Chemokines in cancer and metastatic progression

The critical role of SDF-1/CXCR4 axis in cancer and cancer stem cells metastasis by Stefania Gelmini and 4 co-authors, including Elena Lazzeri, J Endocrinol Invest 2008(Sep); 31(9): 809-19 [PDF]. PubMed Abstract:

Chemokines exert their multifunctional role in several physiologic and pathologic processes through interaction with their specific receptors. Much evidence have revealed that metastatic spread tumor cells may use chemokinemediated mechanisms. In particular, an involvement of stromal cell-derived factor-1 (SDF-1) in growth of primary tumors and in metastatic process has been demonstrated. Indeed, it has been suggested that CXCR4 expression by tumor cells, plays a critical role in cell metastasis by a chemotactic gradient to organs expressing the ligand SDF-1. Moreover, CXCR4 overexpression correlated with poor prognosis in many types of cancer. In physiologic condition, SDF-1 also plays an essential role modulating stem cell proliferation, survival, and homing through its canonical receptor CXCR4. Recently, several studies have demonstrated the existence of a small subset of cancer cells which share many characteristics with stem cells and named cancer stem cells (CSC). They constitute a reservoir of self-sustaining cells with the ability to maintain the tumor growth. In particular, most of them express CXCR4 receptor and respond to a chemotactic gradient of its specific ligand SDF-1, suggesting that CSC probably represent a subpopulation capable of initiating metastasis. This review focuses on the role of SDF-1/CXCR4 axis in cancer and in the metastatic progression by tumoral cells, as well as the role of CSC in tumor pathogenesis and in metastatic process. A better understanding of migratory mechanism involving cancer cells and CSC provides a powerful tool for developing novel therapies reducing both local and distant recurrences.

CD133 is a marker of bioenergetic stress in human glioma

CD133 is a marker of bioenergetic stress in human glioma by Corinne E Griguer and 6 co-authors, including G Yancey Gillespie, PLoS ONE 2008; 3(11): e3655. Epub 2008 Nov 5. PubMed Abstract:

Mitochondria dysfunction and hypoxic microenvironment are hallmarks of cancer cell biology. Recently, many studies have focused on isolation of brain cancer stem cells using CD133 expression. In this study, we investigated whether CD133 expression is regulated by bioenergetic stresses affecting mitochondrial functions in human glioma cells. First, we determined that hypoxia induced a reversible up-regulation of CD133 expression. Second, mitochondrial dysfunction through pharmacological inhibition of the Electron Transport Chain (ETC) produced an up-regulation of CD133 expression that was inversely correlated with changes in mitochondrial membrane potential. Third, generation of stable glioma cells depleted of mitochondrial DNA showed significant and stable increases in CD133 expression. These glioma cells, termed rho(0) or rho(0), are characterized by an exaggerated, uncoupled glycolytic phenotype and by constitutive and stable up-regulation of CD133 through many cell passages. Moreover, these rho(0) cells display the ability to form "tumor spheroids" in serumless medium and are positive for CD133 and the neural progenitor cell marker, nestin. Under differentiating conditions, rho(0) cells expressed multi-lineage properties. Reversibility of CD133 expression was demonstrated by transfering parental mitochondria to rho(0) cells resulting in stable trans-mitochondrial "cybrid" clones. This study provides a novel mechanistic insight about the regulation of CD133 by environmental conditions (hypoxia) and mitochondrial dysfunction (genetic and chemical). Considering these new findings, the concept that CD133 is a marker of brain tumor stem cells may need to be revised.

Excerpts from the Discussion section of the full text (openly accessible):

Figure 7. Tumor progression model

Last paragraph:

We described here that hypoxia and modification of the bioenergetic status of glioma cells govern the regulation of CD133 at post-transcriptional level. Data presented here strongly indicated that changes in the cellular environment that results in alteration of mitochondrial function are responsible for the enhanced up-regulation of CD133 antigen in glioma cells, suggesting that CD133 expression in human glioma cells is not obligatory relative to the stem cell phenotype but rather, reveals the occurrence of a stress response.

ErbB2 induces Notch1 activity and function in breast cancer cells

ErbB2 induces Notch1 activity and function in breast cancer cells by Jaime Lindsay and 18 co-authors, including Richard G Pestell, Clinical and Translational Science 2008(Sep 10); 2(1): 107-115. Abstract:

The ErbB2 (Her2/neu epidermal growth receptor family) oncogene is overexpressed in 30% to 40% of human breast cancers. Cyclin D1 is the regulatory subunit of the holoenzyme that phosphorylates and inactivates the retinoblastoma (pRb) tumor suppressor and is an essential downstream target of ErbB2-induced tumor growth. Herein, we demonstrate that ErbB2 induces the activity of the Notch signaling pathway. ErbB2 induction of DNA synthesis, contact-independent growth, and mammosphere induction required Notch1. ErbB2-induced cyclin D1 and cyclin D1 expression was suficient to induce Notch1 activity, and conversely, genetic deletion of Notch1 in mammary epithelial cells using foxed Notch (Notch^fl/fl) mice demonstrated that cyclin D1 is induced by Notch1. Genetic deletion of cyclin D1 or small interfering RNA (siRNA) to cyclin D1-reduced Notch1 activity and reintroduction of cyclin D1 into cyclin D1-deficient cells restored Notch1 activity through the inhibition of Numb, an endogenous inhibitor of Notch1 activity. Thus, cyclin D1 functions downstream as a genetic target of Notch1, amplifies Notch1 activity by repressing Numb, and identifies a novel pathway by which ErbB2 induces Notch1 activity via the induction of cyclin D1.

At present, the full text of this article is freely accessible.

For examples of news items about this article, see: Breast Cancer - Targeting A Protein Called Cyclin D1 May Block The Expansion Of Cancerous Stem Cells, Medical News Today, November 6, 2008, and, Therapy may block expansion of breast cancer cells, Science Centric, November 6, 2008.

OncoMed press release

OncoMed Pharmaceuticals press release, November 4, 2008 [PDF]. Excerpt:

OncoMed's lead anti-cancer stem cell antibody, OMP-21M18, entered human clinical studies earlier this year with the initiation of a Phase I trial in patients with advanced solid tumors. OMP-21M18 targets a major cancer stem cell pathway, and is a part of OncoMed's collaboration with GlaxoSmithKline. The Phase I clinical trial is designed to evaluate the safety of escalating doses of OMP-21M18 in patients with solid tumors who have received previous treatment. Pharmacokinetics and initial indications of efficacy will also be assessed. OMP-21M18 is the first anti-cancer stem cell antibody against this novel target critical to cancer stem cells growth and development.

For news items about this press release, see, for example: "OncoMed Pharmaceuticals Completes Series B Financing: Lead Cancer Stem Cell Product Candidate Enters Clinical Trials", November 4, 2008 in Yahoo! Finance and The Earth Times. See also: OncoMed raises $93M in add-on funding, Lisa Sibley, Silicon Valley/San Jose Business Journal, November 4, 2008.

Browsing the International Cancer Research Portfolio

The Canadian Cancer Research Alliance has joined the International Cancer Research Portfolio (ICRP). Excerpt from the ICRP website: "Cancer research funders from several countries have joined in a partnership to classify their research portfolios in a common manner". The partners in the ICRP currently include major funders in the US, the UK, and Canada.

The database can be searched in various ways. For example, an Advanced Search can be carried out for the exact phrase "cancer stem cells" in the titles and abstracts of awards made in Canada, by all of the participating Canadian funding organizations, in the years 2007-2008, for all types of cancer, all areas of research and all types of projects. The results obtained for this search:

11 Total Awards
Year = 2008; 2007
This exact phrase = cancer stem cells
Country = Canada
Funding Organization = Canada

For 6 these 11 awards, the funding organization was the Canadian Institutes of Health Research (CIHR). For the remaining 5, the funding organization was the National Cancer Institute of Canada (NCIC). (Note that, at present, some organizations in Canada that provide support for cancer-related research, but within a broader mandate, are not participants in the ICRP. These include some members of the Cancer Stem Cell Consortium: The Canada Foundation for Innovation (CFI), Genome Canada and The Stem Cell Network).

An analogous search can be carried out for the exact phrase "cancer stem cells" in the titles and abstracts of awards made in California, by all of the participating US funding organizations, in the years 2007-2008, for all types of cancer, all areas of research and all types of projects. The results obtained:

25 Total Awards
Year = 2008; 2007
State = California
This exact phrase = cancer stem cells
Country = United States
Funding Organization = United States

An analogous search, for awards made by funding organizations in the US, to all states in the US, yielded a total of 89 awards. Of these, those states receiving more than 2 awards were CA (25, see above); MA (13); NY (11); TX (11); MD (6) and PA (4).

An analogous search for awards made by funding agencies in the UK, to all of the UK, yielded a total of 3 awards.

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.