Metastatic potential

Human cancers vary widely in their ability to produce metastasis. At present, there are no reliable methods to predict metastatic potential. For optimum patient management, however, knowledge of the aggressiveness of a tumor is desirable when deciding which patients should receive adjuvant chemotherapy. This type of information is particularly important for axillary node-negative breast cancer and Dukes B colorectal cancer. 

Traditional markers of prognosis in cancer have relied on histological features such as tumor size and grade and whether or not local lymph nodes have metastasis. While these histological variables have been widely used over the years in assessing patient outcome, none is ideal. 

Generally, larger cancers have a worse prognosis than smaller cancers. However, at least for some malignancies, size is a relatively weak indicator of outcome and is probably an indicator more of the chronological age of the tumor than of aggressiveness. Furthermore, size can be difficult to determine accurately when tumors have poorly defined infiltrating borders. 

The presence or absence of metastases in local lymph nodes is widely used as a prognostic marker. Generally, patients with metastasis in these lymph nodes have a significantly poorer outcome than those patients without metastases. However, at least in the case of breast cancer, about 25-30% of node-negative patients die from their disease within 10 years. As mentioned earlier, there is a particular urgent need for new markers to identify those high-risk, axillary node-negative breast cancer patients. 

In recent years, a large number of new biochemical prognostic markers have been described for cancer. These include steroid receptors, cellular or c-onco-genes, suppressor genes, and molecules directly involved in metastasis, such as proteases and adhesion proteins. 

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Staging of malignant melanoma is important to determine prognosis, categorize patients with regard to metastatic potential and survival probability, and aid in clinical decision making. 

Murakami T, Maki W, Cardones AR, et al. Expression of CXC chemokine receptor-4 enhances the pulmonary metastatic potential of murine B16 melanoma cells. Cancer Res 2002 62 7328-7334. 

Li A, Varney ML, Singh RK. Constitutive expression of growth regulated oncogene (gro) in human colon carcinoma cells with different metastatic potential and its role in regulating their metastatic potential. Clin Exp Metastasis 2004 21 571-579. 

Varney ML, Li A, Dave BJ, Bucana CD, Johansson SL, Singh RK. Expression of CXCR1 and CXCR2 receptors in malignant melanoma with different metastatic potential and their role in interleukin-8 (CXCL-8)-mediated modulation of metastatic phenotype. Clin Exp Metastasis 2003 20 723-731. 

T. J. Yeatman, Activation of c-Src by receptor tyrosine kinases in human colon cancer cells with high metastatic potential, Oncogene 15 3083 (1997). 

Parak WJ, Boudreau R, Le Gros M, Gerion D, Zanchet D, Micheel CM, Williams SC, Alivisatos AP, Larabell C (2002) Cell motility and metastatic potential studies based on quantum dot imaging of phagokinetic tracks. Adv Mater 14 882-885... 

Correlation of Certain Proteases with Metastatic Potential in Model Tumor Systems. A variety of different proteases have been found to correlate with metastatic potential in model tumor systems. Many of these early studies were carried out with B16 mouse melanoma cells. Variants of these cells with different metastatic potential have been selected. In separate experiments, total PA activity, CB activity, and collagenase IV activity have all been found to correlate with metastatic potential in these cells (A4, D6). More recently, levels of mRNA for CB have also been found to correlate with metastasis in these melanoma cells (Ql). Correlations also exist between levels of specific proteases and metastatic ability in a number of other model systems see Table 2 (D6). 

Model Systems Showing Correlations between Levels of Specific Proteases and Metastatic Potential"... 

Inverse Relationship between Protease Inhibitors and Metastatic Ability. All proteases, apart from possibly CD, appear to be controlled by endogenous inhibitors. In theory, therefore, the ability of malignant cells to produce metastasis could depend not only on the levels of the specific protease, but also on the concentration of relevant endogenous inhibitors. Thus, the presence of high levels of protease inhibitors might inhibit metastasis, while low levels of inhibitors might enhance metastasis. An inverse relationship between a number of specific inhibitors and metastatic potential has now been shown. Some examples of this type of relationship include TIMP-1 in Swiss 3T3 cells (K4), cysteine protease inhibitors in mouse melanoma cells (R6), and an alpha-1-proteinase inhibitor in rat mammary carcinomas (N2). Furthermore, a newly described serine protease inhibitor, known as maspin, was found to be expressed less frequently in advanced human breast cancers compared with early cancers (Z2). 

However, high levels of certain protease inhibitors correlate positively with enhanced metastatic potential. For example, high levels of the PA inhibitor, PAI-1, correlate directly with poor prognosis in human breast and gastric cancers (J2, Nl) and indeed correlate with uPA itself (Rl). 

Since certain proteases are directly involved in cancer invasion and metastasis, levels of these proteases in primary cancers should be strong markers of metastatic potential or poor patient outcome. 

H5. Hearing, V. J., Law, L., Corti, A., Appella, E., and Blasi, F., Modulation of metastatic potential by cell surface urokinase of murine melanoma cells. Cancer (Philadelphia) 48, 1270-1278 (1988). 

N2. Neri, A., Bohoslawec, O., Anderson, T. D., and Tokes, Z. A., Differential release of active proteinase inhibitors by 2 rat mammary adenocarcinoma variants possessing different metastatic potentials. Cancer Res. 51, 1318-1325 (1991). 

Ql. Qian, K., Bajkouski, A., Steiner, D. F., Chan, S. J., and Frankfater, A., Expression of 5 cathepsins in murine melanomas of varying metastatic potential and normal tissue. Cancer Res. 49, 4870-4875 (1989). 

Y3. Yu, H., and Schultz, R. M., Relationship between secreted urokinase plasminogen activator activity and metastatic potential in murine B16 cells transfected with human urokinase sense and antisense genes. Cancer Res. 50, 7623-7633 (1990). 

The microarray comprised 9600 nonredundant ESTs from the integrated molecular analysis of genomes and their expression (IMAGE) collection of human cDNA clones arrayed onto nylon membranes. Of these, 1875 clones (19.5%) were verified by resequencing 110 of the 589 genes expressed (18.7%) that correlated with the metastatic potential were among those verified by sequencing. 

While the work of Chen et al. (2001) broadly defined the expression of genes associated with metastatic potential in the lung cancer model, others have more narrowly focused upon relationships for specific genes. For example, Pinheiro et al. (2001) examined gene expression profiles from patients... 

La Riviere G., Schipper C.A., Gebbinck J.W., Koch G., Kuhn L., Lefkovits 1. Roos E. (1992). Putative invasion-specific proteins in mouse T-cell hybridomas that differ in invasive and metastatic potential. Int. J. Cancer, 9 51(5) 745-53... 

La Riviere G., Schipper C., Collard J. and Roos E. (1988). Invasiveness in hepatocyte and fibroblast monolayers and metastatic potential of T-cell hybridomas in mice. Cancer Research, Vol. 48, 3405-3410. 

Microarray analyses of breast cancer have identified unique gene expression profiles associated with patient survival. Sorlie et al. (23) found the expression profiles to distinguish ER-i- from ER- tumors with distinct outcomes in a cohort with locally advanced breast cancer treated with primary chemotherapy. Van t Veer et al. (18) established a 70-gene signature to predict metastatic potential in an untreated, node-negative cohort. Sotiriou et al. (24) showed the concordance with these previous analyses in node-positive and node-negative patients with the majority receiving adjuvant treatment. 

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