Recently I have, together with collaborators from Moffitt Cancer Center, uploaded a pre-print on arXiv on the topic of metastatic spread. I've touched on this topic previously and the work is in part inspired by a book by Leonard Weiss that I've previously reviewed here, and also previous work by the people at Moffitt.
In the last couple of decades the focus of research on metastases has been on the effect of genes, that when mutated provide the cancer cells with the properties necessary to form distant metastases. The answer to the riddle of metastases is believed to be written in the genome. Indeed this must partly be the case, since we know that cancer cells are full of genetic alterations, but what we currently don't know is how important genetic effects are compared to purely physiological constraints. In order to appreciate this it's worth mentioning that a late-stage solid tumour releases roughly 100 million cancer cells per day(!) into the blood stream, but out of this astronomic number at most a handful cells form detectable metastases in the lifespan of the patient.
It is well known that primary tumours from different anatomical locations have a propensity to form metastases in certain organs. For example, breast tumours are known to metastasise to the adrenal gland and the bone. This is known as the 'seed-soil hypothesis', and suggests in analogy with seeds from plants, that the cancer cells will only flourish if they find the right soil/organ. In opposition to the seed-soil hypothesis stands the 'mechanistic hypothesis' which proposes that metastatic distribution is largely explained by the blood flow to different organs. In our paper we try to reconcile these two views by disentangling the effects of biology and physiology.
In order to do this we have to consider the fate of cancer cells as they reach the blood circulatory system and become circulatory cancer cells (CTCs). The blood is not the native environment for these cells and many of them quickly perish, but the main obstacle they face is the capillary beds where the vessels narrow down to roughly 10 microns, which is the size of the CTCs themselves. Most cells get stuck, are damaged, and die, and we know from animal models that approximately only 1 in 10 000 CTCs pass through a capillary bed unharmed. This means that if 100 million CTCs leave a breast tumour then only 10 000 make it past the capillary bed of the lung, and these remaining CTCs are then distributed to downstream organs in proportion to the blood flow each organ receives. The adrenal gland e.g. receives 0.3% of the total cardiac output, which means that of the 100 million cells leaving the breast on average 30 CTCs reach the adrenal gland.
This framework can be used in order to disentangle seed-soil effects from physiological constraints by normalising (i.e. dividing) the metastatic involvement of each target organ with the relative blood flow it receives. This is known as the metastatic efficiency index (MEI) and was invented by Leonard Weiss. A high MEI suggests beneficial seed-soil effects, while a negative MEI indicates detrimental effects.
What we have done is to extend the MEI to take into account the effect of capillary beds. This extension also makes it possible to investigate the effects of micrometastatic deposits, since these in effect increase the number of CTCs downstream, or in other words, reduce the filtration that occurs within that organ. By posing different scenarios of micrometastatic disease one can then show that the MEI is strongly affected by micrometastases, which in turn suggests that knowledge of micromets could have a strong impact on disease progression, and hence that it would be an important biomarker.
Enough said! Please read the paper.