ReviewAngiogenesis in prostate cancer: its role in disease progression and possible therapeutic approaches
Introduction
Prostate cancer is the most commonly diagnosed male malignancy in the European Union and the USA. In Europe more than 100 000 men are found to have prostate cancer and 35 000 men die from the disease per year (Hamdy and Thomas, 2001, Hsing et al., 2000). As populations continue to age and the mortality from other disease processes decreases, prostate cancer is likely to achieve an even greater importance.
The detection of localized disease with digital rectal examination, serum prostate specific antigen (PSA) measurement and transrectal ultrasound guided biopsies is the most realistic opportunity for cure. In early prostate cancer there are three treatment options: radical prostatectomy, radiotherapy and watchful waiting. The study of the anatomy of the prostate, periprostatic plexus and the neurovascular bundles by Walsh has greatly facilitated the approach to radical prostatectomy (Walsh and Donker 1982). The morbidity, such as incontinence and impotence has fallen dramatically and operative mortality is low. Unfortunately, staging methods are not optimal and up to half of the men with clinically confined prostate cancer are found to have extraprostatic disease. Radiotherapy includes external beam radiation and brachytherapy. Brachytherapy has evolved from an open retropubic procedure to perineal seed implantation techniques (Holm et al., 1983). More accurate seed implantation is possible through three-dimensional planning of radiation dosage with new computer software and improved imaging techniques. In older men with a life expectancy of less than 10 years with low-grade and low-volume disease watchful waiting is a good alternative (Adolfsson et al., 1998). To date no valid randomized trial has been performed to compare these three treatment modalities (D'Amico et al., 1998). It has to be remembered that more men die with than from prostate cancer.
In 1941 Huggins and Hodges showed that prostate cancer growth is androgen-dependent and prostate tumors regress after androgen deprivation (Huggins and Hodges, 1941). Since then the ablation of testicular and/or adrenal androgens through surgical or medical castration has remained the mainstay of therapy for metastatic prostate carcinoma. Hormonal therapy provides symptomatic relief of painful metastases and although there is a potential increase in survival it is not curative and metastatic prostatic carcinoma eventually becomes androgen-independent. Furthermore about 15% of the patients will not respond to the treatment and most will relapse within 2–3 years from the initiation of treatment (Schröder, 1999).
Since conventional chemotherapeutic agents exhibit little activity against prostatic tumors alternative approaches for the treatment of advanced tumors are urgently needed (Hegarty et al., 1999). Antivascular or anti-angiogenic therapy might be a new treatment option in advanced or metastatic prostatic carcinoma (Campbell, 1997, Izawa and Dinney, 2001).
Section snippets
Angiogenesis
Angiogenesis is the formation of new blood vessels by capillary sprouting from pre-existing vessels. Folkman originally postulated the importance of angiogenesis for tumor growth and metastasis 30 years ago (Folkman, 1971). However, angiogenesis is not only essential for tumor growth but also for normal physiological processes, such as growth, fertility and wound healing (Campbell, 1997, Los and Voest, 2001, Tuxhorn et al., 2001). It is now generally accepted that tumors can grow to a diameter
Endogenous inhibitors
Several endogenous inhibitors of angiogenesis in prostate cancer have been described such as angiostatin, endostatin, PSA, thrombospondin-1 (TSP-1), interleukin 10 (IL-10), interferons (IFNs) and retinoids (Table 2).
Based on the phenomenon that removal of the primary tumor leads to rapid growth of remote metastases O'Reilly found a 38 kDa plasminogen fragment which specifically inhibited endothelial cell proliferation in mice bearing Lewis lung carcinoma. This fragment was named angiostatin (
Conclusions
Angiogenesis plays a critical role in tumorigenesis and metastasis in prostate cancer. The mechanisms underlying these changes are not fully elucidated yet. With the recent advancement in our understanding of angiogenesis numerous antiangiogenic approaches are currently investigated in prostate cancer. Because antiangiogenic treatment is cytostatic rather than cytotoxic, patients will need long-term therapy to prevent regrowth of the tumor after cessation of the treatment (Kerbel, 2001). The
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