Metastatic capabilities of pancreatic cancer might arise before tumors even form. Only 7 in 100 people with pancreatic cancer survive more than 5 years after diagnosis. Clinicians attribute the low survival rate to the typically advanced stage of the disease at diagnosis and early metastasis.1
“We think that the cells often already have metastatic capacity before even transforming into cancer cells,” said Jörg Hoheisel, PhD, head of the division, Functional Genome Analysis, German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ), Heidelberg, Germany.
This hypothesis that the ability to metastasize could arise before the development of tumors contradicts common ideas that cancer cells undergo a series of mutations during tumor growth that enables metastasis.
“To check this hypothesis, we searched the tumor cells for molecular changes that are indicative of the tendency to spread early,” explained Hoheisel.
The researchers examined samples from cancerous, chronically inflamed, or normal pancreas tissues to determine whether any epigenetic changes affected microRNAs.
Epigenetic changes are changes that affect the expression of genes without changing the sequence of DNA, and microRNAs are molecules that regulate a wide range of cellular functions. Pancreatitis, or chronic inflammation of the pancreas, increases the likelihood of developing pancreatic cancer by 15 times.
The researchers discovered many differentially expressed microRNAs, including microRNA-192 (miR-192). Levels of microRNA-192 were abundant in healthy tissue and low in both inflamed and cancerous tissues. In fact, microRNA-192 levels in pancreatitis and cancer tissues were indistinguishable from each other.
“Our interpretation of these results is that epigenetic changes that occur already in inflamed pancreatic tissue lead to reduced production of miR-192. This means that the cells acquire the capacity of invasion and metastasis, which initially has no consequences,” Hoheisel explained.
“The actual transformation into cancer cells is caused by other, unrelated factors and can occur later. The results are cancer cells that are capable, from the very start, to invade surrounding tissue and spread metastases.”
This study next revealed that survival times of patients after diagnosis of pancreatic cancer were longer if the tumors produced relatively high levels of microRNA-192. These results suggest that microRNA-192 level is a biomarker for the rate of disease progression.
Researchers also discovered that microRNA-192 inhibits SERPINE1, a gene that encodes plasminogen activator inhibitor-1 (PAI-1), a protein known to promote cancer. Finally, when researchers gave additional microRNA-192 to cancerous cells in culture, growth and metastases decreased.
1. Botla SK, Savant S, Jandaghi P, et al. Early epigenetic down-regulation of microRNA-192 expression promotes pancreatic cancer progression [published online May 23, 2016]. Cancer Res. doi:10.1158/0008-5472.CAN-15-0390