Metastatic cascade 2-5

Hydroxamic acid derivatives, which belong to a new class of NO donors, have been shown to inhibit the matrix metalloproteinases (MMPs) [112]. MMPs are a family of zinc-dependent endopeptidases, which play a critical role in multiple steps in the metastatic cascade and facilitate neoangiogenesis. Numerous hydroxamic acids, such as marimastat, have been developed, that bind the zinc atom in the active catalytic domain of MMPs. During a randomized Phase III trial, comparing marimastat with placebo in patients with metastatic breast cancer, marimastat was not associated with an improvement in progression-free survival or overall survival. Other studies also indicated no benefit for MMP inhibitors when used either in combination with chemotherapy or sequentially after first-line chemotherapy in a variety of cancers [113]. Currently, many pharmaceutical companies have suspended clinical development of this kind of agent. 

Surface properties are critical determinants of the metastatic behavior of malignant tumor cells. Adhesion molecules, proteolytic enzymes, antigenic determinants and hystocompatibiUty molecules, cytokine and growth factor receptors are all displayed on the cell surface, and known to play a specific role in the metastatic cascade. Therefore, selection of cell populations based on each and any of these properties can yield tumor cell sub-lines with varying metastatic capabilities. 

In the process of cancer metastasis, tumor cells have to migrate from their primary location to distant sites. Consequently, those cells endowed with higher motility and invasive abilities, and that can resist the shear stress of being transported through narrow capillaries, will have higher chances to complete the metastatic cascade, and develop into metastatic colonies. Hence, selection in vitro for cells in which any of those characteristics is expressed at the highest level could result in some increase of the metastatic ability. 

Metastasis is not equivalent to invasion, adhesion, growth rate, susceptibility to immune cell killing, or any of the many steps in the metastatic cascade. These processes are necessary for successful colonization of secondary sites, but they are not sufficient for a cell to be metastatic. Failure to distinguish between individual steps from the complete process of metastasis has contributed greatly to confusion and misinterpretation in the scientific literature. Just because a cell line is highly invasive or adheres strongly to extracellular matrices does not necessarily translate to its having the ability to metastasize. Yet, this type of faulty extrapolation is common. 

Despite the wealth of useful information than can be gleaned from in vitro assays measuring a step(s) in the metastatic cascade, the only method for assessing metastatic potential involves the use of in vivo models. In vitro models are simply not of sufficient complexity to recapitulate the multitude of steps of the metastatic process. This is not to demean the usefulness of in vitro models. 

Fig. 11. Various overlapping steps of the metastatic cascade. From Leonard Weiss, Principles of Metastasis (Ref. 257) 1985. Reprinted by permission of Academic Press.

One of the first steps to go behind the metastatic cascade is the examination of peripheral blood to detect potential circulating malignant cells. This method is useful to follow-up malignancies spreading via the blood stream such as sarcomas, melanoma, neuroblastoma, prostatic, thyroid and hepatocellular carcinomas. PCR-and RT-PCR-based molecular techniques are found to be the most efficient assay to detect circulating tumor cells in peripheral blood, and allow the detection of one tumor cell in up tolO background nucleated blood cells. However, it is important to consider that the presence of tumor cells in peripheral blood is only one step in a multistep process and not all tumor cells circulating in peripheral blood are able to... 

H. Kato, Z. Liao, J. Mitsios, H. Wang, E. Deryugina, J. Varner, J. Quigley, and S. Shattil, The primacy of (31 integrin activation in the metastatic cascade. PLoS One, 7 (2012)e46576. 

Tumor eells that survive the harsh eirculatory stream and reach distant organs/tissues stiU need to extravasate to begin secondary colonization. How this process occurs is critical in the metastatic cascade and two potential mechanisms have been proposed (Chambers et al. 2002). 

It is generally believed that proteases enhance cancer spread primarily by catalyzing degradation of the extracellular matrix. Since multiple substrates are encountered in this matrix, a number of different proteases are likely to be required to complete the metastatic process. Multiple proteases may also be required to activate different inactive precursor forms. Thus, in vitro, plasmin (D7), cathepsin B (D7), and a trypsin-like protease (K12) can all activate pro-uPA, while plasmin, which results from the action of uPA on plasminogen, can activate certain metalloproteases (M4). As mentioned earlier, completion of the metastatic process may require a cascade of different proteases operating, as shown in Fig. 2. 

The process of cancer metastasis consists of a cascade of events, each of which can be rate-limiting, since failure at any of them blocks the process. The final result at the end of the cascade depends on both the intrinsic properties of the tumor cells and the host response. Since the balance between these two aspects can vary among different patients, the metastatic behavior of individual rnmors is often unpredictable. Theoretically, the steps required to progress from a primary tumor to a distant metastasis are similar in all tumors (Fig. 1.1) ... 

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