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Regulation of Cancer Stem Cell by Microenvironment

Molecular Signaling and Cancer Biology

Description of Regulation of Cancer Stem

Cells by Microenvironment According to the classical model of carcinogenesis, cancer is a result of accumulation of mutations and clonal selection of any cell in an organ. However emerging data showing prevalence of cancer stem cells (CSCs) point that an alternate ‘CSC hypothesis’ may hold true in case of progression and metastasis of multiple cancers such as leukemias, breast, prostate, brain, and colon cancers. The CSC model states that cancer arises from a small population of cells with deregulated self-renewing potential. CSCs share many similarities to normal stem cells such as the ability to self-renew, proliferate, differentiate and evade apoptosis. These mechanisms are highly deregulated in CSCs as opposed to normal stem cells where they are tightly controlled. Furthermore, it has been implicated that some CSCs may acquire mutations that confer anchorage independence and migratory capacity. These ‘metastatic CSCs’ may then lead to establishment of secondary tumor at distant sites. CSCs represent <1% of the tumor and are highly resistant to conventional treatments such as chemotherapy or radiation.

Scientists in this hot topic area investigate: the role of microenvironment in maintaining the characteristics of cancer stem cells; contribution of CSCs in mediating metastatic spread of solid tumors such as breast cancer; identification of CSCs in particular cancers based on the expression of cell surface markers; selective targeting of CSCs by identification of novel compounds; cell of origin of CSCs i.e. whether CSCs arise from mutations in a normal stem cell or from dedifferentiation of terminally differentiated cells. While working in a CSC lab, students learn various biochemical, cell biological, genomic and proteomic approaches (eg. microarray analysis, lineage tracing, gene knockout, flow cytometry, confocal microscopy, zymography, FRET, CFU assays, real time animal in vivo imaging, mass spectrometry) to answer questions using 3-dimensional tissue culture models or humanized mouse models of cancer.

CSC niche using a 3-dimensional culture model of multiple myeloma
Study of the CSC niche using a 3-dimensional culture model of multiple myeloma (MM): Non-proliferating MM-CSCs (green) interacting with stromal cells expressing N-cadherin (red).

Related Research

Gunn, E.J., Williams, J.T., Huynh, D.T., Iannotti, M.J., Han, C., Barrios, F.J., Kendall, S., Glackin., C.A., Colby, D.A., Kirshner, J. The Natural Products, Parthenolide and Andrographolide Exhibit Anti-Cancer Stem Cell Activity in Multiple Myeloma. Leukemia and Lymphoma. 2011.

Multiple myeloma (MM) is an incurable malignancy of plasma cells with a very high rate of relapse. One of the objectives of Kirshner lab is to identify new compounds having selectivity against MM-CSCs. This study is the first report of 2 natural compounds: Andrographolide and Parthenolide that were shown to be cytotoxic specifically to MM CSCs in a 3-dimensional culture model of MM.

Migratory human breast cancer cells
Fluorescence microscopy to study the role of breast CSCs: Migratory human breast cancer cells isolated from a 3-D culture model of metastasis and stained for presence of breast CSCs (CD44+/CD24-/ESA+). Green: CD44; Orange: CD24; Pink: ESA (epithelial surface antigen)

Kirshner, J., Thulien, K.J., Martin, L.D., Debes Marun, C., Reiman, T. Belch, A.R., Pilarski, L.M. A Unique 3-D model for evaluating the impact of therapy on Multiple Myeloma. Blood. 2008, 112(7):2935-45.

This article demonstrates the significance of cell-cell interactions and tissue microenvironment in regulating a stem cell niche. A 3-dimensional culture model was developed using reconstructed human bone marrow matrix. Drug resistant multiple myeloma stem cells were shown to proliferate and interact with stromal cells in this model.

Immunofluorescence analysis of apoptosis in human breast cancer cells
Immunofluorescence analysis of apoptosis in human breast cancer cells based on the expression of early (Green: Annexin V) and late apoptotic markers (Red: Propidium iodide).

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