Process Of Cancer Metastasis

The process of cancer metastasis consists of a series of sequential interrelated steps, with the outcome depending on both the intrinsic properties of the tumor cells and the host.6'8-11 Bone is one of the major metastatic sites for prostate, lung and breast cancer and, in principle, the steps or events in the pathogenesis of metastasis are similar in all tumors (Fig. 2.1).

Recently, new therapeutic modalities have improved the survival of cancer patients; the outcome of the treatment of cancer at the primary site and of lung and liver metastasis has improved. As a result, although bone metastasis alone is not fatal, it poses clinically crucial problems caused by pain or the disturbance of the quality of life. Human bone consists of three major parts: the cortical bone, trabecular bone and bone marrow. The cortical bone contains a small number of osteo-cytes and hard, richly mineralized tissue. It plays an important role in the structure of the bony frame; therefore, its destruction by cancer cells induces pathological fractures, severe pain and

Fig. 2.1. General mechanism of hematogenous metastasis.

movement disturbances. On the other hand, several cytokines and growth factors produced and secreted by osteoblast are also stored in cortical bone tissue: insulin-like growth factor II (IGF-II) is the most abundant of cytokines, followed by TGFp, IGF-I, platelet-derived epidermal growth factor (PDEGF) and bFGF. The incidence of pure osteoblastic metastasis is approximately 95% of prostate cancer skeletal metastases; the remaining 5% is of the mixed type (osteoblastic and osteolytic). Osteolysis is also an important step in the establishment of osteoblastic metastasis from prostate cancer. Two possible mechanisms of osteolysis prior to the osteoblastic metastasis are a cell-mediated mechanism and a non-cell-mediated one.12 The direct release of proteases (serine proteases, cystine proteases or metalloproteases) by tumor cells generally resulting in extracellular matrix degradation and host-cell lysis, and facilitating tumor invasion is the so-called non-cell-mediated mechanism. The capacity to degrade the mineralized matrix, however, requires the involvement of osteoclasts. On the other hand, several cytokines and growth factors - TGFp, parathyroid hormone-related protein (PTHrP), interleukin-6 (IL-6), tumor necrosis factor (TNFa), PDEGF, bFGF and prostaglandin secreted by tumor cells and host immune cells under cell-to-cell interaction,13 stimulate osteoclastic activity, osteoclast growth and differentiation (cell-mediated osteoly-sis).13 Cancer cells that also produce some stimulatory factors, including the above cytokines and growth factors, stimulate the expression of RANKL on the cell surface of osteoblasts. Thus, increased RANKL reacts with the receptor (RANK) on the cell surface of osteoclast-precusor cells and induces cell differentiation to osteoclasts. Trabecular bone tissue, which is much softer than cortical bone tissue, is thought to be an important site for bone remodeling. Osteoclasts absorb bone tissue and release cytokines stored in cortical bone tissue; the cytokines and growth factors then stimulate new bone formation by osteoblasts, which in turn stimulate cancer cell growth.

Bone is a suitable microenvironment for cancer cell growth because large amounts of several cytokines are secreted by bone tissue. Bone marrow, the site of blood cell production, has two types of stem cells: blood stem cells that have the potential of multidifferentiation to all blood cells and osteo-clasts, and stromal cells that differentiate to osteoblasts, muscular cells and adipose cells. Cancer cells pass through the sinus vein and enter the bone marrow, invade the trabecular bone and then grow in cortical bone in close conjunction with two types of stem cells and immunocytes. The interactions of cancer cells, bone tissues and stem cells are shown in Fig. 2.2. Thus, in the development of osteoblastic metastasis from prostate cancer, osteoblasts might play a fundamental role as a site of attachment, as a mediator of skeletal invasiveness by facilitating osteoblastic osteolysis, and as a target for growth-promoting agents to induce bone-forming lesions.

Molecular Mechanism of Prostate Cancer Invasion and Metastasis

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