Somatic cell fusion as a source of genetic rearrangement leading to metastatic variants

Abstract

Tumor cell populations displaying metastatic properties often have higher gene dosage than their less malignant progenitor tumors, as shown by increased ploidy levels, chromosome duplication and gene amplification. The acquisition by tumor cells of high chromosome numbers may be due to endoreduplication or somatic hybridization either between tumor cells or between tumor and host cells. All such mechanisms increase genetic variability and instability in tumor cells since they trigger a polyploidization-segregation cycle. Among the wide variety of segregants which may emerge from high-ploidy cells, variants with increased malignancy can be positively selected in vivo. Evidence for in vivo fusion of tumor and normal host cells has been reported in different tumor systems. However the attainment by tumor-host hybrids of a higher degree of malignancy has only been observed following substantial chromosome segregation. The involvement of a cell of bone marrow origin as preferential host partner in the fusion process has been proved both by studies on tumor-host hybrids in bone marrow radiation chimeras and in vitro hybridization experiments between non-metastatic tumors and normal lymphoreticular cells which have led to the establishment of metastatic variants. Several different segregational mechanisms may bring about homozygosity or hemizygosity of recessive alleles in tumor-host hybrids, leading to their expression. The marked chromosome dynamics of tumor-host hybrids are also responsible for extensive chromosome rearrangements. At the molecular level these may represent mechanisms causing altered oncogene activity. The activation of new oncogenes by transposition or amplification as well as the amplification of previously activated oncogenes are the mechanisms most likely to be responsible for transition from low to high malignancy, occurring through ploidy changes, such as those produced by somatic mating.

Spontaneous Fusion with, and Transformation of Mouse Stroma by, Malignant Human Breast Cancer Epithelium

“…Previous studies have shown that activated stroma is involved in tumorigenesis, and that within malignant lesions, it supports angiogenesis and extracellular matrix remodeling (29,30). We propose that in established tumors, activated stroma may also be genetically transformed, enhancing aggressiveness and metastatic potential because it is composed of hybrid cell variants expressing properties that differ from those of either parental cell (18,31,32). That is, when genetic alterations are induced in stroma by its malignant epithelial partner, the resultant tumor-now a mixture of transformed cell types-will augur a poor prognosis for the patient.…”

Tetraploidization increases sensitivity to Aurora B kinase inhibition

“…10 Moreover, evidence from transformation of mouse epithelial cells also indicates the appearance of tetraploid cells before they undergo a period of chromosome instability. 11 Several processes that cause tetraploidization, including chromosome nondisjunction (which promotes cleavage furrow regression), 12 persistent telomere damage 13 and virus-mediated cell fusion, 14 have been implicated in tumorigenesis. Finally, tetraploids generated by transiently blocking cytokinesis in p53-null mouse mammary epithelial cells can trigger tumor formation after injection into nude mice.…”

Detection of chromosome aberrations in metaphase and interphase tumor cells by in situ hybridization using chromosome-specific library probes

“…Such non-random changes may occur at an early stage in tumorigenesis and can be characteristic or even unique for specific tumor types (Showe and Croce 1987;Bloomfield et al 1987;Hansen and Cavenee 1987). Non-random changes are also associated with an increased metastatic potential (Larizza and Schirrmacher 1984). Chromosomes can exhibit highly complex structural alterations, especially in some epithelial tumors, and these complex alterations are often associated wittl progressive biologi-cal features of malignancy that are detrimental to the organism.…”