A new study uses evolutionary analysis to show that some colorectal tumor cells colonize the lymph nodes before metastasizing to the organs. However, the study finds that most metastases descend from subclones in the tumor itself.

When colon cancer spreads, malignant cells often travel directly to the organs, skipping the lymph nodes, a new evolutionary analysis suggests (Science 2017;357:5560).

More than 150 years ago, scientists noticed that metastases often appeared in the lymph nodes before they did in distant organs. That observation suggested that metastatic cells colonized the lymph nodes first. Node removal has long been a standard surgical procedure to prevent metastasis and to stage cancers, but some studies have questioned whether the practice improves survival, and the issue remains contentious.


Researchers have found that metastasizing colon cancer cells (above) do not necessarily pass through lymph nodes.

To determine the metastatic route for colorectal cancer cells, Kamila Naxerova, PhD, of Massachusetts General Hospital in Boston, and colleagues obtained archived biopsy samples from 17 patients with the disease. The researchers then analyzed 20 to 43 noncoding regions that contain long, uninterrupted stretches of the nucleotide base guanine. These regions don't influence a cancer cell's ability to metastasize, but their rapid mutation rate enabled the researchers to construct evolutionary trees for the primary tumors, distant metastases, and lymph node metastases.

The researchers found that 35% of the time, distant metastases were evolutionarily closer to lymphatic metastases than to the primary tumor, suggesting that the metastases descended from lymph node deposits. But 65% of the time, the distant and lymph node metastases appeared to have arisen from distinct subclones within the primary tumor, which supports the idea that the lymph nodes did not serve as a way station for the metastasizing cells. “In most cases, lymph nodes are not essential intermediaries, at least for colorectal cancer,” says Naxerova.

“It's a very nice way of showing what is true and what isn't true in our understanding of how cancer is spread,” says Sanford Markowitz, MD, PhD, of Case Western Reserve University in Cleveland, OH. Markowitz notes that after Science published the findings and a commentary he wrote about them, a number of posts on social media claimed that the study showed that removal of lymph nodes was no longer necessary (Science 2017;357:35–6). He disagrees, emphasizing that the results “do not mean that lymph nodes cannot be a source of disseminated disease.”

S. David Nathanson, MD, of the Henry Ford Health System in Detroit, MI, says that the trend for the last 20 years has been to remove fewer lymph nodes, “so I don't think that this [paper] will change much in terms of clinical practice.”

Colorectal cancer may not be a typical solid tumor when it comes to metastasis, says Hellmut Augustin, PhD, of Heidelberg University and the German Cancer Research Center, also in Heidelberg, because cancer cells can metastasize to the liver through the portal vein without involvement of the lymphatic system or the general circulation. “The issue clinically is whether this is relevant for tumors like breast cancer and melanoma,” where surgeons have to decide whether to perform surgery on the primary tumor with or without lymph node removal.

Naxerova says that the analysis probably wouldn't work for breast cancers, in which the guanine-containing regions accumulate mutations too slowly to provide an evolutionary signal. However, the technique might illuminate the origins of metastases in cancers where the regions change more rapidly, including melanoma and renal, gastric, and pancreatic cancers. –Mitch Leslie

For more news on cancer research, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.