Tumour cells transformation

Most transformed cells do not express class II MHC molecules and express lower than normal levels of class I MHC molecules. This renders their detection by immune effector cells more difficult. Treatment with cytokines, such as IFN-y, can induce increased class I MHC expression, which normally promotes increased tumour cell susceptibility to immune destruction. 

TNF fails to induce death of all tumour cell types. Although many transformed cells are TNF sensitive, the cytokine exerts, at best, a cytostatic effect on others and has no effect on yet others. The cytotoxic activity is invariably enhanced by the presence of IFN-y. The concurrent presence of this interferon increases the range of transformed cell types sensitive to TNF-a, and can upgrade its cytostatic effects to cytotoxic effects. It can also render many untransformed cells, in particular epithelial and endothelial cells, susceptible to the cytotoxic effects of TNF-a. 

Figure 13.4 Binding of appropriate antibody to tumour-associated antigens marks the tumour cell for destruction. This is largely due to the presence of a domain on the antibody Fc region (see also Box 13.2), which is recognized and bound by macrophages and NK cells. Therefore, congregation of such cells on the surface of the tumour is encouraged. This greatly facilitates their cytocidal activity towards the transformed cells...

An alternative anti-cancer strategy entails insertion of a copy of a tumour suppresser gene into cancer cells. For example, a dehciency in one such gene product, p53, has been directly implicated in the development of various human cancers. It has been shown in vitro that insertion of a p53 gene in some p53-dehcient tumour cell lines induces the death of such cells. A potential weakness of such an approach, however, is that 100 per cent of the transformed cells would have to be successfully treated to fully cure the cancer. Tumour suppressor-based gene therapy in combination with conventional approaches (chemotherapy or radiotherapy) may, therefore, prove most efficacious, and the sole gene-therapy-based medicine approved to date (in China only) is based upon this approach (Box 14.2). 

The interest in bile acids as potential carcinogens was subject to investigation as early as 1940 when Cook et al. reported in Nature that repeated injection of deoxycholic acid into the flanks of mice could induce tumour formation in mice." Furthermore, Kelsey and Pienta showed that treatment of hamster embryo cells with lithocholic acid could cause cell transformation. ... 

Figure 10.5. Upon transformation, cancer cells often express unique surface antigens termed tumour surface antigens (TSAs). Antibodies raised against these will selectively bind the tumour cells. The antibody used may be unconjugated or conjugated to a drug, toxin or radioactive tag...

Cells transformed with the papovaviruses polyoma (e.g. BHK 21PyY, Dulbecco, 1968) and SV40 (e.g. SV28, Wiblin and Macpher-son, 1972) show the presence of tumour antigen by immunofluorescence, but this is not harmful it rather results in an increased growth potential and consequent disregard for neighbouring cells. 

As has already been mentioned, some lipophilic rifamycins and some strepto-varicins and geldanamycins affect the growth of cells transformed by RNA tumour viruses or the RNA-dependent DNA polymerase (reverse transcriptase) characteristic of these viruses. Again, high drug concentrations are needed to produce an effect and only partial, but never absolute, selectivity of enzyme inhibition has been found. 

Fig. 17.3 The expression of two oncogenes, SV40 TAg and H-ras, together with the catalytic subunit of human telomerase, hTERT, transforms normal human cells to immortal cells and eventually to tumour cells. (Information from Hahn et a/. t r see also ref. 15.)...

There have been some attempts to use spin labels to probe for differences in the properties of membranes of normal and tumour cells. Thus mouse embryo fibroblasts have been labelled with C (n = 4, m = 10) and it was found that on transformation with oncogenic DNA or RNA... 

---