Modulation of Metastatic Growth

27 May

A number of factors, both internal and external, have been found to modify or alter metastatic growth. The genetic constitution  of the metastatic cell may be considered  among the internal factors altering metastatic  potential with variable expression  of genes, as indicated above. In addition to the genetic modulation of metastasis, there is also evidence that alteration in DNA methylation  may affect the metastatic potential of neoplastic cells (Olsson and Forchhammer,1984).

A number of external modulators of metastatic growth have been described. Representa- tive examples of such modulators are given in Table 10.5. It should be noted from the table that the systems utilized to study the effects of such modulators on metastatic growth are somewhat artificial. In many instances the treatment occurs in vitro, with subsequent infusion of the cells into a suitable host animal. Angiostatin  is a polypeptide  fragment  of plasminogen  that bears some of the loop structures of the proprotease. This material blocks neovascularization  of me- tastases in a model system. In analogy with tumor promotion (Chapter 8), omega-6 fatty acids enhance, while omega-3 fatty acids inhibit, metastatic growth of primary and transplanted neo- plasms (Erickson and Hubbard, 1990; Rose et al., 1995). In similar artificial systems, both retin- oids and vitamin D3  inhibit the development  of pulmonary  metastases  (Edward and MacKie,1989; Young et al., 1995). The best example of hormonal effects on metastases is seen with the various prostacyclins,  including prostaglandins  (Chapter 8), in which, generally,  inhibition  of metastatic development in a variety of systems has been reported (cf. Chen et al., 1992). Cells subjected to hypoxia in vitro undergo anomalous DNA synthesis and karyotypic changes. Such cells, as expected, have a higher potential for metastatic growth (Young et al., 1988). In a similar vein, another potential progressor agent, ionizing radiation, enhances metastatic growth in a va- riety of different experimental  systems, although the occurrence of such a phenomenon in the human has not been completely substantiated (cf. von Essen, 1991). As suggested from the ear- lier discussion of specific sequences in a variety of cell adhesion molecules and especially po- tential ligands  for integrins  and other cellular  receptors,  congeners  of the tripeptide  RGD generally inhibit the development of metastases in experimental systems. These effects presum- ably occur within the docking and locking pathway depicted in Figure 10.10. Interestingly,  a synthetic peptide of 19 amino acids from the sequence of the A chain of laminin increases exper- imental metastasis in the murine melanoma system (Kanemoto et al., 1990). In an interesting report, Malins et al. (1996) presented data indicating that a greater than twofold increase in hy- droxyl radical damage occurred in metastatic tumor DNA as compared with nonmetastatic  tu- mor DNA.

From these few examples it is apparent that the development of metastases from a primary neoplasm is a very complex phenomenon both anatomically and at the cell and molecular levels. Although successful metastatic growth occurring clonally is a statistically uncommon phenome- non in an animal bearing a primary neoplasm, it actually takes only a single successful meta- static lesion to drastically worsen the prognosis of an individual with the disease. As discussed in Chapter  20, the primary  difficulty  in cancer therapy is the successful  elimination  of me- tastases, either by removal of the primary lesion before metastatic growth occurs or by some form of chemotherapy to curtail and ultimately eliminate the growth and spread of metastases.

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