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Research Worth Watching: When Does a Tumor First Start to Metastasize?

Within the cancer research world, many scientists believe we answered the question about how cancer spread a long time ago. But here’s the thing about science: It’s always a work in progress.

As I’ve mentioned before, when researchers observe a scientific phenomena they develop stories (hypotheses) to explain what they are seeing. But over time, we forget the explanation is merely a story. Why am I bringing this up? Because the results of two new studies published online Dec. 14, 2016, in Nature that explore how tumors spread have each come to a similar conclusion: We are going to need to start telling a much more complex story about when and how cancer cells metastasize.

The standard story of metastases follows a linear model. According to this model, breast cancer starts in the milk duct or lobule and then grows gradually, acquiring more and more mutations until it gains the ability to break away from the tumor mass and move into the blood stream and spread to other organs. It made sense—until new technologies gave us the ability to detect cancer cells/DNA in the blood of people with metastatic disease. Our ability to monitor these disseminated cancer cells (DCCs) led us to develop a whole new story line about how we could use these cells to track over time how tumors mutate and grow and spread and become resistant to treatment. It is a good story—but we are far from being sure it is true.

What is true is that our ability to study DCCs has given us a tool we can use to figure out how metastases develop. And that’s what the researchers behind those two new studied did. Their studies, conducted in mice, have turned our accepted wisdom upside down. Why? Because the findings suggest that the DCCs that first leave the tumor are actually better at starting metastases than the ones that have acquired more mutations and leave the tumor later. These cells that leave the tumor early on are like the first pioneers that moved West in the U.S. or the first group of immigrants to go to a new land. They are going where no one they know has gone before and there is something about them that gives them the strength and resilience to set out on this journey.

The first study looked at the genetic mutations of primary tumors and compared them to the DCC. The researchers found that the primary tumor in the breast (mammary glands) of the mouse had more mutations than the DCCs or the metastases. This surprising finding suggests that cancer cells can escape from the primary tumor very early and spread to other organs, where they mutate independently from the original tumor! This may explain why some women with DCIS or non-invasive tumors are found to have DCCs in their bone marrow. It may also potentially explain why up to 8% of women with DCIS are later diagnosed with a metastatic recurrence.  In mice this has to do with the HER-2 neu protein. Whether the same is true in humans remains to be determined.

The second study, published online Dec. 14, 2016, in Nature tried to figure out the science behind this early migration of cells. It showed that progesterone helps the cancer cells that spread early on. Specifically, the researchers found that two proteins, termed WNT4 and RANKL, which are secreted very early by tumor cells that have a progesterone receptor help cancer cells that do not have the progesterone receptor leave the primary tumor and move into the blood stream and the bone marrow. Over time, as the tumor grows, more cells spread to the bone marrow. But the cells that arrive later are not as good at forming metastases as those early pioneers!

Taken together, the findings from these two studies suggest it is the very early DCCs— the ones that occur before a tumor is detectable by any of our current means—that are most important in developing metastases. It also suggests we need to change the story we have been telling. This may seem like bad news. But it’s not. Rather, it means that this new understanding of cancer can help us to develop more successful approaches to treating metastases. And that, of course, would be great news!