Gene signatures in residual breast cancers after conventional therapy

Gene Signature of Breast Cancer Stem Cells Revealed, Genetic Engineering & Biotechnology News, August 4, 2009. First paragraph:

A consortium of researchers have identified the gene expression patterns of breast cancer stem cells that remain post treatment with either chemotherapy or antihormone treatments. They report that this gene signature differs from those linked to the bulk of epithelial cells in the tumor.

Based on: Gene signature for cancer stem cells may provide drug targets, Glenna Picton, News Release, Baylor College of Medicine, August 4, 2009.

See also: Gene signature for cancer stem cells may provide drug targets, Science Centric, August 4, 2009. First paragraph:

A subset of tumour cells that remain after a woman with breast cancer undergoes treatment with either anti-cancer or anti-hormone therapy shows a 'gene signature' that could be used to define targets for developing new drugs against the disease, said a consortium of researchers led by Baylor College of Medicine. The report appears in the current issue of the Proceedings of the National Academy of Sciences.

The report referred to in the above excerpt is an Open Access publication: Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features by Chad J Creighton and 22 co-authors, including Michael T Lewis, Jeffrey M Rosen and Jenny C Chang, Proc Natl Acad Sci USA 2009(Aug 3). [Epub ahead of print].[Abstract][Early version of OA full text].

Two publications on colorectal cancer stem cells

1) Colon cancer stem cells: implications for prevention and therapy by Emina H Huang and Max S Wicha, Trends Mol Med 2008(Nov); 14(11): 503-9. Epub 2008 Oct 17. Pubmed Abstract:

The recent identification of colon cancer tumor-initiating cells adds further support to the cancer stem cell hypothesis. Ongoing basic and translational research efforts are aimed at gaining an increased understanding of the biology of these cells, as well as methods of targeting them. In addition, the relationship between colon carcinogenesis and inflammatory conditions, such as longstanding colitis and inherited syndromes, might be linked to the effect of the processes on stem cells in the colon. This review summarizes current literature on colon cancer stem cells and proposes strategies aimed at targeting these cells for colon cancer prevention and therapy.

From the "Summary" section of the full text (not publicly accessible):

The identification of colon cancer tumor-initiating cells provides further support for the cancer stem cell hypothesis. Future therapy will be directed not only at these rare cells themselves but also at the microenvironment that regulates stem cell behavior. Furthermore, because cancers might originate from disregulation of normal stem cell homeostasis, strategies for cancer prevention might also target this cell population.

2) CD44 is of functional importance for colorectal cancer stem cells by Lei Du and 10 co-authors, including Quan Chen, Clin Cancer Res 2008(Nov 1); 14(21), 6751-60. Abstract:

Purpose: Both CD44 and CD133 were reported as putative markers for isolating colorectal cancer stem cells (CSC). It remains to be resolved if both of these markers are of functional importance for colorectal CSC.

Experimental Design: The expression of CD44 and CD133 in normal colonic tissues and primary colorectal cancer was assessed by immunohistochemistry in a series of 60 patients on tissue microarray sections. Both in vitro clonogenic and in vivo tumorigenic assay were applied to measure CSC activities from the cells isolated from patients. Lentiviral RNA interference was used to stably knock down CD44 or CD133 in colorectal cancer cells from patients.

Results: We found that CD44+ cells displayed clustered growth and they did not colocalize with CD133+ cells within colorectal cancer. As few as 100 CD44+ cells from a patients' tumor initiated a xenograft tumor in vivo. A single CD44+ cell from a tumor could form a sphere in vitro which has characteristic stem cell properties and was able to generate a xenograft tumor resembling the properties of the primary tumor. Knockdown of CD44, but not CD133, strongly prevented clonal formation and inhibited tumorigenicity in xenograft model.

Conclusions: These results indicate that CD44 is a robust marker and is of functional importance for colorectal CSC for cancer initiation.

From the "Translational Relevance" section of the full text (not publicly accessible):

Cancer stem cells (CSC) represent an exciting avenue for cancer study and novel target for drug discovery. In this study, we showed that CD44 was a robust colorectal CSC marker and it is of functional importance for colorectal CSCs using clinic samples and xenograft models. The expression of CD44 and CD133 was assessed in primary tumors and matched normal tissues of patients with colorectal cancer (CRC) by using immunohistochemistry and flow cytometric analysis. We found that CD133 and CD44 did not appear on the same region of tumor tissue and it is infrequent to detect that both markers coexisted in the same cell. Knockdown of CD44 expression by RNA interference or inhibition of its function by specific antibodies could significantly inhibit tumor initiation and development in nude mice. These results indicate that CD44 and its related signaling pathway could be a critical diagnostic and therapeutic target for CRC.

Distinct populations of tumor-initiating cells

Distinct populations of tumor-initiating cells derived from a tumor generated by rat mammary cancer stem cells by Ileana Zucchi and 13 co-authors, including Benjamin G Neel and Renato Dulbecco, Proc Natl Acad Sci USA 2008(Nov 4); 105(44): 16940–45, published ahead of print October 28, 2008. This is an Open Access Article [PDF]. PubMed Abstract:

Tumors derived from rat LA7 cancer stem cells (CSCs) contain a hierarchy of cells with different capacities to generate self-renewing spheres and tubules serially ex vivo and to evoke tumors in vivo. We isolated two morphologically distinct cell types with distinct tumorigenic potential from LA7-evoked tumors: cells with polygonal morphology that are characterized by expression of p21/(WAF1) and p63 and display hallmarks of CSCs and elongated epithelial cells, which generate tumors with far less heterogeneity than LA7 CSCs. Serial transplantation of elongated epithelial cells results in progressive loss of tumorigenic potential; tumor heterogeneity; CD44, E-cadherin, and epithelial cytokeratin expression and increased alpha-smooth muscle actin I and vimentin expression. In contrast, serial transplantation of LA7 CSCs can be performed indefinitely and results in tumors that maintain their heterogeneity, consistent with self-renewal and multilineage differentiation potential. Collectively, our data show that polygonal cells are CSCs, whereas epithelial elongated cells are lineage-committed progenitors with tumorigenic potential, and suggest that tumor progenitors, although lacking indefinite self-renewal potential, nevertheless may make a substantial contribution to tumor development. Because LA7 cells can switch between conditions that favor maintenance of pure CSCs vs. differentiation into other tumor cell types, this cell system provides the opportunity to study factors that influence CSC self-renewal and differentiation. One factor, p63, was identified as a key gene regulating the transition between CSCs and early progenitor cells.