Research On Temporal Heterogeneity In Tumor Homologous Clones Mediated By Polyploid Giant Cells

It is generally believed that malignant tumors are often monoclonal origin.But still,the extensive intratumoural heterogeneity was commonly existed in most type of cancer.Even a same histological derived local tumor mass can also classified into subtypes and has heterogenous morphology and biologic behavior morphology.It is contradict to explain this specialty in tumor cells.Many studies suggested that it was due to the intrinsic characteristic in tumor cells,such as unstable genetic alterations,DNA repair deficiency or beneficial mutational events.But more others also proposed opposite views.It considered that under different extrinsic environmental stress in vitro or in vivo,cancer cells could undergo different developmental process,leading multiple variant subclones emerged.Thus,the causations for tumors heterogeneity could not just simply ascribed by one or several reasons.Recent years,much more studies derived from clinical tumor specimen also conclude that the heterogeneity in tumor cells even has the spatial and temporal characteristic,which leads different patients have different therapeutic response to same therapeutic manner and different prognosis even in the same cancer type.The spatial and temporal heterogeneity in tumor cells is the major obstacle to improve cancer therapeutic outcome.Unfortunately the underlying mechanism was poorly understood.Some researchers propose that tumor clonal dynamics evolution may be involved.For more clearly demonstration of the cancer evolution,here,we first established three generations of progeny clones by continuously single cell suspension culture.Herein,all colonies examined in the study derived from a single cancer cell of HCT116 cell line and have isogenic genetic background.However,under conventional condition or radiation stress,the spatial and temporal heterogeneity always existed even among the third generation clones,and the unexpected variant cell populations could not be dispelled.That confirmed by karyotype and Copy Number Variation(CNV)analysis and suggested the neutral evolution ubiquity.And under radiation stress,we could also confirm the presence of Darwinian evolution by some selected cell populations observed among more relative resistant clones.These special cell populations(endopolyploid giant cells)with unique characteristic were often unnoticed in other researches.They sustained growth arrest but could viable and can further undergo “neotic” cell division,ultimately giving rise to diploid progeny.Even more interestingly,undergone a series of selected evolution,these new generated diploid progeny could still maintain the similar genetic characteristics as the parental cells.Thus,by contrast with the prevailing view of Darwinian selection on cancer evolution,our study made a further explanation to demonstrate more complex multiple evolutionary models among homologous clones.As for which evolutionary patterns were recruited by tumor cells largely depends on its biological and the environmental context.