13 March 2008

Nuclear Metastasis switch

Pyotr Smirnov, "Newspaper.Ru»Scientists were able to stop the spread of breast cancer metastases and even return cancer cells to their original appearance by "turning off" a single SATB1 gene.

In the human body, it is better not to indulge in the "switch" yet: this will deprive us of the opportunity for wound healing and vascular growth. In addition, it is not easy to get to the protein that encodes SATB1 – it remains in the cell nucleus.

Expression, that is, the reading of genes and the synthesis of the corresponding proteins, is a finely regulated process that has not yet been fully deciphered by scientists. Now science is at the stage of collecting information about the regulators of the cellular genome. As it turns out, the work of several genes can be under the control of the same nuclear factor.

SATB1, an intracellular protein responsible for the activation and differentiation of T–lymphocytes of the immune system, turned out to be the same "multifaceted". As scientists from Berkeley found out, it is also responsible for the development of the most aggressive form of breast cancer. The work of scientists is published in the latest issue of Nature.

Cancer cells need the protein SATB1, a product of the gene of the same name, for metastasis – a stage of development when individual cells break away from the main tumor and with the flow of blood and lymph spread throughout the body.

The maximum harm that one ordinary cell can bring is to clog small vessels, and even then very rarely. But not cancerous – their superpower for rapid reproduction leads to the rapid growth of new tumors in vital organs.

Terumi Kovi-Shigematsu from the University of California, Berkeley, who led the work, explained that this protein changes the work of several hundred genes, accelerating tumor growth and metastasis: "This is a new paradigm in the theory of tumor progression."

As for the paradigm shift, she may have overreacted, but thanks to her work, in the near future she will make significant progress, if not treatment, then diagnosis - for sure.

The work began with a routine screening study, during which genes or their expression are compared in different groups of sick and healthy people. Usually such work leads to the emergence of new "obesity genes", "high growth genes" and the like due to the fact that scientists find a statistically higher occurrence or activation of a gene in a particular group.

This time, the scientists also acted in the spirit marked by the "award" of Science for the past year.They found that tumors in which the SATB1 protein is detected are more likely to progress or recover after surgery.

This would already be enough to consider it a predictive marker. But the scientists didn't stop. Oncologists now have numerous tumor cell lines in their arsenal that differ in their behavior in vivo and in vitro. Scientists took a breast cancer line that does not have the ability to metastasize, inserted the SATB1 gene into the cells and transplanted them to immunodeficient mice – a standard procedure for the study of tumor cells. In all cases, experts noted the rapid progress of the tumor and metastases.

By turning off the work of this gene with the help of RNA, they not only stopped the metastasis and growth of the tumor, but also returned the epithelial cells of the breast to their original appearance – however, this was demonstrated only in in vitro culture, and not in the body of mice.

Expression of SATB1 in breast glandular epithelium acinus cells.

Экспрессия SATB1 в клетках ацинусов железистого эпителия молочной железыLeft: the tumor develops from ordinary cells (first picture on the left) due to increased division (second), transformation into tumor cells (third) with further malignancy and acquisition of the ability to invade surrounding tissues and metastasis (fourth). The microphotographs below depict the extreme stages of this process, green is the integrin alpha 6, responsible for cell contact, blue is the nucleus. It is noteworthy that the normal structure depicted on the left was restored when SATB1 expression was blocked.

Белок SATB1 формирует в ядре клетки трехмерную пещероподобную структуруOn the right: the SATB1 protein forms a three–dimensional cave-like structure in the cell nucleus that rearranges chromatin, binds to certain gene sites, and triggers the work of enzymes that read genes - as a result, the expression of numerous genes is enhanced or weakened.

// Lawrence Berkeley National Laboratory.

Among the objects of the aggressor's attention are already known genes responsible for the progression of lung and bone tumors. And in addition to them, genetic sequences encoding growth factors of connective tissue and blood vessels, and a variety of enzymes like metalloproteinases.

The problem is that the same proteins are also needed for normal processes in a healthy body – vascular growth, wound healing, and reconstruction of the rough connective tissue of scars.

So this is one of the reasons why it is impossible to simply "turn off" SATB1 throughout the body, targeted suppression in tumor cells at the current level of oncology is unlikely. The second reason is the intracellular location of the protein, which makes it difficult for drugs that hardly penetrate the cell membrane, not to mention the nuclear one.

But practical benefits from the work of scientists can be extracted right now – this is a diagnosis that allows you to more accurately determine the stage and nature of the process, which is very important for the correct choice of treatment tactics. The more aggressive the tumor, the more radical the measures should be.

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