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Therapeutics formulated to target cancer stem cells: Is it in our future?

ABSTRACT: With the political, social and financial drives for cancer research, many advances have been made in the treatment of many different cancer types. For example, given the increase in awareness, early detection, and treatment of breast and prostate cancers, we have seen substantial increases in survival rates. Unfortunately there are some realms of cancer that have not seen these substantial advancements, largely due to their rapid progression and the inability to specifically target therapy.The hypothesis that cancers arise from a small population of cells, called cancer stem cells (CSCs), is gaining more popularity amongst researchers. There are, however, still many skeptics who bring into question the validity of this theory. Many skeptics believe that there is not a specific subset of cells that originate with these characteristics, but that they develop certain features over time making them more resistant to conventional therapy. It is theorized that many of the relapses occurring after remission are due to our inability to destroy the self-renewing CSCs. This central idea, that CSCs are biologically different from all other cancer cells, has directed research towards the development of therapy to target CSCs directly. The major dilemma in targeting therapy in myeloproliferative disorders, malignancies of the central nervous system or malignancies in general, is the inability to target CSCs as opposed to normal stem cells. However, with the recent advances in the identifications of unique molecular signatures for CSCs along with ongoing clinical trials targeting CSCs, it is possible to use targeted nanotechnology-based strategies in the management of different types of cancers.

SUBMITTER: Clayton S

PROVIDER: S-EPMC3073868 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Therapeutics formulated to target cancer stem cells: Is it in our future?

Clayton Stephanie S Mousa Shaker A SA

Cancer cell international 20110325

With the political, social and financial drives for cancer research, many advances have been made in the treatment of many different cancer types. For example, given the increase in awareness, early detection, and treatment of breast and prostate cancers, we have seen substantial increases in survival rates. Unfortunately there are some realms of cancer that have not seen these substantial advancements, largely due to their rapid progression and the inability to specifically target therapy.The h ...[more]

PMID: 21439058

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Project description:Chondrosarcoma is a malignant bone neoplasm that is refractory to chemotherapy and radiation. With no current biological treatments, mutilating surgical resection is the only effective treatment. Proline rich polypeptide 1 (PRP?1), which is a 15?amino acid inhibitor of mammalian target of rapamycin complex?1 (mTORC1), has been indicated to exert cytostatic and immunomodulatory properties in human chondrosarcoma cells in a monolayer. The aim of the present study was to evaluate the effects of PRP?1 on an in vitro 3D chondrosarcoma tumor model, known as spheroids, and on the cancer stem cells (CSCs) which form spheroids. JJ012 cells were cultured and treated with PRP?1. An ALDEFLUOR™ assay was conducted (with N,N?diethylaminobenzaldehyde as the negative control) to assess aldehyde dehydrogenase (ALDH) activity (a recognized CSC marker), and bulk JJ012, ALDHhigh and PRP?1 treated ALDHlow cells were sorted using flow cytometry. Colony formation and spheroid formation assays of cell fractions, including CSCs, were used to compare the PRP?1?treated groups with the control. CSCs were assessed for early apoptosis and cell death with a modified Annexin V/propidium iodide assay. Western blotting was used to identify mesenchymal stem cell markers (STRO1, CD44 and STAT3), and spheroid self?renewal assays were also conducted. A clonogenic dose?response assay demonstrated that 20 µg/ml PRP?1 was the most effective dose for reducing colony formation capacity. Furthermore, CSC spheroid growth was significantly reduced with increasing doses of PRP?1. Annexin V analysis demonstrated that PRP?1 induced CSC cell death, and that this was not attributed to apoptosis or necrosis. Western blot analysis confirmed the expression of mesenchymal markers, and the spheroid self?renewal assay confirmed the presence of self?renewing CSCs. The results of the present study demonstrate that PRP?1 eliminates anchorage independent CSC growth and spheroid formation, indicating that PRP?1 likely inhibits tumor formation in a murine model. Additionally, a decrease in non?CSC bulk tumor cells indicates an advantageous decline in tumor stromal cells. These findings confirm that PRP?1 inhibits CSC proliferation in a 3D tumor model which mimics the behavior of chondrosarcoma in vivo.

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Therapeutics formulated to target cancer stem cells: Is it in our future?

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Therapeutics formulated to target cancer stem cells: Is it in our future?

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