Cancer researchers have uncovered a signaling link – like a Snapchat between cells – that could be used to make tumors more vulnerable to therapy.
Photo: Sudarshan Anand, Ph.D., and Cristina Espinosa, Ph.D. (OHSU/Kristyna Wentz-Graff)
It is a signaling mode that’s also active in severe autoimmune diseases. In the new study published online Friday in Nature Communications, researchers showed that boosting the signal, in a mouse cancer model, made tumor cells suffer more DNA damage from anticancer drugs. It also blocked the growth of new blood vessels needed to sustain tumors and it increased survival of study animals.
“Severe autoimmunity is a disease response. We’re trying to harness it to control cancer,” said the study’s senior author, Sudarshan Anand, Ph.D., an assistant professor in the OHSU School of Medicine and member of the Knight Cancer Institute.
The signal is transmitted by a type of microRNA, molecules made of short strings of 20 or so units called nucleotides arranged in a meaningful sequence. Each microRNA can attach to matching-sequenced messenger RNAs, which are much larger molecules and the templates that cells use to assemble the proteins that are encoded in our DNA. The binding of a microRNA to a messenger stops its target gene sequence from being translated into a protein.
Like Snapchat messages, microRNA signals are fast-acting and short-lived, Anand said.
He, and colleagues including first authors RaeAnna Wilson and Cristina Espinosa, set out to discover whether any microRNAs played a role in the death of blood vessel cells after DNA damage from radiation or chemotherapy. They began by looking for changes in the abundance of microRNAs in tissues treated with DNA-damaging agents such as the chemotherapy drug cisplatin.
MicroRNAs may prove useful as a biomarkers of response to radiation therapy or treatment with angiogenesis inhibitors.
One microRNA, called miR-103, stood out for its abundance after exposure to DNA damaging agents. Further work showed that upregulation of this microRNA occurs specifically in blood vessel endothelial and smooth muscle cells, but not in a range of other cell types. The burst of miR-103 levels begins quickly, as early as 30 minutes after radiation exposure. Its effect is to worsen DNA damage.
In one experiment, increasing levels of miR-103 resulted in a 50 percent decrease in angiogenesis, the growth of new blood vessels needed by tumors. When the researchers blocked the expression of miR-103, it restored angiogenesis.
In mouse models of colon cancer and glioblastoma brain cancer, delivering doses of miR-103 into the tumor increased survival of the animals. In a separate mouse experiment, the researchers administered doses of the microRNA and then treated the tumor-bearing mice with a single dose of radiation. In the mice given the miR-103, tumors shrank and there was a 60 percent decrease in tumor blood vessel area compared with the control mice treated with the same dose of radiation but not given the microRNA.
When the researchers traced the genes targeted by the microRNA, they found that miR103 causes the downregulation of three genes involved in autoimmune diseases such as lupus: TREX1, TREX2 and FANCF. For all three genes, boosting miR-103 levels reduces gene expression. The researchers measured decreases in messenger RNA and protein levels from the genes.
The researchers showed that the microRNA’s interference with TREX1 gene expression leads to significant boost in proinflammatory cytokines. That in turn leads to upregulation of cell-death pathways in blood vessel cells supplying tumors – up to a 30-fold increase in two such pathways.
“We don’t know how this will translate in humans,” Anand points out. But the findings have opened up several promising paths forward, he says. It may be possible to use the microRNA as a treatment to make radiation and chemotherapy more effective. Or there may be existing small molecule drugs that could be used to block the TREX and FANCF gene signaling that tumors use to resist treatment. (TREX1, for instance, is upregulated in about half of men with prostate cancer, Anand says.)
The researchers think that miR-103 and other microRNAs could also prove useful as a biomarkers of response to radiation therapy or treatment with angiogenesis inhibitors, which fight cancer by blocking the growth of blood vessels that sustain tumors.
With a blood test for mRNA as a biomarker, Anand said, you could potentially identify patients needing an escalated dose of radiation, or who could benefit from a different chemotherapy drug.
MicroRNA regulation of endothelial TREX1 reprograms the tumor microenvironment, by RaeAnna Wilson, Cristina Espinosa-Diez, Nathan Kanner, Namita Chatterjee, Rebeccca Ruhl, Christina Hipfinger, Sunil J. Advani, Jie Li, Omar F. Khan, Aleksandra Franovic, Sara M. Weis, Sushil Kumar, Lisa M. Coussens, Daniel G. Anderson, Clark C. Chen, David A. Cheresh and Sudarshan Anand, Nature Communications, November 25, 2016.
MicroRNA: Biogenesis, Function and Role in Cancer, by Leigh-Ann MacFarlane and Paul R. Murphy. Current Genomics, November 2010.