Learning How Cancer Spreads and How to Stop It

In the future, clinicians will be able to accurately predict whether a given cancer will spread (metastasize) to another part of the body. Treatments tailored to the individual patient to prevent or block metastasis will also be possible. Before that day can come, however, we must acquire a deeper understanding of how cancer spreads and thrives in new locations. Although great progress has been made over the last two decades in the treatment of cancer, metastasis remains cancer’s most lethal aspect.

The “seed and soil hypothesis” of cancer metastasis was proposed more than 125 years ago. In this hypothesis, successful metastasis occurs only when distant organs and tissues (the "soil") are suitably hospitable to cancer cells (the "seeds") to allow them to survive and grow into new tumors. Although this basic premise still holds, metastasis is now known to be more complex than just a seed finding suitable soil. The type of cancer, the ability of the spreading cells to survive in the circulatory system, and the organ or tissue to which they spread all influence how the metastatic process unfolds.

Many cancer deaths are caused when cancer moves from the original tumor and spreads to other tissues and organs. This is called metastatic cancer. This animation shows how cancer cells travel from the place in the body where they first formed to other parts of the body.

Another important factor is when cancer cells spread. For many years, it was thought that metastasis occurred late in tumor development, but recent evidence indicates that cancer cells can spread throughout the body before the development of a palpable tumor. For example, using a mouse model of breast cancer, NCI-funded researchers were able to show that cancer cells can spread from a tumor even before the tumor is large enough to be detected. In addition, the cells that spread early were more likely to give rise to metastatic tumors than cells that spread later in tumor development.

These findings have implications for the early detection and treatment of metastatic tumors. However, many unanswered questions remain, and additional research is needed to make progress for patients.

Research Priorities

NCI supports research that investigates all aspects of the metastatic process, from how tumor cells metastasize to why certain cancer types colonize some organs and not others.

Understand How Distant Tissues Are Conditioned for Metastatic Colonization

The local environment in an organ or tissue where a metastatic tumor will eventually grow is not a passive player in the process of metastasis. NCI-funded researchers have shown that this environment must first be conditioned to create a hospitable neighborhood—termed a premetastatic niche—before the spreading tumor cells arrive.

Subsequent discoveries have shown that tumors play an active role in creating this niche by, among other things, sending out tiny messengers called exosomes. Tumor cell exosomes contain cellular components, such as DNA and proteins, wrapped up in a piece of the tumor cell’s outer membrane. They transport their contents through the body’s circulatory system to help condition distant locations for metastatic colonization. NCI-funded researchers are exploring the use of exosomes and other tumor-secreted vesicles as biomarkers and potential therapeutic targets for predicting and preventing metastatic disease. (Read about one of these researchers, David Lyden, M.D., Ph.D., of Weill Cornell Medical College.)

Another area of investigation is understanding why specific cancers preferentially metastasize to certain organs or tissues but not to others. For example, breast and prostate cancers often metastasize to the bones, and gastrointestinal cancers frequently metastasize to the lungs and liver. The factors underlying this tissue-specific predisposition for metastasis are largely unknown and are being studied by the cancer research community. Identifying these factors may reveal strategies to limit metastatic disease.

Investigate When Metastasis Occurs

Cancer cells that have spread from a tumor to a distant location may grow to form a new tumor, die, or become dormant. Some cancer cells can remain dormant for 5, 10, or even 20 years before they begin to divide again and form a metastatic tumor. Advances in technology have made it possible to study this phenomenon, called metastatic dormancy, by tracking single cells in animal models and characterizing them at the molecular level. In one example, NCI-funded researchers identified a specific gene signature as a potential biomarker of dormancy in single disseminated prostate cancer cells isolated from the bone marrow of patients. Whether this biomarker can be used to monitor early recurrence in prostate cancer patients is being explored.

Develop Models to Understand Metastasis

Achieving a better understanding of cancer metastasis will require new approaches and models to study the process and how it affects patients. Some NCI-supported programs and initiatives designed to address these needs include the following:

  • The Oncology Models Forum, which is a platform for scientists to share information about animal models, including information about generating, validating, and credentialing new mouse models. In addition, patient-derived xenograft (PDX) mouse models have generated excitement due to their ability to better predict responses to treatment, and, as they are refined, they may prove useful in metastasis research.
  • The Provocative Questions Initiative, through which new approaches to studying metastasis are being developed with NCI support. NCI has funded seven metastasis-related research projects under this initiative, including one to develop a metastasis-on-a-chip assay. Although this assay is still in the early stages of testing, it has the potential to be used for studying how metastatic cells migrate and, ultimately, for testing drugs to inhibit the metastatic process.
  • The Cancer Systems Biology Consortium, which integrates biology, mathematics, computer modeling, and engineering technology to further advance studies of the complexity of cancer. One of the nine academic centers in the consortium focuses specifically on cancer metastasis, and other consortia members study various aspects of metastasis.

Stories of Impact

Metastasis is a complex process that, in everyday life, is a deadly complication of cancer. NCI-funded investigators are leading efforts to discover how tumors spread, with the goal of using this knowledge to predict and prevent the growth of metastatic tumors in patients.

Shining a Spotlight on the Exosome

Metastasis causes about 90% of deaths from cancer. Understanding how cancer spreads throughout the body could reveal new opportunities to curtail tumor growth and help prolong the lives of cancer patients. Pediatric neuro-oncologist and researcher David Lyden is an NCI-funded scientist who has worked arduously for nearly two decades to uncover the steps of cancer cell metastasis.

David’s research focuses on exosomes, tiny sac-like structures, or vesicles, that are secreted by cells and circulate in the blood. Until recently, researchers had largely ignored exosomes and believed that tumor cells alone initiate metastasis at distant sites. However, David and his team discovered that, long before cancer cells arrive at a distant site, tumor exosomes help create a nurturing, or conditioned, environment for metastatic tumor growth. Through this and other work, they demonstrated that a primary tumor actively prepares so-called premetastatic niches in the body.

Key Takeaways

  • NCI supports fundamental research in cancer metastasis to develop ways to prevent or block metastasis and better treat patients with metastatic disease.
  • This research includes studies to increase our understanding of how tumor cells colonize distant organs or tissues, why they preferentially spread to certain sites, and what controls the timing of metastatic spread.
  • NCI also supports the development of models that better represent the metastatic process in humans.