Cancer Stem Cells: Understanding Tumor Hierarchy and Heterogeneity

    Early evidence of intratumor heterogeneity came from experiments in which tumor cells from murine cancers were extracted and introduced into syngeneic hosts. It was determined that not all transplanted cells could reconstitute tumors.Similarly, varying numbers of metastatic colonies resulting from injection of syngeneic mice with murine melanoma tumor-derived cells suggested that the parent tumor harbored cells with diverse metastatic potential.

        In small sets of studies in patients with terminal cancer, tumors were auto transplanted subcutaneously and even then did not initiate new tumors in every case. In glioblastoma (GBM), analysis of tumor fragments from the same tumor revealed various gene losses and amplifications.Additionally, results from mitotic heterogeneity experiments and gene expression signature analysis demonstrated complex cell clonal population hierarchies and the presence of multiple GBM subtypes within a single tumor, respectively. These results clearly indicated the presence of multiple clonal cell populations within the tumors.

    Intratumor heterogeneity was strongly demonstrated at the genetic level in renal cell carcinoma. Study results showed that samples from different regions of the same tumor often displayed varying mutations and chromosomal imbalances. In addition, gene expression signatures of good and poor prognosis were found in different regions of the same tumor, suggesting that intratumor heterogeneity also exists at the RNA-expression level.

    Intratumor heterogeneity is postulated to develop across time as CSCs divide and differentiate asymmetrically.  The loss of normal cellular controls allows the development and propagation of genetic or epigenetic alterations that give the cells novel properties associated with metastasis, self-renewal, treatment resistance, and recurrence.

    As stated, intratumoral heterogeneity complicates cancer prognosis and treatment. Two reasons are: biopsy samples used for diagnosis are taken from small regions of tumors that may not be representative of the entire lesion; and cells may adopt new functional properties and biomarker expression patterns as the disease progresses. Thus, treatment choices based upon a single biopsy taken at a single time point may only be effective for some cells within a tumor population. This may result in the expansion of treatment-resistant cell populations through time.

    As the presence of multiple clonal subpopulations within the same tumor imparts different phenotypes, such as growth advantages or treatment resistance, a substantial therapeutic challenge exists, as only some cells within a tumor would be affected by any one treatment. Logically, combination therapeutic regimens targeting both the bulk of tumor cells as well as CSCs could be an effective approach to improve long-term treatment outcomes.

    Recent research has shown an increase in the number and activity of CSCs in response to radiation. The effect of radiation on CSCs was counteracted with agents shown to inhibit mammosphere formation or expression of stemness-related genes. In both studies, use of these agents led to reductions in the number of radiation-induced CSCs.