Mapping metastasis

An international research team has detailed new discoveries of how cancerous cells spread from primary tumors to form tumors at a secondary site

Kelsey Kaustinen
TAMPERE, Finland—A research team led by Prof. G. Steven Bofa of the University of Tampere in Finland has uncovered new insights into the spread, or metastasis, of cancer. In a study focused on prostate cancer, the team found that cancerous cells can spread from a primary tumor in the prostate to form a secondary tumor at a new location in the body, and similar processes can lead cancers to spread from one secondary site to another. The study detailed patterns of metastasis from primary prostate tumors to secondary tumors.
 
It was previously believed that metastases were formed when a single mutated cancer cell broke away from the primary tumor, but this study has found that in half the study's patients, cells from two or three different subclones broke off from a tumor and traveled to the same location in another tissue to form a new, polyclonal tumor. While polyclonal seeding has been noted in mouse models before, this is the first instance of it being reported in human cancer.
 
Using whole-genome sequencing on 51 tumor samples from 10 prostate cancer patients whose disease metastasized, the researchers identified an average of 20,000 in each sample. Similar mutations were organized into subclones to produce a phylogenetic tree that illustrated how the subclones were related to each other.
 
“In the phylogenetic trees that our data have produced, we see that most of the oncogenic mutations are shared clonally by all the tumor sites in each patient. This common genetic heritage is a potential Achilles' heel of the metastases; however, many of these shared mutations are in tumor suppressor genes, and our approach to therapeutically targeting these needs to be prioritized,” Dr. Ultan McDermott, senior author at the Wellcome Trust Sanger Institute, said in a press release. “It takes a while before a tumor develops the ability to metastasize, but once it does, the patient’s prognosis changes significantly. We have to zoom in on this crucial junction and gather more data on the impact different therapies have on prostate cancer’s evolution and spread.”
 
The study found that all subclones, no matter which organ they seeded in, retained genetic imprints of a common ancestor, most likely in the primary tumor. All patients were treated with androgen deprivation therapy, and many of the metastases were found to have accumulated convergent genetic alterations related to resistance to androgen-ablation therapy, and were therefore still dependent on androgen signaling even if they were no longer in the prostate, suggesting that targeted treatments used to treat the primary tumor could be efficacious against metastases as well. Prof. Tapio Visakorpi, director of the Prostate Cancer Research Center at University of Tampere, noted that “It seems that we need to study the cancer cells not just at the time of diagnosis, but also during the progression of the disease.”
 
Bova, who was senior author for the study, added that: “The diversity we’ve found suggests multiple biopsies might be needed to identify the ‘trunk’ of the cancer’s tree of mutations – we need treatments that target these core weaknesses to destroy all cancer cells in a clean sweep, rather than trimming the branches. We must also study more patients to learn how to apply these findings to develop more personalized treatments for people with the disease.”
 
This study is one of a series of prostate cancer studies as part of the International Cancer Genome Consortium UK prostate cancer project. This initiative is funded in part by Cancer Research UK, the Wellcome Trust and the Academy of Finland. The study was conducted at the Wellcome Trust Sanger Institute, the University of Tampere, BioMediTech Prostate Cancer Research Center, Johns Hopkins University and the National Institutes of Health. The Academy of Finland funded the Finnish part of the study as part of its Finnish Distinguished Professor program.
 
There are nearly 42,000 men diagnosed with prostate cancer annually in the U.K., with more than 10,800 deaths each year. In the United States, the American Cancer Society estimates that there will be 220,800 new cases of prostate cancer in 2015, with some 27,540 deaths from this cancer. Prostate cancer is the most common cancer in men and the third most common cancer overall in both the U.K. and the United States. Global research and consulting firm GlobalData predicts the global treatment market for prostate cancer (with the exception of hormonal and bone therapies) will grow from $2.6 billion in 2013 to nearly $8.2 billion by 2023.
 
“The thing we fear most about cancer is how it can spread around the body – this is what causes 90 percent of all cancer deaths,” said Prof. Peter Johnson, chief clinician at Cancer Research UK. “We have to find out how cancer cells change as they do this, and how they become resistant to our treatments. This research using whole genome sequencing lets us look right into the molecular core of cancer, and reveals the secrets of how cancer cells change and evolve as they grow. By getting to grips with this detail, we can start to work out how to treat prostate cancer better in the future.”

Kelsey Kaustinen

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