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RESEARCH PRODUCT

Cancer Clonal Evolution and Intra-tumor Heterogeneity

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Despite recent advances in understanding cancer onset mechanisms and development of new therapeutic approaches, however, the resistance of tumor cells to different therapies represents the main obstacle to the successful treatment, resulting in poor prognosis and tumor recurrence. Currently, understanding the causes underlying this resistance is the main objective of oncology research in recent years. Tumors are not uniform diseases but heterogeneous entities consisting of cell populations called clones, with different genetic and molecular characteristics. Indeed, most of cancers shows usually a single clonal origin at the early stages of the disease, but, in advanced stages, tumors may include multiple cell populations with different properties. A key event in cancer clonal evolution process is the variability observed within individual tumors, called intra-tumor heterogeneity, which promotes and drives a genetic selection mechanism of fittest cell clones. Usually, the origin of tumor heterogeneity may be explained by two theoretical models potentially complementary, the clonal evolution model and cancer stem cell (CSC) hypothesis. The intra-tumor heterogeneity detected in most of tumors has been shown to restrict therapy response and induce changes in clinical patterns, by affecting the treatment effectiveness. Among tumors, melanoma and non-small cell lung cancer (NSCLC) can provide an interesting example of intra-tumor heterogeneity. In this chapter, we will describe the model of cancer clonal evolution and concept of intra-tumor heterogeneity, discussing how these may affect the tumor recurrence, clinical outcome, therapy response, and emergence of drug resistance.