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How stromal cells influence therapy resistance in breast cancer
Stromal cells can communicate with breast cancer cells
and influence the way they respond to chemotherapy or radiation
treatment. Mirjam Boelens from the Netherlands Cancer Institute has
figured out how this communication can take place and which genetic
pathways are involved. These findings were published on October 23
in the journal Cell.
"We are starting to realize that we should not just look at cancer
cells, but also the cells that are surrounding them", says Mirjam
Boelens. In the past few years, Boelens worked as a KWF-fellow in
the laboratory of Andy Minn in the Abramson Family Cancer Research
Institute at the University of Pennsylvania. There, she worked on
the communication between stromal fibroblasts - the cells of
the connective tissue that surrounds organs - and breast cancer
cells. There were already some indications that these stromal cells
can influence therapy sensitivity of breast tumors. Boelens tried
to figure out the mechanisms behind this. It turns out that stromal
cells communicate with breast cancer cells using exosomes, small
vesicles containing (in this case) pieces of RNA. These tiny bits
of RNA can activate genetic pathways in breast cancer cells that
make them therapy resistant.
"The fact that these cells use exosomes to communicate and
activate resistance pathways is something quite new", says Boelens.
"This offers new possibilities for developing drugs that can
sensitize therapy resistant tumors." Boelens and her colleagues
showed that the activated pathways in the breast cancer cells are
the ones involving the genes STAT1 and NOTCH3. They also showed
that these pathways can predict therapy resistance in primary human
breast cancer. And when the researchers inhibited the NOTCH
signaling pathway in mice, the breast cancer cells in these mice
regained sensitivity against radiation therapy.
A very interesting next step would be to see whether activation of
the resistance pathways in the tumor cells can be prevented by
blocking the communication between the stromal cells and the cancer
cells. That's what Boelens is currently working on as a postdoc in
the research group of Jos Jonkers at the Netherlands Cancer
Institute (NKI). She is now studying the role of the exosomes in a
mouse model that spontaneously develops breast cancer. She wants to
track the exosomes in this natural situation, and try to target
them to see whether this could help prevent the tumor becoming
All work thus far has been done with so-called triple negative
breast cancer cells. Another line of research Boelens is currently
focusing on, is to determine the role of the stromal cells in other
types of breast cancer, among which invasive lobular carcinoma.