REVIEWThe metastatic cascade in prostate cancer
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
References (129)
- et al.
Multistep nature of metastatic inefficiency: dormancy of solitary cells after successful extravasation and limited survival of early micrometastases
Am J Pathol
(1998) - et al.
Solitary cancer cells as a possible source of tumour dormancy?
Semin Cancer Biol
(2001) - et al.
Regulation of angiogenesis by SPARC and angiostatin: implications for tumour cell biology
Semin Cancer Biol
(1996) - et al.
Optimized microvessel density analysis improves prediction of cancer stage from prostate needle biopsies
Urology
(1996) The current role of chemotherapy in metastatic hormone-refractory prostate cancer
Urology
(2005)- et al.
Ecadherin mediates aggregation-dependent survival of prostate and mammary epithelial cells through the retinoblastoma cell cycle control pathway
J Biol Chem
(1999) - et al.
N-Cadherin expression in human prostate carcinoma cell lines: an epithelial–mesenchymal transformation mediating adhesion with stromal cells
Am J Pathol
(1999) - et al.
Different phenotypes in human prostate cancer: alpha6 or alpha3 integrin in cell-extracellular adhesion sites
Neoplasia
(2002) - et al.
Co-ordinated changes in expression of cell adhesion molecules in prostate cancer
Eur J Cancer
(1997) - et al.
Different mRNA and protein expression of matrix metalloproteinases 2 and 9 and tissue inhibitor of metalloproteinases 1 in benign and malignant prostate tissue
Eur Urol
(2002)
Expression of membrane-type 1 matrix metalloproteinase (MT1-MMP) on prostate cancer cell lines
Cancer Lett
A functional thrombin receptor (PAR1) is expressed on bone-derived prostate cancer cell lines
Urology
The distribution of secondary growths in cancer of the breast
Lancet
The organ microenvironment and cancer metastasis
Differentiation
Metastatic patterns of prostate cancer: an autopsy study of 1589 patients
Hum Pathol
Rho-kinase inhibitor retards migration and in vivo dissemination of human prostate cancer cells
Biochem Biophys Res Commun
Normal and malignant prostate epithelial cells differ in their response to hepatocyte growth factor/scatter factor
Am J Pathol
Sialyl Lewis(X) and related carbohydrate antigens in the prostate
Hum Pathol
Metastasis to bone: causes, consequences and therapeutic opportunities
Nat Rev Cancer
Animal models of bone metastasis
Cancer
Persistence of solitary mammary carcinoma cells in a secondary site: a possible contributor to dormancy
Cancer Res
Cancer spread and micrometastasis development: quantitative approaches for in vivo models
Bioessays
Haematogenous dissemination of cells from human renal adenocarcinomas
Br J Cancer
Dissemination and growth of cancer cells in metastatic sites
Nat Rev Cancer
The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited
Nat Rev Cancer
New signals from the invasive front
Nature
The experimental study of tumor progression
Cancer Res
Tumor growth and neovascularization: an experimental model using rabbit cornea
J Natl Cancer Inst
Putting tumors in context
Nat Rev Cancer
Endothelial cell proliferation in prostatic carcinoma and prostatic hyperplasia: correlation with Gleason's score, microvessel density, and epithelial cell proliferation
Lab Invest
Predictors of pathologic stage in prostatic carcinoma: the role of neovascularity
Cancer
A phase II trial of humanized anti-vascular endothelial growth factor antibody for the treatment of androgen-independent prostate cancer
Prostate J
Recent progress in management of advanced prostate cancer
Oncology
Vascular-specific growth factors in blood vessel formation
Nature
Intratumoral lymphatic vessels: a case of mistaken identity or malfunction?
J Natl Cancer Inst
Vascular endothelial growth factor-C expression in human prostatic carcinoma and its relationship to lymph node metastasis
Br J Cancer
Expression of vascular endothelial growth factor receptor-3 by lymphatic endothelial cells is associated with lymph node metastasis in prostate cancer
Clin Cancer Res
Inhibition of lymphogenous metastasis using adeno-associated virus-mediated gene transfer of a soluble VEGFR-3 decoy receptor
Cancer Res
Decreased mutual adhesiveness, a property of cells from squamous carcinomas
Cancer Res
Cadherin cell adhesion receptors as a morphogenetic regulator
Science
Dissociation of Madin–Darby Canine Kidney epithelial cells by the monoclonal antibody anti-arc-1
J Cell Biol
Dissecting tumour cell invasion: epithelial cells acquire invasive properties after loss of uvomorulin-mediated cell adhesion
J Cell Biol
Identification of a putative cell adhesion domain of uvomorulin
EMBO J
Complex cadherin expression in human prostate cancer cells
Int J Cancer
Allelic imbalance within the E-cadherin gene is an infrequent event in prostate carcinogenesis
Genes Chromosomes Cancer
Expression of the cellular adhesion molecule E-cadherin is reduced or absent in high-grade prostate cancer
Cancer Res
E-cadherin and beta-catenin are down-regulated in prostatic bone metastases
BJU Int
A synthetic peptide from fibronectin inhibits experimental metastasis of murine melanoma cells
Science
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