Prostate cancer: are new prognostic markers on the horizon? - Nature

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horizon? M Lijovic1, ME Fabiani1, J Bader1 & AG Frauman1*. 1Molecular Immunology Laboratory, Clinical Pharmacology and Therapeutics Unit,. Department of ...
Prostate Cancer and Prostatic Diseases (2000) 3, 62±65 ß 2000 Macmillan Publishers Ltd All rights reserved 1365±7852/00 $15.00

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Prostate cancer: are new prognostic markers on the horizon? M Lijovic1, ME Fabiani1, J Bader1 & AG Frauman1* 1 Molecular Immunology Laboratory, Clinical Pharmacology and Therapeutics Unit, Department of Medicine, University of Melbourne, Austin and Repatriation Medical Centre, Heidelberg, Victoria 3084, Australia

Current diagnostic methods in prostate cancer are lacking in their ability to predict individual patient outcome which highlights the need for more sensitive prognostic markers. Biological markers are seen as attractive and relevant candidates in current efforts to improve prognostic methods. Since metastasis is the most important component of cancer progression and mortality, markers which are able to predict the likely acquisition of the metastatic phenotype, before the onset of metastases, would be extremely useful clinically. This review outlines various metastasis suppressor genes and metastasis promoters which might have potential prognostic use in prostate cancer. Prostate Cancer and Prostatic Diseases (2000) 3, 62±65.

Keywords: prostate cancer; prostate; metastasis; neoplasia; metastasis suppressor genes; prognostic markers

Introduction Prostate cancer (CaP) is a leading cause of morbidity and mortality in males, accounting for  30% of all new cases of cancer and  14% of cancer deaths.1 Projected ®gures do not suggest a reduced mortality rate in the near future. Although continual advances are being made in current diagnostic and therapeutic techniques, metastasis is still the main cause of death in CaP patients. Furthermore, the possible wide range of clinical manifestations of CaP has hindered efforts to establish the best possible treatment for this somewhat unpredictable disease. As such, the important issues in the management of CaP are determination of risk to the patient and selection of an appropriate treatment strategy.

*Correspondence: AG Frauman, Molecular Immunology Laboratory, Clinical Pharmacology and Therapeutics Unit, Department of Medicine, University of Melbourne, Austin and Repatriation Medical Centre, Heidelberg, Victoria 3084, Australia. E-mail: [email protected] Received 21 February 2000; revised 4 May 2000; accepted 18 May 2000

Current prognostic markers in prostate cancer The need to pursue a diagnosis of CaP is based on symptoms and clinical stage, abnormalities found during digital rectal examination (DRE), elevated serum prostate-speci®c antigen (PSA) levels, ultrasonographyguided biopsy and histological grade of tumour. Histological grade is the strongest prognostic factor in CaP, with the Gleason score being the most commonly used histological grading system for CaP. The grade determined from prostatic biopsy specimens, however, may differ from that found in surgical specimens in as many as 50% of cases.2 ± 4 Another disadvantage using this system of grading is that moderately differentiated CaPs are the most common grouping observed, yet they are the most unpredictable in terms of long-term risk of metastatic disease.5 Pathological stage and tumour extent are other prognosticators currently in use, although they are equally as unreliable as histological grade in terms of prediction of likely outcome.6 Since the predominate form of PSA in the serum of patients with CaP is a PSA/ protease inhibitor complex, free and total PSA levels may be potential markers for cancer staging and aggressiveness.7 Using percentage free PSA has been reported to enhance the speci®city of PSA testing in distinguishing

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between benign and malignant disease.8 The rate of change of PSA with time (PSA velocity) may be the most notable indicator of malignant or premalignant change in the prostate. Like free PSA levels, it can be used to distinguish between patients who have never developed cancer, have benign prostatic hyperplasia and those who have had both localized and metastatic disease.9 ± 11 However, some studies have shown that changes of greater than 30% in PSA levels over periods of less than 1 y are common, thus potentially limiting the clinical utility of PSA velocity.12 One concern in contemporary studies is that DRE, PSA and ultrasonography-guided biopsy detection strategies have yet to be proven to reduce CaP mortality and may be picking up a large number of clinically insigni®cant cancers. Furthermore, many patients are being diagnosed with and treated for slowly growing tumours that may be unlikely to affect longevity. Therefore it is possible that many men are being subjected to unnecessary treatmentrelated morbidity. Thus, one of the major clinical challenges in the management of CaP is selection of the appropriate treatment. Improved prediction of metastatic behaviour and consequent optimization of treatment (surgery, radiotherapy or anti-androgen therapy) in patients at highest risk of metastatic disease before onset of metastases, whilst not yet achievable, would clearly represent a major advance. For example, the Prostate Cancer Intervention Versus Observation Trial (PIVOT) is an ongoing study which aims to determine whether radical prostatectomy or expectant management is the most appropriate therapeutic strategy for localized CaP.13,14 Ultimately, however, better understanding of the molecular biology of CaP development and metastasis should provide the basis for improving prognostic methods, as well as lead to the design of more speci®c therapeutic strategies.

Potential future prognostic markers in prostate cancer Current methods for predicting individual patient outcome are still not entirely reliable for optimizing CaP management. Thus, there is a pressing need to ®nd more speci®c and biologically relevant prognostic tumour markers which are detectable at the onset and early stages of disease. Oncogenes such as c-myc, c-erb-B2 and bcl-2 are potential candidate markers, as are various tumour suppressor genes such as p27(Kip1), pp32r1/2 and PTEN, following ®ndings which implicate their involvement in the control of development and progression of CaP.6,15 ± 23 Several metastasis suppressor, or anti-invasion genes are also implicated in the progression of CaP. As metastases are the main cause of death in CaP, prognostic markers for metastatic behaviour would be extremely useful clinically. Speci®cally, such prognostic factors might allow for the discernment of patients who are at highest risk of developing metastases and enable the choice of treatment(s) appropriate for CaPs likely to follow a particular pathological pathway. Compared to the vast knowledge already acquired concerning the relationship between oncogenes and tumour suppressor genes in CaP, the

area of metastasis suppressor genes (MSGs) in CaP is relatively new. The existence of MSGs was ®rst suggested when it was noticed that fusion of normal cells with metastatic tumour cells gave rise to hybrid cells which exhibited a tumorigenic, though non-metastatic, phenotype.24 ± 27 Studies on the role of MSGs (KAI1, E-cadherin and CD44) and metastasis promoters (nm23 and thymosin b15) on CaP progression are promising and are reviewed below. Findings of markers with potential prognostic value in the prostate may also potentially be translated to other cancers. This already appears to be the case for KAI1, which has been suggested to be a useful prognostic indicator in non-small cell lung carcinoma28 and pancreatic cancers.29 Decreased expression of the KAI1 gene, which encodes a transmembrane glycoprotein involved in cell ± cell and cell ± extracellular matrix interactions, has been found to increase the metastatic potential of CaP. For example, metastases are suppressed in immunode®cient mice inoculated with KAI1-transfected rat prostate cancer cells.30 KAI1 protein, found in the glandular epithelial cells from normal and hyperplastic prostate tissues, has been found to be reduced in more than 70% of primary (untreated) prostate cancers.31 Studies from our own laboratory have also demonstrated that the expression of KAI1 mRNA is reduced in advanced primary prostate cancers32 and is elevated in low-grade primary prostate cancers, suggesting that KAI1 might impart restraint on early primary cancers and suppress future metastatic behaviour. Our laboratory is therefore currently exploring whether it is possible to predict the development of subsequent metastatic behaviour of these primary tumours on the basis of initial KAI1 levels. Reduced or absent expression of E-cadherin, an adhesion molecule, has been found in 30 ± 50% of clinically localized CaPs and up to 70% of E-cadherin alterations are found in tumours that have or are highly likely to metastasize.33,34 The role of E-cadherin loss in tumour progression has also been substantiated in transgenic mouse models of CaP in which the absence of E-cadherin is linked to acquisition of the metastatic phenotype,35 and studies of CaP tissues reveal a strong correlation between decreased E-cadherin staining and increased histological grade,33,36,37 advanced clinical stage33,36,37 and presence of metastasis at diagnosis.37,38 Although normal E-cadherin expression has also been found in some CaP metastases,33 clinically it has been found that aberrant Ecadherin expression is a powerful indicator of adverse patient outcome.36 ± 38 However, it may be possible that Ecadherin is only transiently downregulated in order to promote metastasis.39 It has been proposed that the CD44 gene, involved in lymphocyte homing and activation and matrix adhesion functions, plays a major role in metastasis in various tumour types. Reintroduction of CD44 into the AT3.1 metastatic CaP cell line, in which CD44 expression is normally downregulated, suppresses the metastatic ability of these cells by more than 60%.40 It has been observed that 60% of primary CaPs express strong or moderate levels of CD44, while detectable CD44 expression was present in only 14% of lymph node metastases.41 The correlation between downregulation of CD44 and high tumour-grade, aneuploidy and distant metastasis42 sug-

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gests that decreased CD44 expression might be involved in the progression of CaP to a metastatic state. With regard to the nm23 gene family, involved in microtubule assembly and signal transduction, attention has shifted from nm23-H2 to nm23-H1. Decreased nm23H2 expression was initially thought to be associated with increased stage of CaP,43 although this ®nding could not be replicated.44 In clinically signi®cant CaP it has been found that nm23-H1 mRNA levels were more than 10-fold higher than levels found in latent CaP or normal prostates, which increased with tumour grade.45,46 Strong nm23-H1 immunostaining is also frequently found in malignant cells of localized CaPs and metastatic sites of CaP.47,48 Although encouraging, further studies of the contribution of nm23 regulation in loss of metastasis suppression in CaP are needed. Also of interest is the recent description that thymosin b-15, a cytoskeletal protein which stimulates cell motility, is upregulated in more advanced (malignant) CaPs compared to low grade tumours and correlates well with Gleason grade.49

Conclusions This growing body of evidence suggests that at least several levels of control of CaP growth and motility may be critical in primary and metastatic cancer development and may allow more accurate prediction of those patients most `at risk' of developing more aggressive forms of CaP and metastases. The fact that potential metastatic cancer cells are potentially more motile and capable of `wandering' is important to bear in mind given that this is a crucial step in the metastatic process. Thus, determination of appropriate markers of metastatic behaviours are likely to have important clinical applications. Currently, KAI1 and E-cadherin appear to be the most signi®cant candidates in this setting. What is lacking is how these factors interrelate with regard to clinical staging and outcomes in the disease process of CaP. Therefore, there is a need to evaluate the utility of measurement of these genes or gene products in concert within biopsy or surgical tissues in order to test any associations and interactions with individual patient outcomes. Such information may ultimately lead to new diagnostic and prognostic tools that are more sensitive than those currently available and will hopefully bring us closer to more rationalized and tailored therapeutics of this common malignancy.

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