Elsevier

Surgical Oncology

Volume 15, Issue 3, November 2006, Pages 117-128
Surgical Oncology

REVIEW
The metastatic cascade in prostate cancer

https://doi.org/10.1016/j.suronc.2006.10.002Get rights and content

Abstract

Morbidity and mortality due to prostate cancer are mainly a result of prostate cancer metastases. After the initial neoplastic transformation of cells, the process of metastasis involves a series of sequential steps, which involve neoangiogenesis and lymphangiogenesis, loss of adhesion with migration away from the primary tumour and entry into the systemic vasculature or lymphatics. Metastatic growth in sites such as lymph nodes and bone marrow then involves the specific non-random homing of prostate cancer cells. An appreciation and understanding of this metastatic cascade in relation to prostate cancer is clinically important in order to stratify men with prostate cancer into prognostic groups. Moreover, it is crucial in the future development of therapies that can prevent metastases.

Introduction

Metastatic prostate cancer is an incurable disease, and the natural clinical history is that of progressive severe debilitation and onset of complications, which include bone pain, spinal cord compression, bladder outflow obstruction, renal failure and anaemia. Metastasis is defined as the process by which a malignant cell leaves the primary tumour, travels to a distant site via the circulatory system and establishes a secondary tumour. This is a multi-step process, which consists of a series of sequential events involving complex interactions between the cancer cell and its surroundings [1]. Not all cancer cells have the ability to metastasise. Additionally, it has been shown that the process is inefficient, with only a very small number of cells leaving the primary organ having the potential to survive and establish colonies in secondary sites and eventually proliferating into clinically detectable metastatic neoplasms. This was demonstrated by Rosol et al. [2], who performed intracardiac injections of luciferase-labelled PC3 prostate cancer cell line cells into immuno-compromised mice. Neoplastic cells were localised, using non-invasive imaging, in the lungs, kidneys and long bones 15 min after injection. 24 h later, no viable cells were detected signifying that most of the injected cells were either dead or metabolically inactive. In another study, Luzzi et al. [3] used videomicroscopy of various types of cancer, and showed that only 2% of cancer cells formed micrometastases. Other groups have demonstrated that only 1% of these micrometastatic deposits eventually develop into larger established tumours, despite a significant number of undivided solitary cells remaining in tissues several months after injection [4], [5], [6]. In renal cell carcinoma, Glaves et al. [7] found that cancer cells were released as single cells and multi-cell emboli in 8 of 10 patients undergoing radical nephrectomy, in numbers varying widely between 14 and 7509 emboli per millilitre of blood. Despite a calculated median input into the circulation of 3.7×107 cancer cells per day for at least 180 days, only 3 of 10 patients had extraperitoneal metastases prior to surgery, and only 1 of the remaining disease-free patients subsequently developed distant metastases over a maximum period of 35 months.

After the initial neoplastic transformation of cells, metastasis is thought to involve the following steps [8], [9], [10] (Fig. 1).

Section snippets

Tumour proliferation, neoangiogenesis and lymphangiogenesis

It has been established that if a neoplasm is to exceed a diameter of 1 mm in size at the primary (or metastatic) site, new blood vessel formation must occur [11], [12]. Oxygen can only diffuse from capillaries for 150–200 μm [12], thus when distances of cells from a blood supply exceed this, cell death follows. The process of neovascularisation involves endothelial cell formation, migration, proliferation, vascular loop formation and the development of a new basement membrane. The mutations,

Loss of cell adhesion

Local cell invasion is not able to occur whilst tumour cells are confined by adhesion to neighbouring cells within the primary tumour. Adhesion between normal epithelial cells is strong, so that a necessary early event in invasion and metastasis is the conversion from the stationary to the migratory phenotype. This is associated with the functional down-regulation of intercellular adhesion. However, although it is essential for cell adhesion mechanisms to be disrupted for tumour cells to become

Local invasion of the host stroma

This process involves both the formation of adhesions between the tumour cell and the ECM and the degradation of the host stroma.

Escape of tumour cells via the neovasculature

Once malignant cells have penetrated the lymphatic or vascular channels, they may seed and multiply in these sites, or single cells or clumps of cells may detach and circulate throughout the body. The tumour cells and emboli must survive the turbulence or shear forces of blood flow and immune defences.

There is an intense host immune response against cancer involving humoral and cell-mediated immunity. The neoplasms must avoid this immunological assault, and this is particularly evident when the

The non-random homing of cancer cells and their survival in specific organs

This is due to:

  • (a)

    Directional migration of cancer cells down a chemotactic gradient to organs exhibiting peak levels of the chemoattractant.

  • (b)

    Capillary bed arrest of tumour cells in receptive organs/cancer cell endothelial interactions.

  • (c)

    Extravasation from the capillaries into the surrounding host tissue, proliferation within the amenable host organ microenvironment resulting in the establishment of micrometastases.

These final three steps of the metastatic cascade have been grouped together, as

Conclusion

Recent research has significantly improved our understanding of metastatic prostate cancer. The multiple steps, which are required for successful metastasis, have allowed the development of novel treatment options for this incurable disease. Additionally, an appreciation and understanding of this metastatic cascade in relation to prostate cancer is clinically important in order to stratify men with prostate cancer into prognostic groups. In fact, Varambally et al. [128], [129] recently studied

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