In the September issue of the J. Clin. Investigation, E. L. McCoy et al. from the Univ. of Colorado Sch. of Medicine reported their study results on the role of the homeoprotein Six1 and mammary tumors. Six1 is a homeoprotein which is normally expressed during embryogenesis and downregulated in adult tissues. However, it appears that neoplastic cells overexpress Six1, particularly in breast tumors. With mammary-specific, inducible (tet-operator) Six1 transgenic mice, the investigators found that overexpression of Six1 leads to leads to aggressive mammary tumor formation that is dose-dependent (doxorubicin). Tumors were found to have diverse histologies of which a subset of sarcomatoid tumors undergoing epithelial-mesenchymal transition (EMT). Six1 driven tumors also displayed Wnt signaling which suggest that Six1 and Wnt primarly drives the malignant cells to an EMT state. Additionally, Six1 driven tumors contain cells expressing Sca-1 which seems to indicate a regulatory role for expanding the stem/progenitor pool in the mammary tissues by the transcription factor. Microarray analysis of human breast tumors resulted in low levels of Six1 gene expression concomitant with an increase in cyclin D1 expression. Thus, in human breast cancers, the authors proposed that Six1 in concert with cyclin D1 expression result in tumorigenesis of the mammary glands.

It has been reported that metformin, an inhibitor of neoglycogenesis for type 2 diabetes, protects against pancreatic cancers. In following up on those observations, H. A. Hirsch et al. from Harvard Medical School reported in today's (Sept. 14th) online edition of Cancer Research, their study results on metformin in combinatin of doxorubicin targets cancer stem cells (CSCs) in mammary tumors. The investigators conducted in vitro experiments in which the data revealed the cytotoxic effects of metformin on a subpopulation of mammosphere forming cels expressing the surface markers CD44^hi and CD24^low. Cytotoxic effects were observed in four genetically different types of breast cancer. Metformin in combination with doxcorubicin kills both CSCS and non-stem cancer cells in cultures, and reduces the tumor burden in a xenograft mouse model. The nude mice used in the study were found to be tumor-free for at least 2 months following combination therapy compared to mice receiving dosxorubicin alone in which tumor growth resumed after 20 days. The authors concluded that their study results add support for the cancer stem cell hypothesis and it provide "a rationale for why the combination of metformin and chemotherapeutic drugs might improve treatment of patients with breast (and possibly other) cancers."

In the September 10th online edition of PNAS, G. Bertolini et al. from the Istituto Nazionale dei Tumori (Milan, Italy) reported their study results on isolating small population of tumorigenic cells with stem cell characteristics. With FACS analysis, the investigators found the cancer-initiating stem cells from tumors of 40 patients with nonsmall cell lung cancer (NSCLC) were CD133 and ESA (epithelial-specific antigen) positive. The data showed that approximately 5% CD133+ESA+ cells lung tumors compared to < 1% of CD133+ESA+ cells isolated from normal lung tissues. These CD133+ESA+ cells were found to be high tumorigenic forming xenografts tumors in SCID mice. PCR analyses of the cancer-initiating cells showed that these cells expressed stem cell markers such as Oct4/3, Nanog, as well as α-6 integrin and CXCR4. In vitro studies revealed that the CD133+ESA+ were resistant to the cytotoxic effects of cisplatin which the researchers attribute to the cells expressing the ABCG2 transporter protein. The authors concluded from their study that chemoresistant CD133+ cells that are highly tumorigenic with stem-like features are present in lung tumors. They further noted that "these cells may provide the rationale for more specific therapeutic targeting and the definition of predictive factors in clinical management of this lethal disease."