Genetic Mechanisms of Metastases

27 May

Virtually all successful metastatic lesions from primary neoplasms are aneuploid and in the stage of progression. It is, in fact, the karyotypic instability of neoplastic metastatic lesions that differ- entiate them from nonneoplastic metastatic cells. One must recall that certain normal tissues also have the capacity to metastasize.  The placenta uniformly  metastasizes  during the last several months of pregnancy; in individuals who have died during this period, metastatic cells are found in the maternal pulmonary  vasculature.  Under normal circumstances,  after parturition,  meta- static placental cells die as a result of the alteration in the hormonal environment.  Accessory spleens may be considered  metastases from normal spleens. In certain cases of trauma, espe- cially after fractures of bone, fat cells and other bone marrow elements may metastasize to other parts of the organism, sometimes with acute deleterious effects.

Just as karyotypic instability is probably the genetic basis for the altered phenotypes of neoplastic cells and affords them the advantage of invasion into adjacent tissues, metastatic cells that successfully invade and colonize secondary areas of the host do so because of their evolved genetic constitution. Karyotypic instability of neoplasms in the stage of progression results in a karyotypically heterogeneous neoplasm with cells of unequal metastatic potential (cf. Hart and Fidler, 1981). As already implied and seen in many of the examples used, genetic and epigenetic heterogeneity of neoplastic cells in the stage of progression can account for the complexity of many of the diverse properties of cancer (cf. Heppner and Miller, 1998). The incidence of spon- taneous metastases in both primary and transplanted neoplasms is quite variable (Milas et al.,1983; Giavazzi et al., 1980). In the extreme, highly metastatic cells in experimental animals ex- hibit substantial increases in the rate of mutation (per cell generation) and may, even after clon- ing, generate metastatic variants at an apparent rate of about 10–5 per cell per generation (Cifone and Fidler, 1981; Harris et al., 1982). Neoplastic cells with fewer karyotypic and thus genetic changes have a lower incidence of successful metastatic growth, as evidenced by differences in gene amplification  (Figure 10.12). In this figure, neoplasms  exhibiting  no metastasis  show a lower degree of gene amplification  than neoplasms  exhibiting  successful  metastatic  growth (Donovan-Peluso et al., 1991). It should also be noted that it is possible to select metastatic vari- ants from neoplasms exhibiting little or no spontaneous metastatic activity in vivo (Frost et al.,1987). This finding has significant implications  in the use of cytotoxic drugs capable of such metastatic selection in the therapy of neoplasia (Chapter 20).

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