Nontumorigenic Hybrids Research Articles

Specific chromosome loss associated with the expression of tumorigenicity in human cell hybrids.

Four related nontumorigenic and tumorigenic HeLa x fibroblast intraspecific human hybrid cell lines were analyzed to determine whether specific chromosome(s) are associated with the control of tumorigenic expression. The loss of one copy each of both chromosome 11 and chromosome 14 were associated, with a high degree of statistical significance, with the expression of tumorigenicity in two segregants derived from the original nontumorigenic hybrid population. Although the parental origin of the chromosomes could not be established in this study, our preliminary results suggest that complex, genetically determined, regulatory interactions may operate in the control of neoplastic expression.

A nontumorigenic (mouse X human) cell hybrid inhibits tumorigenicity of its malignant mouse parent cell and unrelated human tumor cells in vivo.

This report describes the modulation of malignant through coinoculation in vivo of a malignant mouse (A9) cell line, and a phenotypically stable, nontumorigenic hybrid clone derived from it by fusion with a transformed mutant human cell. Thus, the tumorigenicity of the A9 cells was suppressed by the hybrid cells, but not by the unrelated normal cells. The hybrid cells also inhibited tumor development of unrelated human cancer cells.

Dissociation of anchorage independence form tumorigenicity in human cell hybrids.

The association between anchorage independence and tumorigenicity was examined using a series of intraspecific human cell hybrids. The cell lines represented non-tumorigenic HeLa/fibroblast hybrids and tumorigenic segregants derived from them. These segregants had lost no more than 5% of the original chromosome complement. Both non-tumorigenic and tumorigenic cell populations formed colonies in methyl cellulose. The relative size of the colonies seemed to be inherited as a stable trait. Serial cloning of nontumorigenic hybrids in methyl cellulose led to an enhanced efficiency of colony formation but no selection for tumorigenic segregants. Thus, the property of anchorage independence is clearly dissociated from tumorigenicity in this human cell system. An ancillary observation was the chromosomal stability of the hybrids over many population doublings. This intraspecific human cell model therefore provides a genotypically and phenotypically stable system for examination of the genetic control of transformation and neoplasia.

Inheritance of malignancy in somatic cell hybrids.

After a recall of the importance of early basic developments of in vitro established cell lines for investigations on malignant transformation, a survey of essential steps in the study of malignancy by means of somatic cell hybridization is presented. Since the early sixties, in vitro crosses of malignant versus nonmalignant parental cells have provided many experimental models in which mechanisms of expression of malignancy have been approached. Allogenic as well as xenogenic cell matings resulted in tumor-producing or nontumorigenic hybrids which have been analyzed, particularly in terms of karyology in order to determine possible chromosomal patterns linked with inheritance of malignancy and its suppression. The authors discuss the successive concepts devised for interpretation of experimental data, implicating specific genetic "normalizing" information, genetic dosage as well as, more recently, epigenetic and cytoplasmic mechanisms.

Lack of correlation between the decreased expression of cell surface LETS protein and tumorigenicity in human cell hybrids

An analysis of the correlation between tumorigenicity and the loss of expression of the large external transformation-sensitive glycoprotein (LETS) was performed on human cell hybrids and their respective normal and tumorigenic parental cell lines. The distribution of cell surface LETS protein in a series of cell lines was examined by both specific immunofluorescent staining and by gel electrophoresis of lactoperoxidase-catalyzed, iodinated cell surface proteins. The tumorigenicity of these cell lines was assayed in nude mice. Although the series of cell lines studied provided a broad spectrum of LETS protein expression, both quantitatively and qualitatively, there does not appear to be a correlation between tumorigenicity and decreased expression of the LETS protein. In a series of transformed, nontumorigenic hybrids, the LETS protein expression was found to be altered with respect to both decreased organizational complexity and decreased content. These hybrids continue to express a number of other transformed phenotypes. Conversely, a number of tumorigenic hybrids continue to express relatively high levels of LETS protein when compared with nontumorigenic hybrids. Thus an alteration in LETS protein expression by itself, or in concert with a spectrum of other transformation properties, does not appear to be a sufficient requirement for tumorigenicity and lends further support to an apparent separate control of the transformed versus tumorigenic phenotype.

Analysis of malignancy in human cells: malignant and transformed phenotypes are under separate genetic control.

Human cell hybrids derived from malignant HeLa and normal fibroblast parental cells expressed many of the transformed properties of the HeLa parent but their tumor-producing capability was suppressed. Hybrids derived from HeLa/HeLa fusions retained both their transformed and malignant phenotypes. Thus, an apparent separation of the control of the transformed versus malignant phenotype is indicated. Furthermore, several transformed properties--including lack of density-dependent inhibition of growth, lectin agglutination, lowered requirement for serum growth factors, and anchorage independence--are expressed coordinately in the nontumorigenic hybrids. This finding suggests that none of these properties by themselves, or in concert, endows a cell with tumorigenic potential.