Question

Briefly explain why you might expect neoplastic cells in a primary tumor to be more heterogeneous to each other (especially in terms of mutations) as compared to the neoplastic cells in a metastasis.

Answer 1

Ans:

The types of variability usually meant by the term tumor heterogeneity are cellular differences within a single neoplasm. Tumors are architecturally complex, differing regionally in vasculature, host infiltrates, connective tissue components, and other characteristics which can alter the phenotype of otherwise identical cells. Marked differences in the proliferation behavior of tumor cells within a single cancer are common place. Some cells are reproductively dead; others are out of cycle; and still others are cycling but are, at a given time, at different stages in the process. Heterogeneity is a feature of neoplastic development that can precede the tumor itself.

Cellular heterogeneity must be viewed then as a feature of both normal and precancerous tissues. It seems not unlikely that the mechanisms that are responsible for variability under these circumstances could also be responsible for generating tumor heterogeneity. Besides "normal" mechanisms, heterogeneity may arise by tumor specific mechanisms. Increased genetic instability is a case in point. This instability leads to more errors in tumor cell DNA (point mutations, genomic rearrangements, chromosome losses, gene amplification, etc.) and is reflected in increased phenotypic variability.

Studies of intratumoral heterogeneity have proliferated in recent years. These studies have developed from two converging sources. First, recent years have seen the creation of numerous agents that target specific biologic pathways, each with its own particular resistance mechanisms. Secondly, the “omics” revolution has revealed the true nature of intratumoral heterogeneity at multiple levels and such epigenomic, genomic, and proteomic analyses have enriched our understanding of why cancers grow and kill.

Examples of tumor heterogenecity includes:

• A pathologist notes that some tumor cells in a breast cancer are amplified for human epidermal growth factor receptor 2 (HER2) by fluorescence in situ hybridization (FISH), while others express normal HER2 copy numbers.
• A medical oncologist, treating a patient with metastatic colorectal cancer with epidermal growth factor receptor (EGFR)-targeted therapy, observes growth of one liver metastasis while another shrinks.