Overview on Clinical Relevance of Intra-Tumor Heterogeneity

Abstract

Today, clinical evaluation of tumor heterogeneity is an emergent issue to improve clinical oncology. In particular, intra-tumor heterogeneity (ITH) is closely related to cancer progression, resistance to therapy, and recurrences. It is interconnected with complex molecular mechanisms including spatial and temporal phenomena, which are often peculiar for every single patient. This review tries to describe all the types of ITH including morphohistological ITH, and at the molecular level clonal ITH derived from genomic instability and nonclonal ITH derived from microenvironment interaction. It is important to consider the different types of ITH as a whole for any patient to investigate on cancer progression, prognosis, and treatment opportunities. From a practical point of view, analytical methods that are widely accessible today, or will be in the near future, are evaluated to investigate the complex pattern of ITH in a reproducible way for a clinical application.

Keywords: cancer spreading; clonal intra-tumor heterogeneity; functional phenotypic plasticity; genomic instability; intra-tumor heterogeneity; morphohistological intra-tumor heterogeneity; stochastic plasticity.

Figure 1

Different types of intra-tumor heterogeneity (ITH) in an organoid structured multiclonal tumor: the primary clone is blue (the peripheral area is light blue and the central one is darker), the other clones are of different size and multicolor.

Figure 2

Schematic representation of an organoid tumor with peripheral cells (yellow) surrounded by stroma components and phenotypically different from the central cells (gray). On the upper part, two metastases are schematically represented.

Figure 3

High-grade ovary serus carcinoma: (A) p16 clonal type intra-tumor heterogeneity (ITH) and (B) Ki67 stochastic plasticity.

Figure 4

Proposal of tumors larger than 2-cm sampling for in situ analyses: (A) multiple sampling locations and (B) organization in the inclusion block.