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17/03/08

Permalink 01:05:50 pm, by Tom, 550 words, 1714 views   English (UK)
Categories: Information

Tumour Metastasis: Pieces of the Puzzle

When engaging in discussion about the role of animals in scientific
research I am frequently frustrated by how polarized the debate can be,
with anti-vivisectionists often claiming that animal research has made
little or no contribution to advancing medical science, while
occasionally defenders of animal research seem to imply that animal
research alone was responsible for said advances. The reality is a
little more complex with many approaches, some using animals, some not,
being crucial to the process. A procedure that uses animals might
confirm and extend the findings of an /in vitro/ experiment, and then in
its turn be verified and enlarged upon by a clinical study in man.

A study published in /Nature/ this week by Dr Terumi Kohwi-Shigematsu
and colleagues (1), and picked up by the /Independent/ newspaper
http://www.independent.co.uk/news/science/gene-discovery-raises-hopes-of-new-treatment-for-breast-cancer-795002.html,
provides a neat illustration of this process in action. Their work
determined that a protein called SATB1, previously identified as a key
factor in driving the expression of genes required for immune system
T-cell development, was also a key player in breast cancer metastasis.
Breast cancer still kills over 10,000 women every year in the UK, the
majority when the cancer spreads from the breast to other tissues.

Dr. Kohwi-Shigematsu's team started by identifying a protein called
SATB1 that was found in cell lines derived from metastatic breast tumour
cells but not in cell lines derived in non-metastatic cells. A screen
of samples from over 1,000 breast cancer patients found that higher
levels of SATB1 in tumour biopsies were associated with a worse
prognosis. These results indicated that higher levels of SATB1 were
associated with metastasis, but not that these higher levels caused
metastasis. After all the higher SATB1 levels could have been a result
of cells becoming metastatic, so they next used RNA interference (RNAi)
to silence SATB1 gene expression in vitro in a metastatic cell line and
found that this caused the cells to grow more slowly and adopt the
characteristics of non-metastatic cells.

At this point they were ready to see what effect different levels of
SATB1 expression had on metastasis in a mouse breast cancer model. In a
series of tests they observed that breast cancer cells expressing SATB1
were far more likely to metastasize and form tumours in other tissues,
and that this metastasis could be blocked by RNAi targeting SATB1,
results that confirmed the key role played by SATB1 in metastasis. They
didn't stop there though, and returned to /in vitro /microarray studies
which demonstrated that SATB1 affects the activity of over 1,000 genes,
notably increasing expression of metastasis-associated genes while
downregulating tumour-suppressor genes.

So where it goes from here? Perhaps the expression of SATB1 will in
future be used as a criterion when deciding whether a patient would
benefit from more aggressive chemotherapy, or maybe SATB1 will itself
become a target for drugs designed to block metastasis. It may even
turn out that a gene whose expression is altered by SATB1 is a more
tempting target for new anti-cancer drugs. What is certain is that with
this very thorough piece of work Dr Kohwi-Shigematsu's team has opened a
promising new avenue for cancer research.

Paul Browne

1) Han H.-J. /et al. /"SATB1 reprogrammes gene expression to promote
breast tumour growth and metastasis." Nature. Vol. 452(7184), Pages
187-93 (2008) PubMed: 18337816.

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