Centre for Research in Biomolecular Interactions presents Prof. Laurie Ailles, Department of Medical Biophysics, Faculty of Medicine, University of Toronto

Talk Title: “Tumour-Initiating Cells in Solid Tumours”

Abstract:

It has recently been demonstrated that in many solid malignancies only a subset of the cells are able to initiate tumour growth in immunodeficient mice. These “tumour-initiating cells” (TICs), can be prospectively isolated based on their expression of various markers, generate tumours that recapitulate the heterogeneity of the primary tumour and have extensive self-renewal ability. In contrast, the remaining cells, which make up the majority of the tumour mass, do not have tumour-initiating ability. Because their properties differ from the majority of other tumor cells, TICs might be able to evade conventional cytotoxic therapies and furthermore, may be at the root of chemo-radiation resistance. TICs may therefore represent an important therapeutic target, particularly with respect to relapse prevention.

Putative head and neck squamous cell carcinoma (HNSCC) TICs were identified when flow cytometric analyses of patient samples revealed consistent heterogeneity for CD44 expression. Upon isolation of CD44+ and CD44- cell populations followed by transplantation into immunodeficient mice, only the CD44+ population had tumor initiating ability, and was ~100-fold enriched for TICs over unfractionated tumor cells. The tumors initiated by CD44+ cells recapitulated the original tumor heterogeneity and could be serially transplanted, demonstrating the TIC-defining properties of differentiation and self-renewal. Immunohistochemistry (IHC) indicated that in well to moderately differentiated tumors, the CD44+ cells were located in basaloid regions, directly adjacent to the stromal cells, and express stem cell-related markers. We are now focusing on refining the phenotype of the HNSCC TIC using basaloid markers, as well as performing experiments to characterize TICs at the molecular level. We are also investigating the role of the stromal microenvironment, and preliminary data suggests that TICs require the support of a stromal fibroblast “niche”. Characterization of cancer-associated fibroblasts and their molecular interactions with TICs are under way. Finally, we are attempting to determine whether the frequency of TICs (TICf) or their associated markers in HNSCC correlates with clinical parameters.

To determine whether serous ovarian cancer (SOC) conforms to the TIC model, we developed a robust assay for quantifying TICs from primary SOC samples. Using this assay, we find that TICs are rare when assayed in either NOD/SCID or NOD/SCID/IL2Rg^-/- (NSG) mice. TICf varies substantially between patients, although it is similar in primary ovarian masses and omental metastases, suggesting that TICf is an intrinsic property of ovarian tumors. CD133 marks all TICs from several primary SOC cases. However, in other cases, substantial TIC activity is found in both the CD133+ and CD133- fractions, whereas still other cases have exclusively CD133- TICs. Furthermore, the TIC phenotype can change in xenografts: primary tumors in which all TICs are CD133+ can give rise to xenografts that contain substantial numbers of CD133- TICs. Our results highlight the need for quantitative rigor in the evaluation of TICs and for caution when using passaged xenografts for such studies. Furthermore, although our data suggest that SOC conforms to the TIC hypothesis, the heterogeneity of the TIC phenotype may complicate its clinical application.

In summary, through the study of 2 different types of solid tumours, it appears that both conform to the TIC model, but that in some cancers TICs may have heterogeneous or unstable phenotypes. The latter suggests that highly genomically unstable cancers such as SOC may evolve away from a hierarchical structure towards a more stochastic, less organized state as they progress.

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