Abstract
Tumour heterogeneity refers to the fact that different tumour cells can show distinct morphological and phenotypic profiles, including cellular morphology, gene expression, metabolism, motility, proliferation and metastatic potential. This phenomenon occurs both between tumours (inter-tumour heterogeneity) and within tumours (intra-tumour heterogeneity), and it is caused by genetic and non-genetic factors. The heterogeneity of cancer cells introduces significant challenges in using molecular prognostic markers as well as for classifying patients that might benefit from specific therapies. Thus, research efforts for characterizing heterogeneity would be useful for a better understanding of the causes and progression of disease. It has been suggested that the study of heterogeneity within Circulating Tumour Cells (CTCs) could also reflect the full spectrum of mutations of the disease more accurately than a single biopsy of a primary or metastatic tumour. In previous years, many high throughput methodologies have raised for the study of heterogeneity at different levels (i.e., RNA, DNA, protein and epigenetic events). The aim of the current review is to stress clinical implications of tumour heterogeneity, as well as current available methodologies for their study, paying specific attention to those able to assess heterogeneity at the single cell level.
Highlights
In oncology, molecular, cellular and architectural variability are frequently referred to with the term “heterogeneity”, a concept that increases the complexity of the pathogenesis of malignant tumours.In terms of cell phenotype, cell density or cell location, cell heterogeneity can be observed between tumours that occur in the same organ and/or between patients
We previously described in detail and discussed advantages and pitfalls of various methodologies suitable for Circulating tumour cells (CTCs) enrichment and isolation [5]
In situ hybridisation techniques make it possible to detect RNA, DNA and protein molecules with high sensitivity in both frozen and formalin-fixed paraffin-embedded (FFPE) tissues [69,70]. These techniques are normally the preferred methods for studying tumour heterogeneity for several reasons: there are many available samples as they are a routine part of pathological diagnostic; they preserve the specificity of tissue context and they have been used to investigate tumour traits at the single-cell level
Summary
Molecular, cellular and architectural variability are frequently referred to with the term “heterogeneity”, a concept that increases the complexity of the pathogenesis of malignant tumours.In terms of cell phenotype, cell density or cell location, cell heterogeneity can be observed between tumours that occur in the same organ and/or between patients. Tissue variation occurs within individual tumours (intra-tumour heterogeneity), meaning that tumour cells can have various functional properties and can express several markers [1,2]. Such heterogeneity is likely to result in tumours adapting to changes in microenvironmental conditions and/or a tool for changing their malignant potential. This in turn will lead to cellular clones with different sets of undetermined hallmarks [1,3]. Tumour heterogeneity has several key clinical impacts: (i) it has been associated with acquired drug resistance; and (ii) it limits the precision of histological diagnoses and reduces the value of a biopsy
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