Current research is supporting the concept that many cancers arise from dysregulated stem cells resulting in cancer stem cells which initiate tumors. To support this concept, S. A. Liaguno et al. from the University of Texas Southwestern Medical Center at Dallas published in the January 9th issue of Cancer Cells their study results using a mouse model to demonstrate that inactivation of a tumor suppressor genes in neural stem/progenitor cells is sufficient to induce astrocytoma. By inactivating p53, Nf1, and Pten in transgenic mice, the investigators were able to show in vivo that transformed cells and their progeny undergo infiltration and multilineage differentiation during tumorigenesis. Cells from tumor suppressor heterozygous neural stem /progenitor cells grown in culture from the transgenic mice (presymptomatic) showed "aberrant growth advantage and altered differentiation." The authors concluded from their in vitro studies that these hyperproliferative cells in which their tumor suppressor genes had been inactivated were, indeed, the pretumorigenic cell population.

In the April issue of Experimental Hematology, K. de Lima Prata et al. from the University of Säo Paul (Brazil) reported their study findings on the effects of high dose chemotherapy (HDCT) on bone marrow-derived mesenchymal stem cells (MSCs). Twelve lymphoma patients (both Hodgkin's and non-Hodgkin's) were treated with a BEAM (BCNU, etoposide, cytarabine, and melphan) conditioning regimen prior to a bone marrow aspirate and autologous stem cell transplantation (28-1836 days before collecting the samples). MSCs were isolated by adherence to plastic and expanded ex vivo in culture flasks. Thirteen normal donors served as controls for the study. The results of the study revealed that MSCs from Hodgkin's disease and non-Hodgkin's lymphoma had decreased potential to form fibroblastoid colony-forming units and increased doubling time compared to MSCs from normal donors. However, the investigators did note that there were no differences in gene expression profiles between the two groups. The authors concluded that "HDCT applied to lymphoma patients damaged MSCs, which was demonstrated by their reduced clonogeneic potential, doubling time, and cell expansion rates when compared to controls."

In the March 26th issue of Science, Y. Wang et al. from Harvard Medical School reported their study results on leukemia stem cells (LSCs) in a mouse model of acute myelogenous leukemia (AML). With either induced coexpression of Hoxa9 and Meis1a oncogenes or of the oncoprotein MLL-AF9, the investigators were able to recapitulate AML in mice for studying LSCs. The experimental results revealed that Wnt/β-catenin signaling pathways were required for LSCs to self renew...a hallmark of LSCs. Self-renewing LSCs were derived from either hematopoietic stem cells (HSCs/Lin-, c-Kit+, Scat-1-) or from granulocyte-macrophange progenitors (GMP/FcRγ+, CD34+). The authors postulated that since the Wnt/β-catenin signaling pathways are normally active in HSCs, but not GMP, β-catenin signaling may be required for transforming progenitor cells by certain oncogenes. Also, the authors noted that although β-catenin signaling "is not required for self-renewal of adult HSCs...targeting the Wnt/β-catenin pathway may represent a new therapeutic opportunity in AML."

One of the hallmarks reflecting tumor progression and activation of cancer stem cells is when a carcinoma undergoes a phenotypic switch from an epithelial-to-mesenchymal transition (EMT). In analyzing the underlying mechanism for EMT in human breast cancer, M. de Graauw from Leiden University (Netherlands) reported in the March 22nd online edition of PNAS that their study results demonstrate that Annexin A1 (AnxA1) is a candidate regulator for the EMT phenotypic switch. The investigators found that AnxA1 expression is associated with a highly invasive basal-like breast cancer in both human breast cancer cell lines and malignant cells from primary tumor tissues. AnxA1 knockdown experiments basal-like breast cancer cells resulted in a reduction in the number of spontaneous metastatic lung lesions. Conversely, upregulation in AnxA1 expression enhanced metastasis. The researchers also noted that their data showed that "AnxA1 promotes metastasis formation by enhancing the TGF-β/Smad signaling and actin reorganization, which facilitates an EMT-like switch, thereby allowing efficient cell migration and invasion of metastatic breast cancer cells."

In the March issue of Nature Biotechnology, Y. Saito et al. from Toranomo Hospital (Tokyo, Japan) published their study results on an approach for activating and eliminating tumor-initiating cells/cancer stem cells in mouse model of human acute myelogenous leukemia (AML). The investigators used AML stem cells residing in the endosteal region of the bone marrow. These cancer stem cells are both quiescent and CD34+CD38-. The cells were transplanted into NOD/SCID/IL2r&gamm;(null) mice and subsequently induced in vivo to enter the cell cycle by administering granulocyte colony-stimulating factor (G-CSF). With a combination of G-CSF and cell cycle-dependent chemotherapy, the researchers were able to induce apoptosis and significantly eliminate the primary AML stem cells in vivo. The authors concluded that "combination therapy leads to significantly increased survival of secondary recipients after transplantation of leukemia cells compared with chemotherapy alone."

In the February 14th online edition of Nature Biotechnology, Y. Saito et al. from RIKEN Research Center (Yokohama, Japan) reported their study results on acute myeloid leukemia (AML) stem cells and the ability to drive the cells to become more drug sensitive. The investigator noted in their previous study that CD34+CD38- residing in the endosteal region of the bone marrow were chemotherapy resistant. With a mouse model of human AML (NOD/SCID/IL2rγnull), the quiescent AML stem cells could be induced to enter the cell cycle by granulocyte-colony-stimulating factor (G-CSF). In combination therapy with G-CSF and cell cycle-dependent chemotherapy, apoptosis was induced in the AML cells and eliminated primary human AML stem cells implanted into immunocompromised mice. The authors concluded that "combination therapy leads to significantly increased survival of secondary recipients after transplantation of leukemia cells compared with chemotherapy alone."

In the March issue of Nature Cell Biology, K. K. Youssef et al. fro Unversité Libre de Bruxelles (Belgium) published in a letter the results of their study to identify the cells that initiate basal cell carcinoma (BCC). With mutant mice conditionally expressing constitutively active Smoothened mutant (SmoM2), the investigators examined activated Hedgehog signalling in different cellular compartments of skin epidermis induces BCC formation. The data showed that SmoM2 activation in hair follicle stem cells did not induce cancer formation; thus, demonstrating that BCC did not originate from bulge stem cells. Clonal analysis revealed that BCC arose from long-term resident progenitor cells of the interfollicular epidermis and the upper infundibulum. The authors concluded that their study results revealed that "the cells at the origin of BCC in mice and demonstrated that the expression of differentiation markers in tumour cells is not necessarily predicitive of the cancer-initiating cells."