| Abstract |
This thesis records the results of a series of experiments on the kinetics
of growth of 7 human malignant melanomas in nude mice, with particular
reference to factors in the host "milieu" that modulate proliferation,
metastasis and phenotypic expression of the tumours. Melanoma cell lines
were established in vitro, from biopsy material obtained from 7 patients
with metastatic malignant melanoma. Two of these lines synthesized
tyrosinase and melanin at a rate that was directly related to cell density.
The five remaining lines did not pigment in vitro. With the exception of
one line they all gave rise to tumours when inoculated subcutaneously into
nude mice. All 7 lines were aneuploid and 5 of the lines showed anchorage-
independent growth in vitro. The growth rate and latency period of these
human melanoma cell lines has been studied in nude mice as a function of
inoculum size. Considerable variation was observed and growth rate in vivo
correlated poorly with the doubling times of the corresponding cells
cultured in vitro. Passage through nude mice had no effect on in vitro
phenotypic characteristics of cell lines. In spite of prolonged in vitro
passage, in a number of instances the histological appearances of the mice
tumours were very similar to those seen in the original patient.
Coinjection of either adult or juvenile skin fibroblasts with
subtumorigenic doses of melanoma cells promoted the growth of tumours that
would otherwise not have formed. One of the melanoma cell lines grew
rapidly in a male host at an inoculum level that did not give rise to
tumours in the female mouse, showing that hormonal influences in the host
have a definitive effect on the growth of some melanomas in vivo.
Castrated male mice also failed to support the growth of this melanoma
cell line. Addition of estrogen and dihydrotestosterone pellets to the
castrated and ovariectomised mice proved in certain cases to be effective
stimulants of tumour growth. By excising the primary tumour before it
reached a size which was lethal to the host, metastases were made evident
in a number of instances, Two of the six melanoma cell lines showed
metastatic melanoma deposits in 100% of the animals inoculated. This
occurred within 12 weeks of removal of the primary tumour. In one of the
two cell lines metastatic spread was directly related to the size of the
primary tumour. One of the cells lines, UCR-Mel 7 elicited an intense
desmoplastic response in the host and the tumours were heavily infiltrated
with host macrophages and fibroblasts. This cell line had a most unusual
behaviour pattern in the mouse as it grew exponentially for a fairly brief
period after which a plateaux phase occurred during which no growth took
place. This was followed by a phase of regression and then a prolonged
period of dormancy after which a rapid exponential growth phase followed.
Tumours transplanted to new mice during this latter phase gave rise to
rapidly growing neoplasms which were lethal to their hosts.
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