Angiogenesis in prostate cancer: its role in disease progression and possible therapeutic approaches

Abstract

The interaction between cancer cells and their microenvironment is a promising area for the development of novel therapeutic anti-cancer modalities. The formation of new blood vessels, angiogenesis, is an important step in cancer progression. Angiogenesis is a complex multistep process involving close orchestration of endothelial cells, extracellular matrix, and soluble factors. Essentially every step has been found to be regulated by inducers and inhibitors. Prostate cancer has the ability to produce angiogenic factors such as metalloproteinases, vascular endothelial growth factor, fibroblast growth factor 2, transforming growth factor-β and cyclooxygenase-2. In several studies in prostate cancer an increased microvessel density is associated with poorer prognosis. On the other hand several endogenous inhibitors of angiogenesis have been described in prostate cancer e.g., angiostatin, endostatin, prostate specific antigen (PSA), thrombospondin-1, interleukin 10, interferons and retinoids. The expanding insight in the process of angiogenesis has resulted in a large number of pharmaceutical agents that have been tested in preclinical studies and are currently tested in clinical trials. These agents inhibit endothelial cell proliferation or migration and induce apoptosis. This ultimately will affect the formation of new vessels thereby inducing tumor dormancy. Because antiangiogenic treatment is cytostatic rather than cytotoxic, patients will need long-term therapy to prevent regrowth of the tumor. Prostate cancer is an ideal tumor for antiangiogenic studies because of the availability of a reliable tumor marker, PSA, the indolent clinical course of this cancer and the low rate of proliferation even in metastatic sites. Furthermore, clinical studies showed limited side effects, which is advantageous in this elderly patient group. Whether the ultimate antiangiogenic treatment is effective as a single agent or in combination with radiation therapy, chemotherapy or immunotherapy remains to be determined.

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).