Targeting cancer stem cells: a new therapy to cure cancer …

Am J Cancer Res. 2012; 2(3): 340356.

Published online Apr 28, 2012.

State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou 510060, China

Received April 20, 2012; Accepted April 25, 2012.

Cancer stem cells (CSCs) have been defined as cells within tumor that possess the capacity to self-renew and to cause the heterogeneous lineages of cancer cells that comprise the tumor. They have been identified in blood, breast, brain, colon, melanoma, pancreatic, prostate, ovarian, lung cancers and so on. It is often considered to be associated with chemo-resistance and radio-resistance that lead to the failure of traditional therapies. Most therapies are directed at the fast growing tumor mass but not the slow dividing cancer stem cells. Eradicating cancer stem cells, the root of cancer origin and recurrence, has been thought as a promising approach to improve cancer survival or even to cure cancer patients. Understanding the characteristics of cancer stem cells will help to develop novel therapies to eliminate the initiating cancer stem cell, and the relevant patents on the cancer stem cell and cancer therapy by cancer stem cells will be discussed.

Keywords: Cancer stem cell, biomarker, signal pathway, drug resistance, natural compound, Mesenchymal stem cells, differentiation therapy

In the world, cancer remains a major cause of mortality. Despite great progresses have been made in understanding the molecular basis of cancer, the progress in cancer detection and treatment, mortality is still high and there still is not a cure despite great improvements have been made in therapies. The current treatment regimens for cancer have shown limited survival benefits when used for most advanced stage cancers, because these treatments primarily target tumor bulk but not cancer stem cells [1,2]. Indeed, conventional cancer therapies target neoplastic cells that are largely fast-growing, suggesting that cancer stem cells may survive due to their high resistance to drugs and slower proliferation rate [3]. All the traditional cancer therapies including surgery, hormonal therapy, anti-angiogenesis therapy, and immunotherapy show a lack of efficacy in terms of long-term outcome because of their failure to target cancer stem cells and toxicity due to non-specific effects on normal cells. In this review, we will focus on the following aspects: 1, Identification of cancer stem cells and therapies that were developed to target them. In recent years, some molecules (such as CD133, CD44, ABCG2, ALDH) have been defined as the biomarkers of some kind of cancer stem cells, and the aberrant signal pathways (such as Wnt, Notch and Hedgehog signal pathway) have also been suggested as another feature of cancer stem cells. Therapeutics that based on those characters have been developed and some are on clinical trials now. 2, we also discussed the natural compounds that own the ability to target cancer stem cells, the mesenchymal stem cell-mediated gene therapy, to induce cancer stem cell differentiation and some other therapies. Current research is helping us to understand cancer stem cells and in turn this will help to develop novel therapies to eliminate cancer and the initiating cancer stem cell.

Cancer stem cells are cancer cells that possess characteristics associated with normal stem cells, specifically the ability to give rise to all cell types found in a particular cancer sample. It is often considered to be associated with chemoresistance and radio-resistance that lead to the failure of traditional therapy [4]. There appear to be several sources from which cancer stem cells may arise. They may arise from normal ASCs (adipose-derived stromal cells), from more restricted progenitor cells or even from differentiated cells [5]. Normal stem cells are more likely to be the targets of mutants and leading to the formation of CSCs for they already possess active self-renewal pathways. It is also possible for progenitors and other differentiated cells to give rise to CSCs, though they would have to acquire more genetic mutations, especially in self-renewal genes. However, it has been hypotheses that CSCs arising from normal stem cells are more aggressive than those from progenitor cells, though this remains to be proven [6]. In cancer research experiments, tumor cells are sometimes injected into an experimental animal to establish a tumor. The efficient tumor formation requires thousands or tens of thousands of cells to be introduced, however, only a small fraction of the injected cells, the CSCs, have the potential to generate a tumor. In human acute myeloid leukemia the frequency of these cells is less than 1 in 10,000. The first CSC was identified in human acute myeloid leukemia (AML), showed that a rare malignant cell with the ability to repopulate the entire original disease over several transplantations, implying self-renewal and capacity to differentiate, was only found within the immature CD34+CD38-, but not the CD34+CD38+ subpopulation [7]. After that, cancer stem cells were found in some solid tumors subsequently. The first solid CSCs were identified in breast tumors in 2003 [8], and then CSCs were isolated from brain [9], colon [10], melanoma [11], pancreatic [12], prostate [13], ovarian [14], lung [15] and gastric [16] cancers. The emerging picture on CSCs is creating significant excitement and interest in the cancer field. It is believe that the targeting of CSCs offers important and revolutionary advances in the targeting of cancer. Eradicating cancer stem cells, the root of cancer origin and recurrence, has thought as a promising approach to improve cancer survival or even to cure cancer. In the research of killing cancer stem cells, many possible ways were developed to achieve this objective, including molecular targeted therapy, target molecular signaling pathways, natural compounds and their potent to target CSCs, the use of mesenchymal stem cells, and differentiation therapy. Though great progresses have been made in recent year, the accurate mechanism of cancer stem cell is still not clear and the really effective therapy is still not found. Here, we will discuss the new therapeutic approaches to cancer based on the existence of the cancer stem cells.

Cancer stem cells have been identified in a growing number of hematopoietic cancer and solid tumors and are typically recognized by virtue of the expression of cell surface markers. These cells have been isolated from the bulk-tumor population by the expression pattern of cell surface proteins (e.g., CD24, CD44, CD133) and cellular activities, such as the efflux of Hoechst dye or aldehyde dehydrogenase activity by flow cytometry and/or fluorescence activated cell sorting (FACS). The identification of markers that allow the prospective isolation of CSCs from whole tumor tissues will lead to the understanding of important biological properties of CSCs and provide the possibility to target them.

CD133 is a glycosylated, 120KD protein with five transmembrane domains and two large extracellular loops. CD133+ phenotype was first used to identify and isolate brain tumor stem cells in malignant tumors and now it has recently been used to define the CSC populations in lung, pancreati
c, liver, prostate, gastric, colorectal, and head and neck cancers. The expression of genes known to play important roles in the maintenance of cancer stem cells have been investigated in putative CD133+ CSC populations of multiple tissues. These CD133+ cells undergo multi-lineage differentiation to neurons, astrocytes, and oligodendrocytes in vitro, and can recapitulate the original tumor phenotype in vivo, unlike the CD133. Some genes associated with cancer stem cell like Nestin, BMI1, Olig2, and Nanog are also found upregulated in CD133+ populations of brain, lung, liver and prostate cancers [17-20]. CSCs is often associated with resistance to traditional chemotherapies, CD133+ cells have had increased survival in vitro and have been enriched in vivo after treatment with cisplatin, etoposide, doxorubicin, and paclitaxel, as the expression of genes known to be markers of stemness, ABC transporters and the DNA repair pathway [21,22].

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