The Cancer Journal - Volume 8, Number 3 (May-June 1995)
The Immune System and Cancer Progression
In this issue, Hammond et al (p. 130 ) report results concerning the role of the immune system in tumour progression According to the concept first put forward by L. Foulds in 1958 and refined by P Nowell in 1986, malignant tumours change in structure during their development They become less and less differentiated at the same time as their malignant, invasive and metastatic capacities increase.
Is the biological mechanism behind this progression towards dedifferentiation and high malignancy genetic or epigenetic? This question is just as burning now as it was twenty years ago.
It is obvious that the chain of phenotypic alterations underlying histological observations cannot be considered in the same way if each stage is determined by a more or less stable mutation in the genome or if, on the other hand, one or a few mutations set off a series of epigenetic changes.
Studies of tumour progression in man are limited to comparing biopsies taken at different times during the development of a cancer and its local or distant recurrences The progression of transplanted tumours can be studied in experimental models To date, these have been either animal tumours for which the tumour, the donor and the recipient are isogenic and the host has the same level of immunocompetence as the original and subsequent donors, or xenogenic systems in which animal or human tumours are transplanted into immunodeficient hosts such as nude or SCID mice.
The strong point of the work by Hammond et al was to use an isogenic system with immunosuppressed hosts, which is the only way to study the role of the immune system per se in tumour progression Up to now, this had never been done Furthermore, Hammond et al had the merit of using first generation (FI ) hybrids of inbred parental strains, thus bringing their model much closer to the natural situation So much work is done, unnecessarily, with inbred donors and recipients It should be remembered that FI hybrids are just as isogenic as the inbred parental strains, whose homozygotic genes do not add anything for the purposes of the experiment.
The loss of phenotypic differentiation, taken as the criterion of progression during the development of the tumours, seemed to depend, at least in part, on the immunocompetence of the host Progression was less frequent and less marked when the isogenic host was immunodeficient, as if immunodeficiency helped to maintain the differentiated state or, on the other hand, immunocompetence favoured dedifferentiation.
Does immune pressure in the immunocompetent host select less differentiated and less antigenic variants? Or does the immune system intervene more directly in cell and tissue differentiation? Both mechanisms are probably involved, at the same time as other factors It should be noted that immunosupression was acheived by giving a single dose of cyclophosphamide This is one technique among many, and all may not work in the same way Hormonal and nervous stimulation may also influence tumour progression In any case, the work of Hammond et al points to an epigenetic progression, which gives hope that it might be reversible Apart from total excision or destruction of the tumour, the proponents of an exclusively genetic mechanism for progression can only suggest gene therapy, and are busy working to develop this.
Smaller resources are deployed in the study of epigenetic mechanisms of tumour progression and dedifferentiation The work of Hammond et al is innovative and should stimulate renewed interest in analysing the underlying mechanisms and searching for therapeutic means to reverse tumour progression.
1 Hammond W.G., Benfield J.R., Tesluk H., Johnson J R., Teplitz R L Tumor progression by lung cancers growing in hosts of different immunocompetence Cancer J 8, 130-138, 1995
2 Foulds L The natural history of cancer J Chron Dis 8, 2-37, 1958.
3 Nowell PC Mechanisms of tumor progression Cancer Res 46, 2203-2207, 1986.