27 May

Just as the basis for the stage of initiation is a simple mutation in one or more cellular genes controlling key regulatory pathways of the cell and the basis for promotion is the selective alter- ation of signal transduction pathways in the initiated cell, the basis for the stage of progression is evolving karyotypic instability. In contrast to initiation and promotion, which do not exhibit any obvious patterns in their development,  substantial  evidence is now accumulating  that the evolution of karyotypic changes, as the basis for the stage of progression, assumes certain pat- terns that appear to be tissue-specific.

Perhaps the first example of the tissue-specificity  of karyotypic evolution in the stage of progression was exemplified by the Philadelphia  chromosome,  characteristically  seen in more than 90% of cases of chronic myelogenous leukemia (Chapter 6). In the early development of this disease, essentially  the only karyotypic  abnormality  seen in neoplastic  cells is the 9:22 translocation, which constitutes the Philadelphia chromosome. However, as the disease evolves, numerous other karyotypic abnormalities become apparent, none of which are as common as the translocation resulting in the abnormal chromosome (Barton and Westbrook, 1994). Using this example in the human as a model, more recent investigations have not only demonstrated char- acteristic  chromosomal  abnormalities  in tissue-specific  neoplasms  (Chapter 6, Table 6.8) but have also developed—from  karyotypic studies in preneoplastic, neoplastic, and metastatic neo- plasms—plausible  schemes or patterns for the genetic and cytogenetic pathways of the stage of progression in specific tissues. Some examples of such patterns of karyotypic evolution are seen in Table 9.12. In several instances, the “early change” is assumed from the most consistent kary- otypic findings in primary neoplasms and their benign counterparts. In the animal, it is possible to localize such changes to a much greater extent than in the human, as exemplified by karyo- typic studies on the development of neoplasia in the mouse epidermis (Aldaz et al., 1989), hepa- tocyte in the rat (Sargent et al., 1997), and the plasmacytoma in the mouse (Ohno et al., 1979). It is of interest that two of these three examples  are associated  with a trisomic  or duplicative change in specific chromosomes as the earliest alterations noted. Similar duplicative changes as early alterations can be noted in the genesis of several other animal and human neoplasms (Table 9.12). The “later changes” noted in the table are not meant to be inclusive, since—as these neo- plasms develop further—subsequent  chromosomal changes can be noted in many, but in others an apparently stable (Heim et al., 1988) and sometimes “normal” (Dutrillaux, 1995) karyotype may be maintained for the history of the neoplasm, especially in the human. In this latter in- stance, subtle alterations in other chromosomes  likely exist, for in most instances, when such neoplasms are placed in cell culture, karyotypic evolution continues. The initial changes seen in the human in chronic myelogenous  leukemia,  Ewing sarcoma,  and myxoid liposarcomas  are translocations;  while in the carcinomas indicated, the early lesions are more frequently repre- sented by trisomic changes. For the process of colon carcinogenesis  in the human, Fearon and Vogelstein have developed a genetic model that includes molecular changes during the early pe- riod of the stage of progression (adenomas and primary carcinomas), while changes in chromo- somes 17 and 18 as well as other molecular changes occur late in the stage of progression, as noted in the table. A diagram of their model of colon carcinogenesis is shown in Figure 9.8. The terms in the boxes indicate the various morphological  and biological  characteristics  of each succeeding  step, with the indication  of the stages of carcinogenesis  in which each may be placed. Note that sequential karyotypic alterations in specific chromosomes are seen during the stage of progression (Fearon and Vogelstein, 1990). The loss of chromosome 22 in meningiomas is a frequent somatic mutation in this benign neoplasm (Chapter 6), but further development of

Table 9.12 Cell Type Patterns of Karyotypic Evolution in the Stage of Progression

the stage of progression results in a number of chromosomal and molecular alterations (Weber et al., 1997).

Thus, as emphasized in Chapter 6, the seemingly random karyotypic alterations occurring during the stage of progression  are now more frequently  being patterned  as a sequence  of changes that only become random during the established portion of the stage of progression. The apparent tissue specificity of many of the patterns of karyotypic evolution in the stage of pro- gression seen in Table 9.12 is of great significance to our understanding of the development of this stage. However, the possible mechanisms for the evolution of karyotypic instability in neo- plastic cells in relation to chromosomal alterations—coupled  to the mutational events initiating carcinogenesis—remain  as a primary dilemma in unraveling the mechanisms of carcinogenesis. The continued evolution and amplification of these genetic alterations are the result of the grad- ual alteration in mechanisms controlling the cell cycle. Unfortunately,  our knowledge of these molecular mechanisms is still in its infancy, and it is unlikely that a rational, effective therapy for neoplasia in general will be found until we understand the molecular basis for karyotypic evolu- tion in neoplasia. However, a number of other parallel processes and abnormalities result from evolving karyotypic  instability.  The next chapter focuses on several of the more important of these processes in the stage of progression.

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