If asked what to bring on a fishing trip in winter, your answer probably wouldn’t be a bathing suit and sunblock. Likewise, when cancer cells metastasize, they need the right equipment to reside in unfamiliar organs; in other words, they must adapt their expression programs to accommodate their new microenvironment. How they do this is exactly a mystery, but now a team of international researchers show that they don’t carry all their tools with them. They have found that some tissue resident cells can help disseminated breast cancer cells to form metastatic colonies in the brain by secreting microRNA-containing exosomes.
To understand how disseminated cancer cells adapt to new microenvironments at distant metastatic sites, Yu and coworkers analyzed publically available gene expression profiles of clinical metastasis and found that PTEN mRNA was strongly downregulated in brain metastases.
Even more interestingly, experiments involving clinical samples and animal studies showed that PTEN loss occurred after tumor cells had migrated to the brain and was reversible. Co-culture experiments with different cell types showed that the brains own astrocytes were downregulated PTEN in tumor cells presumably by the actions of secreted factors.
Suspecting the involvement of microRNAs, the authors created a mouse model in which a cluster of microRNAs known to target PTEN was specifically knocked out in astrocytes and found that:
- Astrocyte-specific depletion of PTEN-targeting microRNAs completely blocked PTEN downregulation in brain metastases in vivo and significantly impaired the tumor cell growth.
- miR-19a was the major astrocytic microRNA downregulating PTEN
- Astrocyte-conditioned media contained exosomes with high levels of miR-19a and blocking astrocyte exosome secretion restored PTEN levels in tumor cells and inhibited tumor outgrowth in vivo.
- PTEN reduction itself was found to increase the secretion of the chemokine CCL2, which recruits IBA1-expressing myeloid cells which, in turn, enhanced tumor outgrowth.
Thus, it appears that astrocytes are accommodating hosts and welcome travelling cancer cells with a gift basket filled with tumor suppressor inhibiting microRNAs.
Take a trip over to Nature, November 2015 for the full story.