27 May

In the past, the term somatic mutation has been used broadly to encompass cell differentiation. However, it is likely that most processes of cell differentiation occurring in the development of multicellular organisms do not involve a series of directed genetic mutations with the possible exception of the hypermutation seen in the development of immunoglobulins  and related mole- cules (Neuberger and Milstein, 1995). Rather, the heritable phenotypes that occur during differ- entiation are associated  with alterations  in the regulation  of genetic expression  of a genome identical in most cells of the organism. The mechanisms of cell differentiation are for the most part still relatively  obscure, but despite rapid advances in our understanding  of the molecular biology of both germline and somatic mutations, significant efforts have been directed toward understanding neoplasia in the light of developmental biology.

Many experimental and histopathological  investigations in oncology during the past cen- tury have pointed to a loss of the capacity of neoplastic cells to differentiate. However, during the last several decades, investigators  have pointed out examples in plants (Braun and Wood,

1976), lower animals (Pierce and Wallace, 1971; Pierce, 1974), and humans (Rangecroft et al.,

1978) in which neoplastic cells have exhibited the capability of specific differentiation.  As we shall see in Chapter 9, continued differentiation of malignant neoplasms may lead to regression and conversion to a benign or nonneoplastic condition. In addition, studies beginning with those of Friend and her associates (1971) have demonstrated that experimental and even human neo- plasms can be induced to differentiate  in vitro by the addition of a variety of chemicals  (cf. Freshney, 1985). Furthermore, Sachs (1993) and colleagues have demonstrated that both normal and leukemic  hepatopoietic  cells can be induced to differentiate  by a variety of endogenous growth factors and hormones. These studies and others (cf. Lynch, 1995) have led to the concept that endogenous  factors may be capable of regulating  the development  and differentiation  of neoplastic cells.

That such endogenous factors are important in the regulation and suppression of neoplasia was best exemplified by the studies of Mintz and Illmensee (1975), Papaioannou et al. (1975), and others. These experiments,  which were the actual forerunners of the embryonic stem cell technology discussed in Chapter 5, were carried out by the inoculation of malignant teratoma cells that had originated from a genetically  distinct line of mice, the line 129 inoculated  into blastocysts of normal mice of another line (Figure 6.10). The resultant animals exhibited cells of the genotype of the 129 line but no neoplasms. Later studies by Stewart and Mintz (1981) dem- onstrated that cells from the malignant teratoma line had populated the germline of the chimeric animal. It was found, however, that this phenomenon was not always reproducible with the ter- atoma cells, and thus for controlled experiments embryonic stem cells were preferable.

As extensions of these investigations, attempts have been made to suppress the neoplastic phenotype by inoculation of neoplastic cells at later stages of embryonic development and even in the adult. Gootwine and his associates (1982) inoculated myeloid leukemia cells into mouse embryos in utero at 10 days of gestation with the result that healthy adult mice were obtained, although the cells contained a genetic marker derived from the leukemic cells, implying the sup- pression of their neoplastic  phenotype.  Somewhat  similar experiments  were carried out with neuroblastoma cells, with a different end point (Pierce et al., 1982). More recently, Coleman and his associates (1993) have demonstrated that malignant liver epithelial cells in culture, when in- oculated directly into the liver or the spleen of an adult rat, resulted in the suppression of their

Figure 6.10 Experimental  demonstration  of the normal development  of malignant teratoma cells origi- nating from strain 129 mice inoculated into the normal blastocyst of strain C57 mice with subsequent pro- duction  of chimeric  offspring  (seen  as striped  129/C57  progeny).  Details  of the experiment  may be obtained from the original reference (Mintz and Illmensee, 1975). (From Mintz and Illmensee, 1975, with permission of the authors and publisher.)

malignancy  and their incorporation  into hepatic plates in a differentiated  state. In sum, these experiments  suggest that, under appropriate  environmental  conditions,  malignant cells can be induced to revert to a normal phenotype and lose all obvious characteristics  of the neoplastic transformation for the apparent lifetime of the host.

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