Apparent reversion of stable in vitro genetic markers detected in tumour cells from spontaneous metastases

Abstract

The evolution towards more aggressive and autonomous behaviour of many cancerous tumours, often referred to as tumour progression¹, is thought to stem from the development of heterogeneity within the tumour cell population, combined with the continuous selection of progressively more malignant cellular phenotypes^2,3. During the course of the disease, the tumour cells show multiple phenotypic changes in a stepwise, but apparently random fashion, becoming more anaplastic, increasingly independent of growth controls and more metastatic⁴. Several laboratories, including our own, have analysed aspects of tumour heterogeneity and cancer metastasis by selecting and studying the properties of lectin-resistant (Lec^R) membrane mutant tumour sublines^5–8; in a few cases, such variants have been claimed to be less tumorigenic^5,6 or metastatic^7,8 than the parental cells from which they were derived. We have attempted to study the factors involved in the reestablishment of tumour heterogeneity by monitoring the stability in vivo of Lec^R phenotypes of metastatic tumour cells after injection of cloned Lec^R tumour cells. We now report that spontaneous metastases arising after a subcutaneous (s.c.) injection of cells from variant tumour lines selected from a highly metastatic DBA/2 mouse tumour known as MDAY-D2⁹, and which were stably resistant in tissue culture to wheat germ agglutinin (WGA), no longer carry the WGA-resistant (WGA^R) phenotype. The results demonstrate that WGA^R tumour cells do not metastasize, but rather, ‘revertants’ for the WGA^R phenotype, which presumably were generated in vivo after injection, were the cells actually capable of metastatic growth.