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In the natural history of neoplastic development,  cellular replication plays a major role (Table 9.5), especially when the natural history of the replicating neoplastic cell population extends to its ultimate conclusion, the metastatic neoplastic cell. Certain populations of normal cells within the mammalian organism also undergo cellular replication, in some cases continuously, as in the bone marrow and intestinal epithelium, but in others more intermittently or only under specific circumstances, as in the liver following partial hepatectomy. In the epithelium of the bronchus, epidermis, and cervix, there is constant turnover and loss of cellular populations as the result of cell division from the basal or stem cells and subsequent migration and further cell replication (with final cell loss from the surface of the epithelium). It has been estimated that during the life span of an individual, the renewal of these epithelia represents between 1014 and 1016 cell divi-sions. Since the background mutation rate is 10–6 per gene per cell division, there is presumed to be some mechanism  to eliminate  or repair the numerous  mutations  that presumably  occur in these cells during the lifetime of the individual. Theoretically, one or more such mutations might then lead to the conversion of a normal to an initiated cell. Subsequent mutation(s), spontaneous or induced, would transit the cell into the stage of progression.

Cairns (1975) has suggested that at least two mechanisms safeguard against such conver- sion. One mechanism involves the loss of cells that harbor such mutations through normal elim- ination such as desquamation or terminal differentiation. Second, it is theoretically possible that the daughter cell remaining  in the stem cell population  after division, the so-called immortal daughter cell, always receives the DNA molecules that represent the older of the two parental strands. In this way mutations occurring during replication would not collect in the stem cell population.

Although these ideas are unproven, they do have a counterpart in the development of can- cer at several sites in the human. Oehlert (1973) and others have shown that the earliest changes seen in the development of neoplasia in the skin and bronchus are focal increased mitotic activ- ity, loss of polarization, and breakdown of the structure of the epithelium. In the colon, where stem cells for the mucosal epithelium  occur deep within the crypts, an increased  rate of cell proliferation was noted in the deep region of the colonic crypts in aberrant crypts, putatively a preneoplastic lesion (Roncucci et al., 1993). However, earlier studies by Deschner (1982) sug- gested that an increased rate of DNA synthesis was seen in the upper (lumenal) region of crypts with colon cancer (isolated polyps) and familial polyposis. Since individual crypts were not ex- amined, it is difficult to compare the two studies. In any event enhanced cell replication in cer- tain regions of the crypt occurs very early during the development of these preneoplastic lesions in the genesis of colon cancer (Yamashita et al., 1994). In the case of carcinoma of the cervix, some early lesions, including carcinoma in situ and its precursors, have been shown to regress and disappear spontaneously, while others continue their development to carcinoma (Christoph- erson, 1977).

The growth characteristics of neoplasms in vivo have never been adequately investigated. Most scientists rely on a simple external measurement or on a determination from radiological studies to estimate the volume of a neoplasm (e.g., Greengard et al., 1985), considering  such changes a function of time. Studies have also employed radioactive techniques either in vivo or in vitro, with labeled precursors  of DNA, especially  thymidine  (for example, Newburger  and Weinstein, 1980; Schiffer et al., 1979). On the basis of such investigations, the doubling time of the average human neoplasm,  estimated  as the time required to double the size of the tumor mass, has been reported to be between 50 and 60 days (Charbit et al., 1971). During the last decade, another method for determining cell proliferation in tissues, which has the advantage of not requiring prelabeling of the tissues with a precursor, is the immunohistochemical  staining of a nuclear protein associated with cell proliferation, termed the proliferating cell nuclear antigen (PCNA). Analysis of PCNA expression in histological sections has been utilized for the estima- tion of growth fractions in neoplasms (Kamel et al., 1991; Gelb et al., 1992). PCNA functions as a processivity factor for DNA polymerase δ, the latter being the enzyme responsible for the rep- lication of chromosomal DNA (Kelman, 1997). PCNA also interacts with cyclin D and p21 (Fig- ure  9.5)  and  also  appears  to function  in DNA  repair  (Kelman,  1997).  More  extensive measurements (Steel, 1977) have shown a variety of doubling times in a number of human tu- mors and their metastases. The values for such measurements for a number of histogenetic neo- plasms of the human is seen in Table 9.9. From these data, adenocarcinomas of the colon appear to have the longest doubling times; metastatic lesions grow more rapidly. In most examples, hu- man rectal cancer proliferates more slowly than normal rectal mucosa (Britton et al., 1975). In a more recent study of human tumor proliferation with bromodeoxyuridine  administered in vivo to label DNA, Wilson (1991) found an enormous variation in the potential doubling time of sev- eral of the more common human carcinomas, ranging from a few days to more than 100 days in the case of lung cancers. An added complication is that apoptotic indices—the relative number of apoptotic  bodies in a neoplasm—also  vary in different neoplasms  (Staunton  and Gaffney, 1995). In general, apoptotic indices are greater than or similar to mitotic indices in neoplasms, but with exceptions such as melanoma and occasional metastatic lesions, where the rate of mito- sis exceeds that of apoptosis. In malignant lymphomas, high apoptotic indices correlated signifi- cantly  with overall  lethality  (Leoncini  et al., 1993).  However,  most  neoplasms  are quite heterogeneous with respect to replicating cell populations (Nervi et al., 1982). As with normal tissues, it has been demonstrated that a small fraction of cells (the stem cells) are responsible for maintaining the integrity and continued survival of the neoplasm (cf. Trott, 1994; Chapter 14). By definition, a stem cell is capable of an indefinite number of divisions. For example, during the lifetime of a human being, a typical hematopoietic stem cell may divide some 2000 to 3000 times, with an exact stability of its genomic and functional integrity. It may be said that stem cells have a proliferative capacity that is equal or superior to that of virtually all neoplastic cells (Trott, 1994). As shown in Chapter 20, if any neoplastic stem cells survive therapy, a recurrence of growth of the neoplasm will occur. With a technique of quantitative  transplantation,  it has been demonstrated that the number of stem cells in the neoplasm varies from every cell being a potential stem cell to one stem cell per 105 to 106. Whereas stem cells of normal tissues (such as epithelia and bone marrow) exhibit restrained,  orderly proliferation  and differentiation,  stem cells of neoplastic tissues exhibit a relative degree of autonomy, as exhibited in the entire neo- plasm and in line with our original definition of neoplasia (Chapter 2).

Most experimental tumors in laboratory animals exhibit a growth pattern that is character- ized by a declining rate of cell replication.  Such growth has been regarded as an exponential

Table 9.9 Anatomic Site, Histological Type, and Volume Doubling Time of 780 Primary and Metastatic Human Tumors

growth function limited by an exponential retardation. As seen in Figure 9.6, the initial exponen- tial growth of the neoplasm is characterized by successive mean generation times that increase according to an exponential equation, but growth is soon limited by an exponentially decreasing function. Laird (1965), in a comprehensive study of a large number of spontaneous, induced, and transplantable neoplasms in several species, showed that the number of cell doublings required for a neoplasm to grow unperturbed from a single cell to a predicted upper limit was essentially constant in the majority of systems studied in a specific species. In both animal and human, the smallest neoplasm likely to be detected by physical or radiological examination is about 1 g in weight, containing from 108  to 109  neoplastic cells. This lesion will be the result of about 30 doublings in cell number if it is clonally derived from a single neoplastic cell (Tannock, 1989). Another 10 doublings of the cells in the lesion will result in a potentially lethal tumor of approx- imately 1 kg. Therefore the period of neoplastic growth that is reasonably measurable represents only about one-quarter of the total development of the neoplasm itself. Obviously, this scenario

Figure 9.6 A plot of the growth of a murine neoplasm transplanted into a susceptible host. The theoreti- cal Gompertz curve that best fits the data is shown, as is a single exponential curve, the latter constructed on the basis that the doubling time observed during the first interval measured remains constant throughout the growth of the tumor. (After Laird, 1965, with permission of the author and publisher.)

describes a neoplasm in the stage of progression,  since, as we have already seen, cells in the stages of initiation and promotion represent different genetic populations incapable of the dou- bling pattern of the cell in the stage of progression.

The preceding description of tumor growth, however, does not take into account the poten- tial for metastatic growth. Figure 9.7 shows a Gompertzian model of the growth of a mammary neoplasm in the human. The shaded region represents the variation in growth that could occur in the primary neoplasm (T) and in metastatic lesions (M). As discussed above, neoplastic lesions growing within the time frame and cell number are limited by the threshold of detection, and zero time would not be clinically or experimentally  evident. Most important, one notes that at zero time, at which the neoplasm is first detected, one might predict that almost one-third of the metastatic lesions that will ultimately occur were initiated and present during the 12 months pre- ceding the diagnosis (Tubiana, 1982).

This consideration of cell kinetics and cell proliferation in neoplasia has significant practi- cal applications, as discussed later in the text (Chapter 20). In addition, from the model shown in Figure 9.7, it is obvious that a knowledge of the doubling times of neoplasms can also be related to the appropriate intervals between screening examinations that are necessary for the effective discovery  of a neoplastic  lesion before a cancer disseminates  beyond  the region of origin (Spratt, 1981).

Figure 9.7 Gompertzian model of growth of human breast neoplasm. As predicted by the Gompertzian model, the doubling time of both the primary neoplasm (T) and the metastatic lesions (M) lengthens pro- gressively with growth and time. The shaded areas represent the potential variation in the development  of different lesions in different individuals, and the box labeled “threshold of detection” indicates the history of neoplastic growth prior to clinical or experimental  detection. As noted, this model predicts that nearly one-third of the metastases eventually occurring were initiated during 12 months preceding the diagnosis. (Adapted from Tubiana, 1982, with permission of the author and publishers.)

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