M

40 60 60 100

40 60 60 100

Space (arbitrary units)

Fig. 9.9 Tumor progression if the initial cell line has largely escaped inhibition, and promotion is the dominant force. Now the tumor grows in space as a single lesion until the whole tissue is invaded. Parameters were chosen as follows; r = 1;J = 0.1; ap = 5; bp = 0.1; a/ = 0.1; 6/ = 0.01; Dc = 0.00001; £>/ = 0.001, L = 2.

Space (arbitrary units)

Fig. 9.9 Tumor progression if the initial cell line has largely escaped inhibition, and promotion is the dominant force. Now the tumor grows in space as a single lesion until the whole tissue is invaded. Parameters were chosen as follows; r = 1;J = 0.1; ap = 5; bp = 0.1; a/ = 0.1; 6/ = 0.01; Dc = 0.00001; £>/ = 0.001, L = 2.

(ii) The first mutation shifts the balance between promoters and inhibitors to a lager extent which is sufficient to result in the generation of multiple lesions (Figure 9.8). The multiple lesions do not, however, occur immediately. First, the tumor grows as a single and self limited lesion (Fig ure 9.8). Over time, this lesion bifurcates to give rise to two lesions, or further lesions if the degree of promotion is large enough relative to the degree of inhibition (Figure 9.8). The temporal sequence from a single and self-controlled lesion to the occurrence of multiple lesions is the same as in the previous case. But in contrast to the previous case, no further mutations are required. This is because multiple foci arise from the split and migration of a single lesion. The number of foci that form depends on the exact degree of promotion which was achieved by the initial mutation. The higher the degree of promotion, the larger the number of lesions. Growth beyond this number of lesions (which will eventually result in maximal invasion) then requires higher levels of promotion. This is in turn achieved by further mutational events according to the same principles as described in the previous section.

(iii) Finally, assume that the initial mutation shifts the balance so much in favor of promotion that maximal invasion of the tissue is possible (Figure 9.9). Now we observe cancer progression without the generation of multiple foci. Instead, a relatively small single lesion expands in space until all the tissue has been invaded.

In summary, the model predicts different modes of cancer progression in relation to the evolution away from tumor inhibition and towards promotion. A single cancer lesion may spread across the tissue without the occurrence of multiple lesions. Alternatively, the cancer can first grow as a single, self-contained lesion. This can then bifurcate to give rise to multiple foci, either as a result of additional mutations, or as a result of the natural pathway by which multiple foci are generated, depending on the degree of tumor promotion conferred by the initial mutation. Further evolutionary events can then induce the multiple foci to become a single, maximally invasive mass. The occurrence of multiple foci therefore represents an intermediate stage in tumor progression towards malignancy.

9.5 Clinical implications

The occurrence of multiple lesions is observed in a variety of cancers. That is, not one, but several lesions are observed within a given tissue. Multiple lesions can occur by two basic mechanisms [Hafner et al. (2002); Hartmann et al. (2000); Ruijter et al. (1999); Tsuda and Hirohashi (1995); Wilkens et al. (2000)]. Either they originate independently by separate carcinogenic events, or they are generated by a single transformation event (monoclonal origin). Sometimes, the term "multi-centric cancers" is used to describe the occurrence of clonally unrelated lesions, while the term "multi-focal" refers to a monoclonal origin [Teixeira et al. (2003)]. Clinically, it is important to determine the nature of multiple lesions. The occurrence of multiple lesions can be indicative of a familial cancer, especially if they occur at a relatively young age. Examples are familial adenomatous polyposis (FAP) in the colon, and familial retinoblastoma [Marsh and Zori (2002)]. The genetic predisposition of such individuals renders multiple independent carcinogenic events likely. Alternatively, multiple independent lesions can arise because a large area of tissue has been altered and is prone to the development of cancer, such as Barrett's esophagus [van Dekken et al. (1999)], or by other mechanisms which are not yet understood. On the other hand, genetic analysis has indicated that multiple lesions in several cases have a monoclonal origin [Antonescu et al. (2000); Holland (2000); Junker et al. (2002); Kupryjanczyk et al. (1996); Louhelainen et al. (2000); Middleton et al. (2002); Miyake et al. (1998); Noguchi et al. (1994); Rosenthal et al. (2002); Simon et al. (2001); van Dekken et al. (1999)]. Examples are mammary carcinoma, gliomas, renal cell carcinoma, hepatocellular carcinoma, and esophageal adenocarcinoma.

The models discussed here show that multiple foci with a monoclonal origin can develop through a dynamical interplay between tumor promoters and inhibitors. The cancer can only grow to high loads as a single mass if it has largely escaped all inhibitory effects. Otherwise, the cancer is likely to grow via the generation of a relatively small and self limited tumor which then bifurcates into multiple foci until it finally invades the entire tissue. The occurrence of multiple foci is therefore an intermediate stage in cancer progression. The higher the number of foci, the further advanced the stage of cancer progression.

A clinically important step in carcinogenesis is the process of metastasis. That is, the spread of tumor cells to the lymph node, entry into the blood supply, and the spread to other tissues. Various studies have investigated the metastatic potential of multi-focal compared to uni-focal cancers [Andea et al. (2002); Junker et al. (1999); Junker et al. (1997)]. In uni-focal cancers, tumor size has been found to be a predictor of metastatic potential. For staging multi-focal breast carcinomas, it has been suggested to use the diameter of the largest tumor only [Andea et al. (2002)]. This, however, assumes that the other foci do not significantly contribute to tumor progression. According to our arguments, this would under-stage the cancer. According to the model, the number of foci correlates with the stage of the disease. This has also been concluded in clinical studies, and is supported by data which show reduced patient survival with multi-focal compared to uni-focal cancers [Andea et al. (2002)]. Moreover, because our model suggests that multi-focality can occur as a result of reduced tumor cell inhibition, successful metastatic growth might be easier to achieve. Although under debate, some data suggest that inhibitors produced by the primary tumor can prevent metastatic cells from growing [Ramanujan et al. (2000)]. If multi-focality correlates with reduced inhibition, then it could also correlate with an increased chance that metastatic cells grow and do not remain dormant.

Further, it is important to note that studies which aim to assess the correlation between multi-focality and metastatic potential should not only concentrate on the number of foci, but also on the size of the foci. As we have shown with the model, cancer progression might start with a small single lesion which can be considered uni-focal. It can then bifurcate to give rise to multiple foci, and finally spread through the entire tissue. When such spread occurs, the multiple foci turn into a big and single mass, and this would again be considered uni-focal. Hence, the cumulative size or volume of the tumor is likely to be the best predictor of malignant progression.

Chapter 10

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