The Natural History of Neoplastic Development: Progression

27 May

The stages of initiation and promotion were discussed in Chapter 7 as the beginning processes leading to the ultimate development  of cancer. However,  it should be clear to the reader that many of the behavioristic  characteristics  of malignancy  (Chapter 2) are not expressed  in the stages of initiation and promotion. Thus, the cellular populations of these stages are rightfully said to represent preneoplasia.  It is in the final stage of neoplastic development,  the stage of progression, that neoplasia is expressed as a true clinical disease condition.

The transition from the early progeny of an initiated cell to the biologically malignant cell population is essential to the development of cancer in the host. In the human, the conversion of the reversible lesion of leukoplakia in the mouth to a frankly invasive malignant epidermoid car- cinoma is an excellent example of such transition. A number of neoplasms may change from a low degree of malignancy to a rapidly growing, virulent, fatal neoplasm at some time in their development within the host. Collectively, these processes, especially the increasing growth rate, have been termed the progression of neoplasia.

Foulds (1954) was one of the first to recognize the importance of the development of neo- plasia beyond the appearance  of an initial gross tumor. He postulated that the early stages of initiation  and promotion  were really part of a larger and continuous  process of progression. Later, Noble (1977) characterized progression as “the tendency for a cell to escape from its in- herent limited capacity for proliferation.”

Foulds (1964) suggested  that tumor progression  may be considered  from at least two viewpoints. The first he termed the “independent progression of neoplasms,” which meant that progression occurred independently in each of several different primary neoplasms in the same animal. The second component of progression he termed the “independent progression of char- acters,” in which any one of a number of characteristics of a neoplasm changed (or progressed) independently of others. The “characters” referred to by Foulds included growth rate, invasive- ness, metastatic frequency, hormonal responsiveness,  and morphological  characteristics.  Many of the characteristics  described by Foulds are a direct function of demonstrable changes in the genome of the cell or closely associated with them. Karyotypic alterations in neoplasms may be directly correlated with increased growth rate (Fisher et al., 1975; Wolman, 1983; van Echten et al., 1995), invasiveness  (Bevacqua et al., 1988), metastatic potential and capability (Nicolson,1987; Frost et al., 1987), hormone responsiveness (cf. Wolman, 1983), and morphological char- acteristics  (Ritchie,  1970). Thus, the characters  and their changes during progression  as de- scribed  by Foulds  (1964)  are  a reflection  of the  genetic  and  karyotypic  heterogeneity characteristically seen in the stage of progression both by karyotypic analyses and more detailed molecular studies (Heim, 1996; Sengstag, 1994). Concomitant  with these changes, the karyo- type of the cell population in the neoplasm changes as progression occurs. An example of such a

change in karyotype may be seen in Figure 9.1, which depicts the normal karyotype of the rat at the top of the figure; the next three karyotypes are those of stem cell lines from early transplant generations 3 to 5 years later. At the bottom of the figure, the karyotype of the cell line 7 to 8 years after continued transplantation  are seen. The increase in marker chromosomes  (arrows) dramatically indicates the changing karyotypes, especially in the later transplant generations. In most instances, repeated transplantation  results in more rapidly growing tumors with a higher degree of aneuploidy.

A similar karyotypic evolution has been described with successive  passages of Chinese hamster cells explanted to cell culture as euploid cells, which progressed through various pas- sages to a heteroploid  tumorigenic  cell line (Cram et al., 1983). Similarly,  Kerler and Rabes (1996) have demonstrated the karyotypic evolution of a clonal rat liver cell line during the stage of progression in vivo as well as in vitro. In the human, a large number of examples of karyo- typic evolution in vivo have been described (Jacoby et al., 1995; Atkin and Baker, 1969; Haapasalo et al., 1991; Norming et al., 1992; Sato et al., 1991; Hemmer and Schön, 1993; Morse et al.,1994). Nowell (1982, 1986) pointed out the importance of clonal evolution of cells exhibiting abnormal karyotypes both in relation to tumor cell heterogeneity and also to tumor progression, especially in various human leukemias such as chronic myelogenous  leukemia. Yosida (1983) related invasiveness  and metastatic capability of neoplastic cells—both  characteristics  of pro- gression as noted by Foulds (see above) to the karyotypic evolution of neoplastic cells. Thus,

Figure 9.1 Karyotype of normal male rat (upper karyotype) with three karyotypes of serial transplanta- tions from cell lines growing in 1961–62, 1965–67, and 1968–70. Arrows indicate the change in marker chromosomes  in stem line cells of the neoplasms. (Adapted from Yosida, 1983, with permission of author and publishers.)

there is considerable  evidence that progression  is closely correlated  with the appearance  and subsequent evolution of karyotypic abnormalities in neoplastic cells, if not caused by them (cf. Nowell, 1990).

Kraemer and associates (1972) noted that, in a population of neoplastic cells exhibiting an extremely rapid growth rate and a high degree of aneuploidy, the DNA content of the average cell remained quite constant. Despite the constancy of the DNA content per cell, the population exhibited  an extreme range of karyotype,  extending  at times from near diploid to hypotetra- ploidy. An example of this phenomenon,  taken from the work of Kraemer and his associates (1972), is seen in Figure 9.2. In view of the myriad of karyotypes present in the population, they explained this phenomenon by postulating that the neoplastic cell had lost the ability to maintain a stable karyotype and that chromosomal components were interchanged with considerable fre- quency during successive cell cycles in this population. The changes seen do not reflect simply variation in numbers of chromosomes but also in their structure (Kraemer et al., 1974).

Although the exact mechanism of the phenomenon described by Kraemer and associates is not understood at the molecular level, the implications of such a phenomenon are clear. Some neoplastic cells in the stage of progression “shuffle” their chromosomes and components of their genome at some time during the cell cycle. It also appears from these studies (Kraemer et al.,1974) that cloning of a single cell from the HeLa heteroploid population results in a clone exhib- iting the same DNA content as the original culture but also exhibiting a variety of karyotypes. If this conclusion is correct, then the heteroploid clone could only be accomplished  by breakage and/or reconstitution  of DNA strands during successive cell cycles, as well as aneuploidy,  by mechanisms that are only incompletely understood at present (see below). More recently, Dues-

Figure 9.2 Auramine O-Feulgen-DNA  distributions and chromosome number histograms of (a) normal human diploid WI-38 and (b) malignant HeLa cells in culture. The DNA content was determined by flow cytometry and the chromosome number by standard karyotyping. (Adapted from Kraemer et al., 1972, with permission of the authors and publisher.)

berg and associates (Duesberg et al., 1998; Rasnick and Duesberg, 1999) suggested a mechanism for the phenomenon described by Kraemer and reproduced in part by Duesberg. Their sugges- tion is that aneuploidy destabilizes the karyotype on the basis that it biases balance-sensitive mi- tosis proteins and organelles such as centrosomes, tubulin, etc. By their mechanism, aneuploidy tends to generate variations in chromosome number and evolution autocatalytically, resulting in karyotypic instability of neoplastic cells that is proportional to their degree of aneuploidy.

Although significant phenotypic heterogeneity has been described during the stage of pro- motion in hepatocarcinogenesis  in the rat (Pitot et al., 1978; Peraino et al., 1984), significant biochemical homogeneity (Eriksson et al., 1983) and the lack of demonstrable genetic heteroge- neity and instability characterize the stages of initiation and promotion (Chapter 7). Unlike the relatively  limited phenotypic  characteristics  of cells in the stages of initiation and promotion, those in the stage of progression may undergo a continued evolution toward increased autonomy from host influences (Pitot, 1989). This process is accompanied by—or a reflection of—the con- tinued evolution of karyotypic changes that accompanies the evolution of the stage of progres- sion, as has been described  in a variety of systems,  both experimental  (Aldaz et al., 1987; Sargent, 1996) and in the human (Nowell, 1986; Korabiowska et al., 1997).

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