Coming home to roost: The self-seeding hypothesis of tumor growth

Reprinted from NCI Cancer Bulletin for February 8, 2011

The spread of cancer cells from their original location to other sites in the body, known as metastasis, has long been thought of as a one-way journey. But some researchers also believe that metastatic cancer cells can fuel primary tumor growth, with potentially important implications for the timing and nature of cancer treatment.

The concept of tumor self-metastasis, or tumor “self-seeding,” originated at Memorial Sloan-Kettering Cancer Center, based on a series of studies led by Drs. Joan Massagué, head of the Metastasis Research Center, and Larry Norton, deputy physician-in-chief of the center’s breast cancer programs.

In studies of mice, Dr. Massagué observed that breast tumors expressing genes associated with metastasis were growing faster than tumors that didn’t express these genes, even though the genes had no apparent role in increased cell division or decreased cell death. “Moreover, the fraction of dividing cells was not higher in fast-growing tumors versus tumors that are slower growing,” explained Dr. Norton.

These results did not fit in with the standard theories of tumor growth. In 2006, the two researchers proposed that cells that break free from a tumor and colonize distant tissues may also return home via the circulatory system to the welcoming microenvironment in which they first developed.

“We started discussing the possibility that maybe some tumors are growing faster not because the cells were dividing faster or because there was a higher percentage of dividing cells—because none of those things seemed to be true—but because the tumor mass itself was a recipient of metastatic cells,” said Dr. Norton. “Twenty masses growing at rate x are going to be growing 20 times faster than one mass growing at rate x.”

Proof of Concept

The two researchers tested their hypothesis in a mouse model of cancer and published their results in 2009 in Cell. For one experiment, they chose a non-metastatic breast cancer cell line and an isolated set of daughter cells from that line that had gained the ability over time to metastasize to the lungs.

When the researchers implanted the parent cells in one mammary gland and the metastatic daughter cells in the opposite gland to serve as “donor tumors,” the daughter cells migrated to the lungs and to the tumors that were being formed by the parent cells in the opposite gland, accounting for 5 to 30 percent of the eventual size of the parent tumors. Parent tumors seeded by daughter cells grew faster than parent tumors that were implanted alone without daughter cells in the opposite gland.

The researchers observed this same seeding behavior with daughter cells that metastasize to the bones and brain, and with colon cancer and melanoma cell lines, but they did not see the effect when they transplanted daughter cells that were not metastatic.

In a set of follow-up experiments performed in the laboratory, the researchers showed that cells from primary tumors can attract circulating metastatic tumor cells, and they identified several proteins that likely encourage this migration. They also found that the returning metastatic cells promoted primary tumor growth by releasing proteins that change the tumor’s microenvironment, including blood vessels and immune cells, explained Dr. Massagué in an e-mail.

Their hypothesis began to get support from other researchers who were testing it in their own laboratories. “Since publishing this work, we get about an e-mail a week from someone who has repeated our experiment with a tumor line they’re working with, and who has found that their tumor line self-seeds,” recounted Dr. Norton.

Room to Grow

Systems biologists at the Center of Cancer Systems Biology at Tufts University School of Medicine in Boston have provided a clearer picture of how self-seeding could fuel rapid primary tumor growth.

In 2009, Dr. Philip Hahnfeldt and his colleagues published the results of computer modeling studies designed to look at the intersection of two biological phenomena found in tumors. One of these phenomena is that a small population of cancer cells may act like stem cells; they may have the ability to reproduce an infinite number of times, creating more cells like themselves with the capability for endless proliferation but also producing daughter cancer cells that eventually lose the ability to divide.

The second phenomenon is that tumor growth is limited by the space available for expansion. Normal, healthy cells have an amount of space between them that is not available in a tumor. Cancer cells grow tightly together in a dense mass until all available space has been occupied, at which point cell division stops. But at the edges of the tumor, where the normal tissues are less dense, cancer cells continue to multiply and push outward, expanding the tumor’s size.

“This gives value to the idea that tumor growth is helped by metastatic movement,” explained Dr. Hahnfeldt, “where tumor cells get away from the main mass through migration and then…the resulting space [is filled],” creating many smaller masses growing together at a faster rate. Thus, the growth of a primary tumor may be more dependent on metastatic cells populating areas adjacent to the tumor than on the outward growth and invasion of the primary tumor itself.

Their models showed an important—and counterintuitive—relationship between cell migration, cell death, and tumor growth. When the progeny of a cancer stem cell in the model did not migrate or die spontaneously, tumor growth stagnated at around 110 cells. In contrast, a combination of high death rate among the non-stem cell progeny and a high cell migration rate produced the largest tumors in the shortest amount of time, to almost 100,000 cells in just over 3 years.

Clinical Implications of Self-Seeding

This theoretical phenomenon—accelerated tumor growth jump-started by a high rate of tumor cell death—has potential implications for the clinical treatment of cancer. Traditional cytotoxic chemotherapy drugs kill large numbers of rapidly dividing cancer cells, but may not affect cancer stem cells in every tumor type.

“Our model suggests that discouraging migration might provide an alternative means of cancer suppression. Importantly, the results suggest that antimitotic treatments alone, despite killing cancer cells, may actually promote tumor progression if eradication of cancer stem cells cannot be achieved,” wrote Dr. Hahnfeldt and his colleagues in their 2009 paper.

Currently, no anticancer drugs exist that specifically interfere with the process of metastasis, though researchers are actively working on understanding the genetic changes that drive a cancer cell’s ability to break away from a tumor and survive in the blood stream, in the hopes of making metastasis a valid therapeutic target.

And, although the concept of cancer stem cells remains under debate, if self-seeding can be confirmed in cancer patients, what is learned could influence the timing and nature of cancer treatment.

“Some of the things that we do to a tumor—are they inhibiting the process of seeding or are they augmenting the process of seeding?” asked Dr. Norton. “That’s something we don’t know the answer to yet, but it is something we need to seriously consider.” In some cases, removing a primary tumor without first attempting to kill circulating tumor cells may actually encourage distant metastases, as those cells lose their preferred “home” and lodge elsewhere in the body, he explained.

Dr. Massagué’s laboratory is working to understand the molecular basis of self-seeding, which may supply future targets for anticancer drugs. Dr. Norton is also interested in exploring immunotherapeutic approaches to encourage cells within the primary tumor to attack returning self-seeds, a so-called “poison sponge” effect.

Dr. Hahnfeldt is also expanding his modeling work with a grant from NCI’s Integrative Cancer Biology Program (ICBP), overseen by the Division of Cancer Biology. That research will look at how the immune system influences the way cancer cells interact with each other.

“Systems biology has focused a lot on the cancer cell itself, on the genetic changes that occur within that cell. And because cancer is a genetic disease, we’re interested in the changes that occur within a normal cell that cause it to take on these cancer characteristics and become malignant,” said Dr. Dan Gallahan, director of the ICBP. “But it’s also true that population dynamics or cell interactions are equally important. We now know that these dynamics, along with the microenvironment and the immune system, are critical to tumor development.”

The self-seeding of a tumor with its own metastatic cells, Dr. Gallahan continued, may represent a crucial step in this development.