MicroRNAs can limit cancer spread

February 03, 2015

Cancers that have spread throughout the body, a process known as metastasis, are difficult, often impossible, to control. They are the leading cause of cancer-related deaths.

Twenty years ago, however, two University of Chicago cancer specialists--Samuel Hellman, former dean of the University of Chicago's Division of the Biological Sciences, and Ralph Weichselbaum, chairman of radiation oncology--described what they considered an intermediate and potentially treatable state between a single tumor and widespread cancer. They labelled it oligometastasis.

Like oligarchy, the rule of the few, oligometastasis denotes a stage of cancer in which a primary tumor has spawned only a few localized secondary tumors, typically no more than five. The two researchers, nationally recognized authorities on radiation therapy for cancer, suggested and subsequently proved that oligometastatic tumors could often be cured with targeted local treatment such as surgery or focused radiation.

In the February, 2015, issue of the journal Oncotarget, Weichselbaum, co-director of the Ludwig Center for Metastasis Research at the University of Chicago, and colleagues present the first glimpse of the biological mechanisms behind oligometastasis.

They gathered genetic information from tumor samples from their own published clinical trials, the only known datasets of patients with oligometastases. They used this information to identify small clusters of gene-blocking microRNAs expressed only by oligometastatic cells. They also show how certain microRNAs can shut down specific genes, by attaching to their messenger RNA, essentially silencing them.

The researchers found that 14 of these microRNAs, including the most important ones, were encoded by a small chromosomal region known as 14q32. This region is important for early embryonic development. Mutations of genes found on 14q32 have been linked to several childhood diseases.

When the researchers studied the genes that these microRNAs suppressed, they found that many of them were involved in pathways that enabled cancerous cells to adhere to other cell types, invade tissues and migrate to distant sites, the hallmarks of metastasis.

"We call this the AIM phenotype," Weichselbaum said. Tumor cells that express certain microRNAs from 14q32 lack the ability to adhere, invade or migrate (AIM). Instead they give rise to a small number of less aggressive tumors, many of which are curable with local therapy."

The researchers suggest these microRNAs could provide a personalized biomarker, helping physicians predict how aggressively a tumor can spread. "We could use that knowledge to guide treatment," Weichselbaum said.

His team identified four microRNAs from the 14q32 cluster that correlated with a good prognosis. Overexpression of these four microRNAs was associated with a prolonged recurrence-free interval after surgical removal of secondary tumors. Sixty percent of 24 patients with elevated levels of these microRNAs had no metastatic recurrence after five years of follow-up. Seventy percent of 24 patients with low microRNA expression had a recurrence, usually within the first year.

Additional tests, using an animal model of human breast cancer that measures tumor spread to the lungs, confirmed the initial results. Three of the four microRNAs (miR-127-5p, miR-544a and miR-655-3p) suppressed the rapid growth of new lung tumors in immunocompromised mice injected via the tail with breast cancer cells.

They were able to trace some of the benefits to inhibition of specific genes. Blocking a gene called TGFBR2 suppressed cellular adhesion and invasion and reduced the number of lung metastases. Inhibiting ROCK2 suppressed invasion and also led to a decrease in metastasis number.

These findings, the authors conclude, "support our hypothesis of oligometastasis as a clinical entity with biological mechanisms and molecular properties that may differ from polymetastatic disease.... Our results set the stage for improved identification of patients with oligometastasis and guide the development of therapies to limit metastasis development.
-end-
The Virginia and D.K. Ludwig Fund for Cancer Research, the Lung Cancer Foundation, the Prostate Cancer Foundation, and the Foglia family funded this research. Additional authors include Ludwig Board member Samuel Hellman, Abhineet Uppal, Sean Wightman, Stephen Mallon, Go Oshima, Sean Pitroda, Qingbei Zhang, Xiaona Huang, Thomas Darga, Lei Huang, Jorge Andrade, Mark Ferguson, Geoffrey Greene, Mitchell Posner and Nikolai Khodarev of the University of Chicago; and Huiping Liu of Case Western University.

University of Chicago Medical Center

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.