Monday 6 May 2013

The principles of metastasis

I have, since the beginning of my scientific career, been under the somewhat naive impression, that science moves relentlessly forward, and that we (as scientists) slowly accumulate more and more knowledge about the world. Things are discovered, communicated and never forgotten within the realms of science. Of course this cannot be true in every single case, but reading this book by Leonard Weiss put me into first-hand contact with the loss of scientific knowledge, which struck me particularly hard since it is about a topic I myself am concerned with. This book was published for everyone to read in 1985, so what I talk about is not a straight denial of scientific fact, but rather a collective amnesia or erosion of knowledge.

Let me be a bit more specific, and mention two things that caught me by surprise when I read this book. Firstly, it was established in the 40's that cancer cells from primary tumours in the breast and prostate can travel to the vertebrae and pelvis without first passing through the capillary bed of the lung. This passage is mediated by a structure known as Batson's venous plexus, which allows for a reversal of flow in the veins, in particular during coughing of sneezing. This, at least in part, explains the predilection for breast and prostate tumours to metastasise to the bone, yet these organ pairs are today often mentioned as prime examples of the seed-soil hypothesis, i.e. the idea that cancer cells thrive in certain organs with favourable 'soil'.  This is often talked about in terms of micro-environmental compatibility, which compared to physical blood flow is quite a far fetched and complex explanation.

My second moment of surprise came when Weiss discussed the literature on cancer cell clump size distribution, meaning the size of the cancer cell clusters that enter the circulation and eventually arrest in capillary beds. I'm far from an expert in the field of metastasis but the view that I have acquired from reading review articles and papers on the topic is that cancer cells travel on their own, never collectively. This mistake from my side (or of the authors I've previously read) is made even more serious since it turns out that the success of cancer cells when they arrest in foreign organs depend very much on the clump size; larger clump of cancer cells means higher chance of forming a metastases.

I sincerely hope that the above mentioned 'surprises' are isolated occurrences, but the impression I get from reading this book is that many fundamental insights into the dynamics of the metastatic process have been lost since the 80's. When did you last hear about the transit times and arrest patterns of circulating cancer cells in different organs, intravascular growth prior to extravasation, the rate at which metastatic cells appear in the primary tumour and the number of CTCs that pass through a capillary bed?

In my view these questions lost their appeal when we entered the 'gene-centric' era with its expectation that the answer to every question in biology lies in the genome, and in deeper and yet deeper sequencing. (On a side note I think the gene-centricity in turn is driven by the love of new technology which implies that any data that is acquired with the previous technology is worthless and does not need any explanation.) When focus moved to the genome a lot of the knowledge about the physical aspects of metastasis was ignored, and when those facts had been forgotten they were re-examined in genetic terms. That said, I'm happy to witness how genetic and proteomic techniques have advanced since the publication of this book, and I can honestly say that the chapters that deal with the biochemistry of cancer have not aged well. Today we know a lot more about the biochemistry of the metastatic cascade, but on the other hand possibly less about its physical aspects.

Apart from providing a new (or rather old) perspective on the process of metastasis the book also contains something that I find lacking in the current scientific literature: the critical review. Dr. Weiss takes the time to dissect the experimental setup of the studies he reviews and identifies loop-holes and mistakes in the deduction and hence conclusions in many of the referenced papers. The typical review article of today tells a pleasant story (via numerous studies) of an important topic and sets the agenda for future research. I think this mainly happens since the author often is an authority on the topic, and hence has much to loose on criticising the techniques or methods used within the field. It is much more tempting then to show off your research field as a successful endeavour where experiments are successfully carried out and theory is steadily improving. What I would like to see is a much more critical stance when writing review articles: most experiments are good, but some are bad, and just repeating the conclusions drawn by the authors does not in my opinion advance science.

These are some of the thoughts that passed through my mind when reading Leonard Weiss' 'The principles of metastasis', an excellent companion for those who are interested in the dynamics of metastatic spread. I'll leave you with a figure from the book that I think summarises the authors view of metastases.

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