In breast cancer, one of the most common cancers in women, tumours contain a small amount of so-called cancer stem-like cells (CSCs).

Being able to eliminate breast cancer stem-like cells in a targeted way is essential for developing successful therapies - as conventional treatments, such as chemotherapy or radiotherapy followed by drug intake, do not target CSCs.

A better understanding of the processes generating CSCs in breast cancer tumours is needed. Noriko Gotoh from Kanazawa University and colleagues have now uncovered a signalling pathway directly related to the proliferation of CSCs in breast cancer.

These findings are published in the journal PNAS.

A property of stem cells is that they can self-renew and differentiate. 

Two types of stem cell division can occur which include symmetric or asymmetric division. 

In the former, two self-renewing stem cells are generated; in the latter, only one (and a differentiated cell).

It is now believed that malignant CSCs have a higher tendency to divide symmetrically, thus increasing the number of CSCs.

Gotoh and colleagues looked at how the microenvironment of CSCs, called the CSC niche, causes and sustains an increased rate of symmetric division. 

The researchers started from the observation that a particular gene encoding a type of cytokine known as Semaphorin 3 (Sema3) was one of the most-expressed genes in the CSC niche.

Cytokines are small proteins that, when released, affect the behaviour of cells around them.

The production of Sema3 activates another protein, called MICAL3, the expression levels of which were also found to be high in the CSC niche.

Through a series of in vitro experiments, Gotoh and colleagues were able to confirm the critical roles of Sema3 and MICAL3 in breast cancer tumour development.

Specifically, MICAL3 was shown to be required for tumour sphere formation, since tumorigenicity is associated with spherical cell shapes.

The scientists showed that Sema3-stimulated MICAL3 triggered a whole sequence of biomolecular interactions which ultimately resulted in the induced symmetric division of CSCs, and hence their proliferation in breast cancer.

The establishment of this important pathway is highly relevant for developing treatments for breast cancer, as Gotoh and colleagues said "by inhibition of MICAL3 or knockdown of each component in the signalling pathway, the symmetric cell division may be inhibited, leading to a reduction of breast-cancer stem-like cells."

Source: Kanazawa University