"An attempt is made in this paper to consider "metastasis" in malignant disease, and to show that the distribution of the secondary growths is not a matter of chance."
"Then as regards "metastasis." Here, too, we shall find evidence of predisposition; we shall see that one remote organ is more prone to be the seat of secondary growth than another. In cases of cancer of the breast, it is strange how often the liver is the seat of secondary cancer.....This frequency of secondary disease of the liver is of course a familiar fact; but it acquires fresh interest when we contract it with the immunity enjoyed by other organs. The spleen has, so to speak, the same chances as the liver; its artery is even larger than the hepatic artery; it cannot avoid embolism. Yet the liver was the seat of 276 cases; the spleen in 18 only. Such a great disproportion cannot be due to chance."
What Mr. Paget observed was that some organs and tissues preferentially developed secondary metastatic tumors and this was dependent upon the tissue of origin of the primary tumor, in this case the breast. Concluding his article he wrote:
"All reasoning from statistics is liable to many errors. But the analogy from other diseases seems to support what these records have suggested. The eruptions of the specific fevers and of syphilis, the inflammations after typhoid, the lesions of tuberculosis, all show the dependence of the seed upon the soil. The best work in the pathology of cancer is now done by those who, like Mr. Ballance and Mr. Shattock, are studying the nature of the seed. They are like the scientific botanists; and he who turns over the records of cases of cancer is only a ploughman, but his observation of the properties of the soil may also be useful."
His words are compelling and quite prophetic, as we'll explore in a moment. The 'seeds' he talks about refer of course to cancer cells, which had already been identified back in 1845. Decades earlier, German scientist Rudolf Virchow first proposed the idea that cancers and cancer cells are abnormal versions of normal cells. Virchow was one of the first scientists to observe cancers of the blood and named these blood cancers leukemia. (As a side note, I find it interesting that Virchow did not believe in Darwinian evolution, which happens to also play a fundamental role in cancer progression and is commonly known as micro-evolution - but that's a topic for another day.)
What Paget brings to light for the first time in his paper is his reference to the 'soil', or the environment in which a metastatic cancer cell finds itself in after separating from the primary tumor and riding the circulatory or lymphatic systems towards another tissue. Each of our organs needs specific nutrients, hormones, metabolites, and signaling molecules to function properly. The local tissue and cellular environment of the brain will have a different chemical make up than that of the liver, or lungs, or bladder (some factors do remain common). Paget hypothesized that these tissue- and organ-specific environments can either stimulate or inhibit metastatic cancer cells growing into secondary tumors. Paget's theory would become known as the 'seed and soil' hypothesis.
Paget had both his supporters and detractors when he published his paper, as is often the case in science. Unfortunately the nature of what cancer is, how it initiates and progresses, and how to treat it, was still completely unknown at the turn of the 20th century after his paper had been published. Like Einstein's theory of gravity waves, the knowledge didn't exist to empirically test his prediction.
But in the last 30 years, the onset of molecular biology finally began to explore and reconsider Paget's hypothesis. The 'soil' he mentions is now referred to as the tumor micro-environment, and it plays an essential role in secondary tumor growth. How and why specific tumors relocate and metastasis to specific organs is still on ongoing discussion. Last November, a team researchers from the University of Texas and elsewhere shined a spotlight on this question when they published their recent work in Nature. Their paper, Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth, finally confirms Paget's predictions definitively.
To make a long (but elegant) story short, Zhang and colleagues proved that when cancer cells from primary breast tumors metastasize to the brain, the micro-environment in the brain is fertile soil for breast cancer cells to grow into secondary tumors. Their experiments demonstrate that astrocytes, a type of cell abundant in everyone's brain, can signal to the freshly-deposited metastatic cancer cell and promote its growth, division, and subsequent tumor formation. It's definitive proof that the 'soil' influences the 'seed' in metastatic cancer and that this phenomena occurs specifically in the brain (for specific cancers originating from the breast). Simply put, astrocytes make little packages (called exosomes) that contain signaling molecules and proteins that are delivered out of the astrocyte, into the micro-environment of the brain, and picked up by the invading cancer cell. Once the cancer cell opens these packages, the content inside promotes the growth of the cell into a new tumor.
The results are challenging and thought-provoking, as most significant scientific breakthroughs tend to be, because the mechanism proven in this paper implicates normal, healthy brain cells as essential players in the development of metastatic tumors. Unfortunately, this means that not only do cancer cells arise as mutated offspring of our own normal cells, but our own normal cells can also promote the growth of metastatic tumors in specific organs. (This was already proven for primary tumors. Scientists have previously shown that tumors and tumor cells recruit the help of local cells in the surrounding micro-environment of the primary tumor to promote its own growth. So the 'seed and soil' hypothesis is also an important paradigm in this respect.)
The good news is that this work details new mechanisms of tumor growth that could serve as targets for drug therapy and personalized medicine. I won't go into detail, but this paper identifies specific molecular factors involved in this signaling process that could also be therapeutic targets. It's a well-executed research story that draws on both historical and contemporary scientific work and theory. The researchers concluded their study (and pay homage to Mr. Paget) by saying:
"Beyond a tumour cell autonomous view of metastasis, our findings highlighted an important plastic and tissue-dependent nature of metastatic tumour cells, and a bi-directional co-evolutionary view of the 'seed and soil' hypothesis."
Now I want to take a step back for one moment to discuss scientific theory, evidence evaluation, and prediction in a more fundamental sense. Above we have two examples of researchers who made an observation, gathered evidence, and made a prediction based upon those observations and results. Incredibly, 127 years ago was not too early to predict something like the tumor micro-environment. Paget did this without the use of molecular biology or even the knowledge of the existence of genes (Gregor Mendel's work on genetics and inheritance wouldn't be re-discovered until the early 1900's). Many scientific contemporaries of Paget's were making predictions that would end up being validated once new technology was developed to address those predictions. I wrote a previous post about the recent confirmation of gravity waves, a theory put forth by Einstein nearly a 100 years ago! The fact that the echoes of these individuals can be heard a century later is remarkable. However, what is more important is that this is evidence that the scientific method of evidence gathering and hypothesis generation is a bonafide, tried-and-true methodology. It is the backbone of nearly all scientific progress and most of technology development.
It is also why it's so frustrating to me that people choose to be selective about the science they believe in or consider accurate. It's deeply concerning that politicians and individuals can choose to believe in the latest cancer medication or weapon technology, yet are staunch climate-change deniers or don't believe in the efficacy or power of vaccines (spoiler alert: the HPV vaccine works, is safe. and is drastically reducing HPV prevalence in teenage women). For each of this issues, it is the same scientific method that tested all the science and technology we have available to us. Picking and choosing what we want to believe can be a dangerous precedent when it comes to science and more scientists need to be proactive about discussing and communicating these issues.
I will note here that there are always cracks in the system. Humans are human after all, and ego, bias, financial incentives, and even simple mistakes are influencing factors on what we believe and promote. There is actually an entire website dedicated to highlighting retracted scientific papers that are fraudulent or manipulated or even pulled because of simple errors in analysis. However, these retracted articles are a small portion of what is published each year and this website highlights the growing list of additional checks and balances within the scientific community that go beyond the initial peer-review process and will hopefully allow research to become even more transparent (open access journals are another layer to this process).
The hardest challenge for some in science today is that sometimes it takes a long time to fully validate a theory. It took 20+ years to go from identifying cancer-causing genes all the way to the development of new drugs that target said genes. For some, like Paget and Einstein, it can take a lot longer, but it is just as satisfying to see when their hypotheses are validated too.
