Integrins in Prostate Cancer Invasion and Metastasis

Paulynn Chin Suyin, Joanne Louise Dickinson and Adele Frances Holloway

Additional information is available at the end of the chapter http://dx.doi.org/10.5772/53482

1. Introduction

Prostate cancer is the most commonly diagnosed cancer in men and is the second leading cause of cancer deaths in men after non-melanoma skin cancer. According to the United States National Cancer Institute, it was estimated that almost 241 740 men would be diagnosed with prostate cancer in the United States alone in 2012 and more than 28 170 would die of prostate cancer. Despite considerable advances in prostate cancer research, this cancer is still associated with significant mortality and morbidity [1]. The risk factors involved in the development of prostate cancer include advancing age, race and family history. If detected in the early stage of disease, prostate cancer is considered curable by surgical excision methods, radiotherapy and androgen deprivation therapy [2]. However, in a percentage of men disease recurs, is frequently refractory to treatment and this is associated with poor prognosis. It is thought there is a population of prostate tumour cells that have the capacity to invade and metastasize, with bone being the most common metastatic site. Autopsy studies have found that more than 80% of men who die of prostate cancer have metastatic boney lesions [3].

The current prostate specific antigen (PSA) screening tool has allowed early detection of prostate cancer, when still locally confined. PSA is a protein produced by the cells in the prostate gland. The PSA screening tool measures the level of PSA in the blood where a high PSA level is indicative of the presence of cancer. However, benign conditions may also show elevated levels of PSA. Therefore, the PSA screening tool has significant limitations resulting in false positives. Further, it is unable to distinguish the aggressive tumours requiring immediate intervention from those that are more appropriately managed by regular surveillance. Thus, there is considerable interest in identifying and discovering new prognostic and diagnostic markers for prostate cancer, particularly markers that can identify those tumours likely to progress to a more aggressive state.

Prostatic intraepithelial neoplasia (PIN), in particular high-grade PIN have been identified as precursors to prostate cancer. High-grade PIN is an abnormal condition of the prostate gland and is considered a pre-malignant condition. Studies have reported that approximately 30% of men with high-grade PIN lesions will develop prostate cancer [4]. Atypical small acinar proliferation (ASAP) is also a precursor to prostate cancer. ASAP lesions mimic cancer and have been found to be strongly predictive of subsequent prostate cancer, with approximately 60% of men with ASAP found to subsequently develop prostate cancer [5]. The progression of prostate cancer may be driven by the accumulation of genetic and epigenetic changes, leading to the activation of oncogenes and inactivation of tumour suppressor genes [6]. These changes lead to the development of PIN and ASAP which may progress into localised invasive cancer and finally metastatic tumours.

Metastasis is a multistep event and it arises when there is a loss of tumour cell adhesion to the primary site leading to cell detachment. These cells then invade through the extracellular matrix (ECM) and subsequently adhere to secondary sites. The transition from a normal prostate gland to the formation of PIN and to invasive and metastatic cancers involves alterations in the cell surface adhesive receptors, integrins. Integrins play important roles in normal prostate development where they are involved in the interaction of the prostate epithelial cells with the ECM and also influence cell signalling, growth, survival and differentiation. During metastasis, changes in integrin expression results in changes in the tumour cell adhesion to adjacent cells and to the ECM leading to increased cell motility. Thus, integ-rins are key players in metastatic events since they mediate cell to cell (homotypic) and cell to ECM (heterotypic) interactions of prostate cells.

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