional methods to treat the strictures such as balloon dilation, cold knife incision, electrocautery, and Holmium laser technology have met with limited success. These failures lead to a decrease in the quality of life for prostate cancer survivors. To alleviate one of the major side effects of prostate cancer surgery, Dr. Nathaniel M. Fried and colleagues at the Johns Hopkins School of Medicine in Baltimore, MD embarked on the application of a new laser technology in urology. Exploiting methodology in use for painless cosmetic wrinkle removal, Dr. Fried has shown that the Erbium:YAG laser is up to 30 times more precise than the Holmium:YAG laser for urological purposes. Wound healing studies demonstrated that the Erbium laser is capable of producing incisions and opening up the urethra with minimal thermal damage to surrounding healthy tissue, which should translate into reduced scarring and recurrence of strictures. Importantly, a major focus of the Fried laboratory has been to devise an optical fiber delivery system. By using the optical fiber system, the Erbium laser energy treatment may be delivered through an endoscope, thus promising a minimally invasive treatment of urinary incontinence. These ongoing studies may lead to hope for millions of men with prostate cancer and increase their quality of life after prostate cancer surgery.

Publications:

Fried NM, Tesfaye Z, Ong AM, Rha KH, and Hejazi P. 2003. Optimization of the Erbium:YAG laser for precise incision of ureteral and urethral tissues: In vitro and in vivo results. Lasers in Surgery and Medicine 33(2):108-114.

Chaney CA, Yang Y, Fried NM. 2004. Hybrid germanium / silica optical fibers for endoscopic delivery of Erbium:YAG laser radiation. Lasers in Surgery and Medicine 34(1):5-11.

Link:

Abstract: Erbium: YAG Laser Incision of Urethral Strictures for Treatment of Urinary Incontinence after Prostate Cancer Surgery

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