Cancer researchers identify 'bad' stem cells

Brussels, 15 Jul 2005

A team of researchers at the Italian Cancer Research Centre in Milan has made a major breakthrough in breast cancer research by isolating stem cells of adult breast cancer tissue and propagating them in vitro.

The experiment has enabled the identification of 'bad' stem cells responsible for the growth of tumours. These cells are different from the types of stem cell employed in transplants to help treat lymphoma and leukaemia.

While some cancerous tumours are treatable, many still constitute a death sentence despite the best efforts of medicine. Even if all traces of the tumour are removed surgically, new cancer cells can quickly arise to take the original tumour's place. Some cancers also overcome toxic chemicals and intense beams of radiation, powerful weapons that kill rapidly dividing cells and suppress the growth of other tumours.

The answer to why many tumours are so difficult to treat may lie in the cancer stem cells.

For decades, cancer researchers have wrestled with two competing visions of tumours: in one scenario, all the cells of a tumour are alike and they all have an equal capacity to divide and form new tumours. In the other scenario, only a few select cells have the capacity to initiate new tumours: the cancer stem cells.

The concept of cancer stem cells has been around since at least the 1950s, but for a long time scientists couldn't come up with the experiments needed to prove their existence by separating the cancer stem cells from other tumour cells.

The first successful experiments were carried out using blood cells. In 1997, a research team of the University of Toronto implanted cancer cells harvested from leukaemia patients into mice, and was able to show that roughly one human leukaemia cell in a million had the capacity to replicate the disease. Those rare cells, the researchers concluded, could be considered cancer stem cells.

All cancer cells have unique patterns of proteins, called markers, on their surface membranes. These markers are similar to fingerprints. Scientists observed that those dangerous cells capable of regrowing the disease bore distinctive proteins on their surfaces: leukaemia stem cells sport a protein, called CD34, that healthy haematopoietic stem cells also carry but other cells don't. Furthermore, the human-leukaemia stem cells consistently lack another protein, CD38, that most other leukaemia cells have.

In 2003, another research team from the University of Michigan Medical School in Ann Arbor, led by Dr Muhammad Al-Hajj, reported that a small minority of human breast cancer cells, roughly between 1 and 2 percent of the tumour, could forms tumours when implanted into mice. Later in 2003, two research teams independently presented evidence that cancer stem cells underlie brain tumours as well.

The Italian team at the National Cancer Research Centre has reached a new milestone by isolating breast cancer cells with stem cell properties and, for the first time, propagating them in vitro. The results of the research, carried out by Dario Ponte, Grazia Daidone and Marco Pierotti, were recently published in the Cancer Research Journal.

The team reported the isolation and in vitro propagation of breast cancer-initiating cells from three breast cancer lesions and from an established breast carcinoma cell line. The breast carcinoma-derived cultures encompassed undifferentiated cells capable of self-renewal, extensive proliferation as clonal non adherent spherical clusters, and differentiation along different mammary epithelial lineages.

These cultured cells, identified by two markers of their membrane (CD44 and CD24), presented one particular stem cell marker, Oct-4, and were able to produce new tumours when as few as 103 cells were injected into mice, compared to the million of cells necessary when there is no previous selection.

Long-term cultures of tumorigenic cells with stem cell properties could represent a suitable in vitro model to study cancer-initiating cells, as well as being a valuable tool for developing specific drugs and therapeutic strategies aimed at eradicating the cancer stem cells within tumours.

Research on cancer stem cells also promises new insights into how cancers spread, or metastasise. The conventional theories hold that metastasis is an evolutionary process in which a small number of cells within a primary tumour gradually accumulate genetic mutations that enable them to spread to other tissues and establish new tumours. The alternative model now being put forward is that many cells in a primary tumour spread in the body, but a second tumour only can arise when a rare stem cell reaches a new site.

At the Italian Cancer Research Centre, a new research line led by Dr Ponti is already working on another type of neoplastic stem and progenitor cell present in lung tumours.

For further information, please consult the following web address: http://www.istitutotumori.mi.it

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