A Study of the Factors Which Affect the Growth of Tumour Cells at Distant Sites


The aim of this thesis is to investigate some of the factors which affect the growth of metastasising cells at distant sites. Previous experiments, mostly involving intravenous injection of cultured murine B16 melanoma and other tumour cell lines, have suggested that subpopulations of cells exist within tumours which are capable of metastasis, sometimes to specific organs. One criticism of these studies is that growth at a distant site is but one characteristic required for a cell to successfully form a metastatic deposit. The cell must also express other phenotypic characteristics such as motility and invasion and in some cases evasion of host defences. Much of the experimental work in this thesis makes use of the B16 melanoma F10 and F1 cell lines. The F10 cell line was derived many years ago by repeated in vivo passage through the lungs of syngeneic mice while the F1 cell line was passaged in vivo only once and has been maintained exclusively in vitro. In this study it was found that the F10 cell line formed tumours at a high rate, exclusively in the lungs, whereas the F1 cell line was much less metastatic and selective in its site of growth. The use of radio-labelled cells showed that the F10 cells were more avidly trapped in the lungs than the F1 cells but the difference in lung trapping between the two cell lines was less marked than the difference in lung tumour formation. These results broadly confirm the results of earlier studies and show that despite prolonged culture the cell lines have been stable with respect to these properties. In contrast to the results of intravenous injection, when F1 and F10 cells were injected into the peritoneal cavity it was found that there was no difference in the number of tumours produced. Each cell line was then subjected to repeated intraperitoneal passage to see whether passaged cells formed more local tumours when injected peritoneally, whether such cells would home to the peritoneal cavity following intravenous injection, and if passage in the peritoneum would effect lung homing properties particularly of the F10 cell line. After 16 passages an F10 cell line was produced which grew more readily in the peritoneal cavity but did not produce abdominal tumours when injected intravenously: lung tumour formation was unaffected. When F1 cells were passaged it was found that after 8 passages cell growth in vitro and in the peritoneal cavity was so greatly reduced that in only one of three sets of experiments was it possible to proceed beyond the eighth passage. The set of F1 cells which reached passage 16 continued to show poor growth in vitro and after intraperitoneal injection but surprisingly produced a much larger number of lung tumours following intravenous injection than the parent cell line. This latter change was not accompanied by increased cell trapping in the lungs. By way of comparison a benign virus-induced salivary tumour was studied. This model was limited by failure to culture the tumour cells in vitro. When a cell suspension derived from this tumour was injected intraperitoneally no tumours resulted. Thus the benign nature of this tumour may have been partly due to an inability to grow at a distant site. An attempt was made to correlate adhesion of B16 and salivary tumour cells to tissue sections with their sites of growth but in contrast to previous studies no such correlation was found. Mechanisms to account for these results are discussed with particular reference to the effects of selection, trapping by the vasculature and the influence exerted by local tissue environments on tumour cells. While these mechanisms are often difficult to separate experimentally there was some evidence that local environments may play a larger part than hitherto realised in controlling the growth of metastasising tumour cells. Little is known of the molecular basis of tumour cell metastasis, though attempts to identify cell surface proteins and more recently the genes involved in the process have met with some success. Since the histo-compatability proteins are known to participate in a wide range of cellular interactions, they may be involved in the process of metastatic tumour growth. (Abstract shortened by ProQuest.)

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This paper was published in Glasgow Theses Service.

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