Identification and Characterization of Tumor Initiating Cells in Chronic Lymphocytic Leukemia
Francisco Vega M.D., Ph.D.
University of Texas M. D. Anderson Cancer Center
Abstract:
Emerging evidence in solid tumors and acute leukemias suggests that the capability of a tumor to grow and propagate depends on a small subset of cells, termed “tumor initiating cells” or “cancer stem cells”. The cancer stem cell model postulates that tumors are maintained by a fraction of cancer cells with stem cell properties (self-renewal) and high resistance to apoptosis. There is also evidence suggesting that a number of embryonic signaling pathways, involved in adult stem cell maintenance (i.e., BMI-1, NOTCH, WNT, and SHH), are aberrantly re-activated in tumors supporting the hypothesis that deregulated self-renewal and proliferation of “cancer stem cells” may be critical for tumor growth.
Using flow cytometry and the DNA-binding dye Hoechst 33342 we identified a distinct small subset of neoplastic cells, termed the side population (SP), in several human and murine lymphoma cell lines and in CLL samples. Our experimental data in lymphoma cell lines indicates that the SP-cell fraction, in comparison with the non-SP fraction, is enriched with cells with stem cell-like properties including longer telomere length, higher levels of BCL-2 and ABCG-2 proteins, higher clonogenicity capacity and higher capacity to reconstitute tumors in xenograft transplant experiments.
We are also investigating the activation status and the biologic role of the Sonic Hedgehog (SHH) pathway in CLL. Our preliminary data suggest that SHH pathway may be a survival factor for CLL cells, either in an autocrine and/or paracrine manner, and could represent a new target for therapy in CLL.
Based on our preliminary data, this proposal has the following specific aims:
1) To isolate and characterize putative tumor initiating cells in CLL.
2) To elucidate the biologic role of SHH signaling pathway in CLL cell biology.