Tumor heterogeneity: Causes and consequences

Abstract

With rare exceptions, spontaneous tumors originate from a single cell. Yet, at the time of clinical diagnosis, the majority of human tumors display startling heterogeneity in many morphological and physiological features, such as expression of cell surface receptors, proliferative and angiogenic potential. To a substantial extent, this heterogeneity might be attributed to morphological and epigenetic plasticity, but there is also strong evidence for the co-existence of genetically divergent tumor cell clones within tumors. In this perspective, we summarize the sources of intra-tumor phenotypic heterogeneity with emphasis on genetic heterogeneity. We review experimental evidence for the existence of both intra-tumor clonal heterogeneity as well as frequent evolutionary divergence between primary tumors and metastatic outgrowths. Furthermore, we discuss potential biological and clinical implications of intra-tumor clonal heterogeneity.

Cancer cells in epithelial-to-mesenchymal transition and tumor-propagating–cancer stem cells: distinct, overlapping or same populations

“…In fact, cell populations in cancers are genetically very heterogeneous, as demonstrated by several groups (Campbell et al, 2010;Marusyk and Polyak, 2010;Yachida et al, 2010). This genetic diversity within breast cancers is similar within the lesions and the invasive regions, and is predictive of progression (Merlo and Maley, 2010).…”

“…They need not be expressed in all cancer cells or at the same time. This is synthesized in the word 'phenotypic plasticity' (Polyak and Weinberg, 2009;Marusyk and Polyak, 2010). Besides such transient phenotypic fluctuations, cancer cell populations also evolve by genetic and epigenetic mechanisms.…”

Cancer Stem Cells in Tumor Heterogeneity

“…While direct evidence for any model of tumor progression is difficult to come by, the clonal evolution hypothesis is compatible with several characteristics of cancer including phenotypic heterogeneity (Marusyk and Polyak, 2009), genetic instability (Hanahan and Weinberg, 2000) and the frequent emergence of chemotherapy-resistant clones after treatment (Shah and Sawyers, 2003). The clonal evolution model further rests on the widespread notion that primary tumors and metastases frequently share the vast majority of genetic aberrations, but that metastases (that are thought to arise from cells generated by clonal evolution within the primary tumor) have acquired additional hits not present in the primary tumor.…”

Culture of low passage colorectal cancer cells and demonstration of variation in selected tumour marker expression

“…The progression and growth of a tumour is a complex process, and as cells develop and proliferate, further mutations occur. This could be due to interactions with other cells and changes in the microenvironment that allow certain cells to gain differential abilities to proliferate, maintain their ''stemness'' in particular niches, gain resistance to various drugs and treatment modalities and metastasize even though they may originate from a single cell or a homogenous group of cells (Li et al 2008;Lodish et al 2000;Marusyk and Polyak 2010). This tumour diversity leads to various responses to treatment, recurrence and relapses after initial treatment and is therefore recognized as the major hurdle to cure cancer (Li et al 2008;Quintana et al 2010;Sharma et al 2010).…”

“…However, the use of established homogenous cell lines from different sources may not reflect the possible spectrum of tumour cells that exists in a single population or even a single person. Moreover, within a supposedly ''homogenous cell'' population, genetic differences among cells have been found presumably because cells will mutate and transform away from their original primary characteristics with each increasing passage (Marusyk and Polyak 2010;Rubin 2001Rubin , 2005Stockholm et al 2007). …”