Tumor Heterogeneity: Mechanisms and Bases for a Reliable Application of Molecular Marker Design

Abstract

Tumor heterogeneity is a confusing finding in the assessment of neoplasms, potentially resulting in inaccurate diagnostic, prognostic and predictive tests. This tumor heterogeneity is not always a random and unpredictable phenomenon, whose knowledge helps designing better tests. The biologic reasons for this intratumoral heterogeneity would then be important to understand both the natural history of neoplasms and the selection of test samples for reliable analysis. The main factors contributing to intratumoral heterogeneity inducing gene abnormalities or modifying its expression include: the gradient ischemic level within neoplasms, the action of tumor microenvironment (bidirectional interaction between tumor cells and stroma), mechanisms of intercellular transference of genetic information (exosomes), and differential mechanisms of sequence-independent modifications of genetic material and proteins. The intratumoral heterogeneity is at the origin of tumor progression and it is also the byproduct of the selection process during progression. Any analysis of heterogeneity mechanisms must be integrated within the process of segregation of genetic changes in tumor cells during the clonal expansion and progression of neoplasms. The evaluation of these mechanisms must also consider the redundancy and pleiotropism of molecular pathways, for which appropriate surrogate markers would support the presence or not of heterogeneous genetics and the main mechanisms responsible. This knowledge would constitute a solid scientific background for future therapeutic planning.

Expression of miR-146a in patients with ovarian cancer and its clinical significance

“…An extensive range of miR-146a expression levels observed in primary tumor tissues in the present study may support this hypothesis. Primary tumors are composed of cell clones with different invasive potentials (35). It was demonstrated that the pattern of miRNA expression varied between cultured SKOV-3 and OVCAR-3 cell lines and was associated with invasiveness (36).…”

Clonal intratumor heterogeneity of promoter hypermethylation in breast cancer by MS-MLPA

“…Nevertheless, rare subclones not detected by MS-MLPA may have the capacity to become driver events (and vice versa) as environmental selection pressures change during tumor growth and therapeutic intervention. 24 In summary, we have demonstrated that clonal epigenetic heterogeneity is present within most primary breast carcinomas and can lead to aberrant methylation status calling by MS-MLPA, indicating that analysis of a single random sample may not be representative of the whole tumor, which may hamper epigenetic biomarker discovery and validation. Intertumor heterogeneity was nevertheless more pronounced than intratumor heterogeneity.…”

Apoptosis as a Therapeutic Target in Cancer and Cancer Stem Cells: Novel Strategies and Futures Perspectives

“…The features in common with stem cells are: indefinite self-replication, asymmetric cell division, and resistance to toxic agents, owing, in part, to elevated expression of ABC transporters [199,200,201]. In addition, they are also characterized by genetic instability (chromosomal and microsatellite), changes of chromatin, transcription and epigenetics, mobilization of cellular resources, and modified microenvironment interactions (tumour cells, stromal cells, extracellular, endothelium) [202]. Both paradigms of tumour propagation are likely to exist in human cancer but only the CSC model is hierarchical.…”

“…This theory continued to evolve, and the isolation of four different tumour subpopulations from a single breast cancer in a mouse was reported in the decade of the 80s [204]. Tumour heterogeneity is reflected in different phenotypic aspects such as cell morphology, gene expression, metabolism, motility and proliferation, immunogenic, angiogenic and metastatic potential [202]. Molecular characterization of CSCs is necessary to develop a targeted therapy (Table 6).…”