The trendy cancer stem cell theory highlights that there is a functional hierarchy between different tumour cells and only a small portion, the so called cancer stem cells, have crucial role in initiating tumour growth. In a stronger form the assumption is that only a tiny minority of tumor cells have the ability to initiate tumor formation.

This assumption was confirmed in the case of blood (1) breast (2) and brain(3) for example. These cells are similar to stem cells in their renewing capability as they can maintain the population through the series of division as well as giving rise to a large population of differentiated progeny that make up the bulk of the tumor. Cancer stem cells are posing multiple threats: repairing the radiation induced DNA damage better than nonstem cancer cells, they can stimulate angiogenesis, the formation of new blood vessels that support tumor growth and can drive metastasis, the spread of tumor in the body. Indeed, in human pancreatic cancer a distinct subpopulation of migrating cancer stem cells turned out to be essential for tumor metastasis different from the ones responsible for tumor growth (4).

Based on the stem cell theory, a new therapeutic approach of cancer is delineated which can induce differentiation of tumour cells rather then killing them. Indeed a very natural and useful stem cell targeted therapy by concept: redifferentiate cancer stem cells into harmless and in some cases useful functional tissue cells. I call it the concept of cancer regenerative medicine: redifferentiate all the tumour initiating cancer stem cells in a patient into functional tissue and organ cells.

In a Nature article (5) Piccirillo et al. addressed the question whether the stem-like tumour initiating cell subpopulation of a glioblastoma, marked with a specific antigen, CD 133+ can be differentiated with Bone Morphogenetic Protein (BMP) into a functional type of brain cells? Glioblastoma (GBM) is the most common adult malignant brain tumour, CD133+ is a neural precursor cell marker and the members of the BMP family make neural precursor cells differentiatie into mature astrocytes, glial cells. So they were dissociating solid tumour samples into single-cell suspensions and were testing their response to BMP. The large picture is that BMP treatment (specially BMP4) reduced cancer cell proliferation, induced astrocyte-like differentiation, effectively blocks the tumour growth and prolonges survival:

These findings show that the BMP–BMPR signalling system—which controls the activity of normal brain stem cells—may also act as a key inhibitory regulator of tumour-initiating, stem-like cells from GBMs and the results also identify BMP4 as a novel, non-cytotoxic therapeutic effector, which may be used to prevent growth and recurrence of GBMs in humans.

Problem could be that certain cancer cells survived the BMP-treatment which can lead to recurrence at a longer latency. This problem could be solved with improved purification of the subpopulation of CD133+ cells, so true cancer stem cells are expected at the exit!

Combined with classical therapy BMP, redifferentiation treatment can reduce the lethality of cancer patients.

Skeptics of cancer stem cell theory have arguments too: Some argue that the original cancer-causing mutations can strike more developmentally advanced, although still immature, progenitor cells. Stem cells of a given type of cancer may arise from different cells and the origin varies from patient to patient- all the work has involved transplanting human cancer cells into immunodeficient mice. This has raised concerns that the experiments do not accurately reflect what happens during cancer development in humans.

There are several implications of this work.

• “By gaining a sophisticated understanding of how normal and cancer stem cells differ, we’ll be able to design a new class of drugs that is less toxic”;
• Searching for markers specific for cancer stem cell populations;
• New clues on cancer development by examining cancer stem cells focusing on the different the signalling pathways needed for the maintenance and development;
• Convergence of cancer and stem cell research, as both are very well funded.

Peer review literature:

1. Lapidot et al: A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 1994 Feb 17;367(6464):645-8.
http://www.ncbi.nlm.nih.gov/sites/entrez?holding=npg&cmd=Retrieve&db=PubMed&list_uids=7509044&dopt=AbstractPlus

2. Al-Hajj et al: Prospective identification of tumorigenic breast cancer cells PNAS 2003 100(7):3983-3988 http://www.pnas.org/cgi/content/abstract/100/7/3983

3. Singh et al. Identification of human brain tumour initiating cells. Nature. 2004 Nov 18;432(7015):396-401.
http://www.ncbi.nlm.nih.gov/sites/entrez?holding=npg&cmd=Retrieve&db=PubMed&list_uids=15549107&dopt=AbstractPlus

4. Hermann et al. Distinct Populations of Cancer Stem Cells Determine Tumor Growth and Metastatic Activity in Human Pancreatic Cancer. Cancer Stem Cell Volume 1, Issue 3, 13 September 2007, Pages 313-323 doi:10.1016/j.stem.2007.06.002

5. Piccirillo et al. Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature. 2006 Dec 7;444(7120):761-5.
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17151667&query_hl=7&itool=pubmed_docsum

Professional media:

Jean Marx: Cancer's Perpetual Source? Science 24 August 2007:
Vol. 317. no. 5841, pp. 1029 - 1031 DOI: 10.1126/science.317.5841.1029
http://www.sciencemag.org/cgi/content/summary/317/5841/1029

Blogosphere:

Pimm: Redifferentiating brain tumour stem cells: the concept of cancer regenerative medicine
http://pimm.wordpress.com/2006/12/14/redifferentiating-brain-tumours-the-concept-of-cancer-regenerative-medicine/

Pimm: Biopolis profile and cancer stem cells in current Cell Stem Cell http://pimm.wordpress.com/2007/10/05/biopolis-profile-and-cancer-stem-cells-in-current-cell-stem-cell/