Colorectal cancer is the third most common cancer worldwide and the third-leading cause of cancer-related deaths.
The main cause of death in patients with colorectal cancer is liver metastasis, with nearly 70% of patients eventually developing a liver tumour.
Recent research has revealed low levels of a tumour suppressor called protein kinase C zeta (PKC zeta) in human colorectal cancer cells and distant metastasis, but it has not been clear how this contributes to the spread of tumours and poor prognosis in patients.
A new study by Sanford Burnham Prebys Medical Discovery Institute (SBP) researchers helps explain the connection between PKC zeta and metastatic colorectal cancer.
Published in Cell Reports, the research describes how PKC zeta deficiency promotes liver metastasis through the inactivation of an enzyme called ADAR2 and the subsequent secretion of molecules called miR-200s from cancer cells into the blood.
In addition, treatment with a compound that inhibits the secretion of miR-200s significantly reduced liver metastasis in mice with colorectal cancer.
"Our findings suggest that elevated blood levels of miR-200s could serve as a non-invasive diagnostic marker for patients at risk of metastasis," says senior study author Jorge Moscat, Ph.D., director of Metabolism Initiatives and director and professor of the Cancer Metabolism and Signaling Networks Program at SBP's NCI-designated Cancer Center. "Moreover, our study is of great potential therapeutic relevance because it provides proof of concept that targeting signals that are activated by the loss of PKC zeta can be useful anti-metastatic therapies."
In a previous study, Moscat and his collaborators identified PKC zeta as a tumour suppressor in colorectal cancer.
As reported in 2013 in the journal Cell, they found that loss of PKC zeta leads to metabolic changes that allow cancer cells to survive and proliferate under conditions of nutrient deprivation, resulting in tumour formation in mice and poor prognosis in human patients. But it has been challenging to develop therapies that target PKC zeta to restore tumour suppressive activity.
"An alternative approach is to look for cell vulnerabilities created by the loss of the tumour suppressor's function," says study author Maria Diaz-Meco, Ph.D., a professor in the Cancer Metabolism and Signaling Networks Program at SBP. "This is the rationale behind investigating the signalling pathways unleashed during PKC zeta inactivation in cancer."
To address this question, Moscat and Diaz-Meco focused on the potential involvement of miRNAs--molecules that play an important role in regulating gene activity.
An increasing body of evidence has shown that dysregulated miRNAs are associated with certain hallmarks of cancer, including sustained proliferation, resistance of cell death, and metastasis.
"Understanding the mechanisms controlling the expression of miRNAs is emerging as a novel approach to design better strategies to treat metastasis," Moscat says. "Whether PKC zeta is involved in the repression of tumour initiation and survival--and also restrains metastasis through the regulation of the expression of miRNAs, had not previously been explored."
In the new study, the researcher team screened PKC zeta-deficient human colorectal cancer cells for changes in miRNAs.
They found that loss of PKC zeta is most prominently associated with decreased levels of the miR-200 family.
Additional experiments showed that PKC zeta deficiency promotes liver metastasis of colorectal cancer cells through ADAR2 inactivation, which increases the loading of miR-200s into vesicles that are subsequently secreted by the cells.
Consistent with this finding, colorectal cancer patients with metastatic tumours have increased blood levels of vesicles containing miR-200s.
In mice with colorectal cancer, injection of a compound that inhibits the secretion of miR-200s significantly reduced liver metastasis.
"Altogether the results reported here highlight the importance of identifying signalling vulnerabilities unleashed upon the inactivation of tumour suppressors and establish PKC zeta-derived signals controlling miR-200s as potentially important therapeutic targets in cancer metastasis," Diaz-Meco says.
Moreover, the discovery that ADAR2 is a key vulnerability of PKC zeta-deficient cells could have broad clinical relevance, in light of past studies showing that this enzyme acts as a tumour suppressor in brain cancer, stomach cancer, liver cancer, and oesophageal cancer.
Despite the importance of ADAR2 in a wide range of cancers, little is known about how it inhibits tumour growth and migration.
In future studies, Moscat and his collaborators will address this question by investigating how ADAR2 regulates the secretion of miR-200s.
"Given that metastasis accounts for more than 90% of all cancer-related deaths, identifying a therapeutic target that regulates the spreadof multiple types of tumours could have a tremendous impact on patient survival," Moscat says.