Experimental systems for analysis of the malignant phenotype

Abstract

Identification of the cellular and subcellular alterations responsible for the metastatic behavior of malignant tumor cells and development of reliable screening programs for detecting new therapeutic agents for improved treatment of metastatic disease both depend crucially on the availability of experimental systems that can serve as relevant models of human cancer. Recent advances in our understanding of the pathogenesis of cancer metastasis have raised serious doubts about the usefulness of many of the experimental approaches that have long been used in the study of metastasis. Recent findings showing that metastases are caused by specific subpopulations of metastatic tumor cells, and that not all cells in a malignant primary tumor possess metastatic properties, are of profound importance for experimental efforts to understand the mechanism of metastatic phenotype among cells from the same tumor means that the traditional, and widely used, approach of analyzing primary tumors and cultured cell lines containing multiple, phenotypically heterogeneous, subpopulations of cells may provide little or no insight into the properties of the metastatic subpopulations, particularly if they represent only a minor fraction of the entire population. Similarly, the practice of screening potential therapeutic modalities for their ability to reduce the mass and/or growth rate of a primary tumor may be inadequate in predicting the responsiveness of metastatic lesions. Solution of these problems requires that new methods must be devised to isolate and characterize the specific subpopulations of tumor cells endowed with metastatic potential. In addition, knowledge of how the extraordinary phenotypic diversity found in tumor cell subpopulations from the same tumor is generated and how subpopulation diversity is regulated during progressive growth of both the primary tumor and its metastases are of fundamental importance if we are to design meaningful experimental systems for studying the metastatic process. This article reviews our current understanding of these complex issues and their implications for the experimental analysis of the malignant phenotype. The merits and shortcomings of different experimental systems are discussed in detail together with the identification of areas in which new experimental strategies and models are now needed.'

Expression of the metastatic phenotype in cells transfected with human metastatic tumor DNA.

“…Such tumors often contain cells that are heterogeneous in their expression of a variety of traits, this being perhaps due to an underlying genetic variability in this cell population (1)(2)(3)(4)(5)(6). Among the individual cells in the tumor, there may be several that have acquired genetic alterations that promote dissemination.…”

Origin and biology of cancer metastasis

“…It has also been successfully used to produce tumor cell lines with increased metastatic capacity from many of the experimental tumors tested (for review, see Reference 15). The increase in metastatic capacity of the recovered cells does not result from the adaptation of tumor cells to preferential growth in a particular organ during the selection process (15,17,18,25,27,64,65,69,70).In the second approach, cells are selected for the enhanced expression of a phenotype believed to be of importance in one or another step of the metastatic process. The cells are then tested in the appropriate host to determine their metastatic potential.…”

Heterogeneity in a spontaneous mouse lung carcinoma: Selection and characterisation of stable metastatic variants

“…Unfortunately many experimental systems do not meet (in contrast to CMT64 -see conclusion) the basic requirements of a suitable model. (For a detailed discussion of these problems, see Hewitt 1976Hewitt , 1980Poste, 1982. ) Another problem associated with choice of models for metastasis is that many of the tumours used do not metastasise spontaneously.…”

“…Most naturally occurring tumours are epithelial, but many experimental systems for metastasis studies are derived from non-epithelial tumours, or even if epithelial have often been induced by irradiation, chemicals or viruses. Induced tumours often express a level of immunogenicity rarely found with spontaneous tumours (Hewitt, 1976;Poste, 1982).…”