- Hyaluronic Acid and Hyaluronidase: Promising Prognostic Indicators for Prostate Cancer
- Putting Prostate Cancer Genes on the Map
- Cholesterol and Prostate Cancer
- From Cosmetic Concerns to Quality of Life: The Journey of Laser Technology in Prostate Cancer Treatment
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, FloridaIncreased 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:
Putting Prostate Cancer Genes on the Map
Posted September 21, 2004Your 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: Mapping Hereditary Prostate Cancer Genes (HPC2, HPC3,...)
Cholesterol and Prostate Cancer
Posted June 25, 2004
Michael R. Freeman, Ph.D., Children's Hospital Boston, Boston, MassachusettsDiet 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
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, MDFollowing 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:
Magnetic Resonance Imaging of Prostate Cancer
Posted April 8, 2005
David L. Buckley, Ph.D., University of Manchester, Manchester, EnglandAdvances in the development of effective local therapies for prostate cancer have been hindered by the lack of imaging techniques that can reliably identify the location of the cancer within the prostate. Magnetic resonance imaging (MRI) is a promising candidate for imaging the prostate because it can provide sharp images in soft tissue, give multi-dimensional images, and provide unique biological information not available with other imaging modalities. However, MRI is rarely used as a first-tier imaging modality for prostate cancer because current systems are limited in their sensitivity and specificity for prostate cancer. Prostate cancer growth is accompanied by the development of a large network of immature, leaky blood vessels that may cause an increase in blood flow, blood volume, and permeability in the area of their development. Dr. David Buckley has developed techniques to measure this vascular signature of prostate cancer. He used MRI coupled with computer technology to measure blood flow, blood volume, and vasculature permeability by tracking a contrast agent, a type of MRI "dye," over time. In a study of 22 men with adenocarcinoma of the prostate, the addition of the MRI contrast agent showed that blood flow to the prostate cancer tissue exceeded that to the non-cancerous prostate tissue. Dr. Buckley was able to produce three-dimensional images of the prostates that could distinguish tumor tissue from the surrounding normal tissue with this MRI technique. The areas of the images visualized as tumors were confirmed by pathology reports. He also found that there was little difference in blood volume or vasculature permeability between normal and tumor tissue. This is consistent with pathologists' observations of the differences between tumor vasculature and normal vasculature. This MRI technique represents considerable promise in improving prostate cancer diagnosis and prognosis.
Publications:
Buckley DL, Roberts C, Parker GJM, et al. 2004. Prostate Cancer: Evaluation of vascular characteristics with dynamic contrast-enhanced T1-weighted MR imaging initial experience. Radiology 233:709-715.
Buckley DL. 2002. Uncertainty in the analysis of tracer kinetics using dynamic contrast-enhanced T1-weighted MRI. Magnetic Resonance in Medicine 47:601-606.
Link:
Abstract: A Quantitative MRI Study of Prostate Cancer Before and After Radiation Therapy
Getting to the Bones of Prostate Cancer
Posted February 11, 2005
Zelig Eshhar, Ph.D., The Weizmann Institute of Science, Rehovot, IsraelBones are a common site of spread for many cancers including prostate cancer. Prostate cancer bone metastases cause bone pain and fractures, severely reducing the quality of life for the patient. Treatment for prostate cancer bone metastases has been aimed primarily at reducing the pain and delaying the time to bone fractures through the use of hormone therapy and/or chemotherapy, radiation therapy, or bisphosphonates. Professor Zelig Eshhar and his colleagues at the Weizmann Institute of Science (Rehovot, Israel) and the Sheba Medical Center (Tel Hashomer, Israel) have shown that a common treatment for prostate cancer may help redirect immune cells to prostate cancer in the bones. The treatment uses immune cells from the patient's body that are engineered to detect specific cancer cells and have the capacity to fight and kill the invading cancer cells. Dr. Eshhar called these custom-modified cells T bodies. After developing a strategy to create these cells, he and his colleagues needed to get the T bodies to the bone metastases in the bone. Initial experiments using mice with prostate cancer growing in their leg bones and bone marrow showed that the T bodies did not appear to be able to get to the bone metastases. However, a significant drop in the tumor marker prostate-specific antigen, a reduction in the tumor load, and increased survival time were observed when prostate cancer-bearing mice were "preconditioned" using some common forms of cancer therapy such as low doses of radiation or chemotherapy drugs before T body injection. Dr. Eshhar believes that the preconditioning cancer therapy produces bone marrow disruption, causing the bone marrow to release chemical distress signals to the immune system. These signals not only warn immune cells of potential danger in the bone marrow but also help attacking immune cells pinpoint the problem area and traverse barriers that otherwise might prevent them from getting to the treatment site. This method, developed in an experimental mouse model, holds promise for bone metastases in prostate cancer and other types of disseminated cancers resistant to conventional therapy.
Publications:
Pinthus JH, Waks T, Malina V, Kaufman-Francis K, Harmelin A, Aizenberg I, Kanety H, Ramon J, Eshhar Z. 2004. Adoptive immunotherapy of prostate cancer bone lesions using redirected effector lymphocytes. J Clin Invest 114:1774-1781.
