PMC

Tumor heterogeneity. Levels of heterogeneity. (A) The differences among tumor cells are termed intratumor or intercellular heterogeneity. The dominant subclone () in the primary tumor (top) was also the founder of metastases (bottom). (B) The differences among the primary tumor () and metastatic () tumors and among metastases constitute intrapatient intertumor heterogeneity. (C) The differences among tumors from different patients are termed interpatient heterogeneity. Heterogeneity bases. (D) Genetic heterogeneity arises from various changes within genome. On this scheme, the primary tumor (top) contains cells wild type given some gene as well as cells harboring a mutated allele. Wild-type subclone was the founder of two metastases (bottom left). However, one of them acquired a mutation in this gene (middle). The mutated subclone was the founder of third metastasis. (E) Heterogeneity of transcriptome and proteome constitute heterogeneity of gene expression. Low-expressing subclone was the founder of one metastasis, which is homogeneous given this gene expression. However, the other two metastatic tumors were formed by a high-expressing subclone, although both metastases heterogeneously express this gene on mRNA/protein marker level. (F) The primary tumor is homogeneous given methylation status of some gene promoter – remain nonmethylated. One metastasis mirrors the status of primary tumor, while the other two metastatic tumors are heterogeneous. One tumor (middle) exhibits epigenetic heterogeneity developed during progression since one of the tumor cells acquired an epimutation. The last metastasis is homogeneous because the founder cell acquired an epimutation. Therefore, methylation of promoter is present in all tumor cells.

The narrow metabolomic diversity of the so-called CSC states could be employed to reduce multidimensional tumor heterogeneity into dynamic models of fewer actionable subtypes.

Different types of tumor heterogeneity. (A) Intratumor heterogeneity: the presence of multiple subclones within a primary tumor resulting in heterogeneity among tumor cells. (B) Interpatient heterogeneity: the presence of unique subclones in the tumor of each patient. (C) Intermetastatic heterogeneity: the presence of different subclones in different metastatic lesions of the same patient; some subclones may have been derived from the primary tumor and some may have emerged as a result of acquired alterations within each metastatic lesion. (D) Intrametastatic heterogeneity: the presence of multiple subclones within a single metastatic lesion.

Tumor heterogeneity. Levels of heterogeneity: (a) different subclones in the primary tumor and metastasis define the spatial intra- and inter-tumoral heterogeneity; (b) differences among the primary tumor and tumor evolution after first, second, and third-line therapy and among metastases constitute temporal heterogeneity; (c) tissue biopsy performed on the primary tumor allows the assessment of only partial intra- and inter-tumoral heterogeneity; (d) liquid biopsy and sequencing allow detection of both the spatial and temporal tumor heterogeneity.