“When a plant goes to seed, its seeds are carried in all directions; but they can only live and grow if they fall on congenial soil. …While many researchers have been studying ‘the seeds’, the properties of ‘the soils’ may reveal valuable insights into the metastatic peculiarities of cancer cases.”
Before physician-scientists had access to state of the art technology, keen observations formed sound hypotheses. Stephen Paget, an English surgeon and pathologist, was the first to document that metastasis did not occur randomly. Metastasis, the spread of primary tumor cells to a secondary organ, is responsible for approximately 90% of cancer deaths.
Upon review of 735 autopsy reports of women who died from breast cancer, Paget found that breast cancer reliably metastasized to the visceral organs and bones. His study — published in the very first issue of The Lancet, one of the most respected medical journals — demonstrated that metastases only develop when the seed and soil are compatible.
Paget’s theory lay dormant until challenged in 1928 by James Ewing, an American pathologist. Ewing hypothesized that cancer spreads by purely mechanical factors that are a result of the circulatory system. Ewing’s theory remained the predominant explanation for more than 50 years, until 1984, when it was disproven.
Biology is never random
Nearly a century after Paget put forth his hypothesis, it finally fell on fertile ground with Isaiah Fidler, D.V.M., Ph.D. Trained as a veterinary surgical oncologist, Fidler later specialized in pathology and became interested in the process of metastasis. While his mentor tried to dissuade him from studying what was then considered a random process driven by anarchy, Fidler was not deterred.
Instead, he dedicated his career to unraveling the complexities of metastasis. Earlier this year, he was awarded the Medal of Honor in Basic Science Research by the American Cancer Society, one of the most prestigious recognitions in the cancer research community.
Fidler’s seminal studies demonstrated that tumors are composed of heterogeneous cell populations and that metastases are non-random biologic events whose outcome depends on the interaction between unique tumor cells with unique organ microenvironments. By uncovering the complex workings of these biological processes, he showed that they are not random, but that we simply fail to adequately understand them.
To assure survival, a plant sends out thousands of seeds in the hope that one fit seed will fall on fertile soil and germinate. However, not all seeds are created equal. This is known as heterogeneity.
Similar to plants, tumors produce an overabundance of seeds, shedding approximately four million cells per gram of tumor each day. Despite this, very few tumor cells ever succeed in colonizing new areas of the body.
Fidler set out to determine how cancer cells are disseminated in the body and how many survive. When radio-labeled melanoma cells were injected into mice, he found that only 0.01% of the cells survived and went on to form metastases. Additionally, while the radio-labeled cells reached every organ, they only formed metastases in the lung.
Wanting to understand what allowed the cells to differentially survive and grow, Fidler took metastatic tumors from the lung and isolated the cells, then re-introduced them into mice. This time 1% to 2% of the cells survived, demonstrating that metastatic cells can be selected for, but they only have a proclivity to grow in select tissues.
Clearly some organs are receptive to metastasis, and some are not. Considering Paget’s theory, if the most fit seed falls on unfertile soil, germination will not occur. But does that analogy also hold true for tumor cells in humans?
To determine the role of soil, now known as the host microenvironment, Fidler and his postdoctoral fellow at the time, Ian Hart, Ph.D., currently at the Barts Cancer Institute, University of London, set out to perform the definitive experiment.
They implanted lung and kidney tissue into the muscle of a mouse and injected melanoma cells intravenously. Their hypothesis: If blood flow was the sole driver of metastasis, then the implanted tissues would have an equal likelihood of metastasizing. If, instead, the host environment influenced metastasis, then the actual lung and the implanted lung tissue would have the same likelihood of metastasizing.
Again they radio-labeled the melanoma cells. This demonstrated that the same number of cells reached the implanted lung and kidney tissues. However, metastases only grew in the lung and the implanted lung tissue. This finding conclusively demonstrated that in the process of metastasis the soil of the host microenvironment is just as important as the seed of the tumor cell.
Seed and soil go by many names today
Fast-forward nearly 35 years and tumor microenvironment is a field of intense study.
Because successful metastasis requires many steps, which requires factors from both host and tumor, many disciplines outside traditional realms of cancer biology are contributing to the collective understanding of the process. Subsequently, many terms are used to describe the seed and soil of Paget’s day.
Seeds are known as stem cells, progenitor cells, metastatic cells or metastatic clones.
Soil is known as microenvironment, niche or stroma.
The following four sections highlight just a few different approaches to understanding the tumor microenvironment currently pursued at MD Anderson.
Related stories: Delving further into the soil