What causes cancer? The answer has changed over time. Supernatural spirits. Curses. Divine retribution. Viruses. Environmental insults. Oncogenes. Epigenetics. Combined factors. New research points to genetics as the underlying factor in the initiation and progression of cancer. Not the familiar array of oncogenes and suppressor genes, but rather the genetic elements that regulate genes are to blame. MicroRNAs, small strands of noncoding RNA, are the key regulators of both cancer initiation and progression.
“Cancer is a genetic disease,” said Carlo M. Croce, MD, professor and John W. Wolf Chair in Human Cancer Genetics and director of the Institute of Genetics and the Human Cancer Genetics Program at The Ohio State University in Columbus, OH. “Alteration of miRNA occurs in 100 percent of human cancers and contributes to the pathogenesis of cancer.”
Dr. Croce discussed the research path that unraveled the role miRNA plays in human chronic lymphocytic leukemia (CLL) during the Saturday plenary session. Once a pair of miRNAs were identified as the active agents in CLL, other miRNAs were found to regulate other cancers. MicroRNAs are already being used in the diagnosis of certain cancers and will likely emerge as therapeutic agents.
“MicroRNAs can act as suppressor genes or as oncogenes” he said. “It all depends on the cellular context. The same miRNA can act as a cancer suppressor and as a promoter in different cells.”
One of the key stumbling points in deciphering the role of miRNA is their ability to act like oncogenes even though they are non-coding. Dr. Croce began his search for the cause of CLL by mapping the most frequent and recurrent chromosomal abnormalities seen in the human form of the disease.
CLL is often an indolent disease, but about 60 percent of patients with the indolent form eventually progress to more aggressive disease. Four chromosomal abnormalities account for nearly all CLL. His lab was able to trace the chromosomal abnormalities to specific deletions. At the time, chromosomal deletions were thought to be the result of gene changes. His lab spent seven years searching for genes linked to these abnormalities and found nothing.
“We were seriously depressed,” he said, “but we thought the gene had to be there somewhere. It turned out to be a translocation, but not of a gene. It was the translocation and loss of two microRNAs, miR16 and miR15. That was the first clue that cancer can be caused by alterations in non-coding RNA.”
It turned out that miRNAs are potent regulators of genetic expression. More than 90 percent of genes have been shown to be regulated by miRNAs. As genetic tools became more sophisticated and flexible, genetic analysis emerged as a practical method to distinguish indolent from aggressive CLL based on miRNA alterations. ZAP-70 has emerged as a reliable prognostic marker for aggressive CLL.
In CLL, miR15 and 16 act to suppress Tcl1 expression. If Tcl1 expression is low, the disease is indolent. As Tcl1 expression increases, the disease becomes more aggressive. A 2013 publication noted a selective inhibitor of BLC-2, a downstream component of miR15 and 16 activity, had dramatic antitumor activity while sparing platelets.
Similar miRNA activity has been documented in prostate, lung, breast, pancreatic, colon, liver, thyroid, gastric, and other solid cancers. In colon cancer, for example, miR135b has emerged as a significant oncologic hub by turning off four major tumor suppressor genes. Other miRNAs are hormones, secreted by cancers to increase the metastatic potential of the original tumor.
“The discovery of microRNA has already led to novel approaches to diagnosis and prognosis,” Dr. Croce said. “They will be used as treatments in several cancers within the next two to three years.”