A unifying theory on the causes of cancer metastases has been proposed by Alexander R.A. Anderson, Ph.D., chair of Integrated Mathematical Oncology at Moffitt Cancer Center, and Jacob Scott, M.D., a Moffitt Radiation Oncology Program resident that is studying for his Ph.D. at the University of Oxford Centre for Mathematical Biology.
Their commentary was published online in Nature Reviews Cancer on May 24, 2012.
"In patients with advanced primary cancer, circulating tumor cells (CTCs) can be found throughout the vascular system," said Anderson, a senior member at Moffitt. "Recent technological advances that have enabled measuring CTCs in patients have spurred interest in the circulatory phase of metastasis. However, when, how and where CTCs form metastasis is not fully understood and is now the subject of intense study."
Using the metaphorical hypothesis of "seed" and "soil" -- that cancer is the seed and the soil is the site of metastasis -- Anderson and his co-authors fault the metaphor's utility by saying that just how the seeds are "sown" in the soil is still a big question to which there have been no metaphorical or practical answers.
"We hypothesize that the rich variety of possible metastatic disease patterns not only stems from the physical aspects of the circulation, but also from the heterogeneity of CTCs," wrote Anderson and his co-authors. "The 'seeds' represent many different populations that are derived from phenotypically diverse competing populations within the primary tumor."
According to the authors, the seeds need to pass through a system of biological and physical "filters," or organs, in the circulatory phase of metastasis.
"If the seed is to propagate, it must find its soil," Anderson said. "We hypothesize that this is governed by solvable physical rules that relate to the dynamics of the circulatory flow between organs and how the organs filter."
The authors propose four key biological processes that need to be quantified:
1) the shedding rate at which the tumor sheds CTCs into the vasculature;
2) the CTC phenotypic heterogeneity;
3) the filtration fraction (the proportion and type of CTCs that are "arrested" in a given organ) and;
4) the rate at which CTCs are cleared from the blood or organ.
"Using this representation to develop a mathematical model, we can define both the concentration of CTCs and their phenotypic distribution at any point in the network, as well as organ-specific filtration values," explained Anderson.
The authors conclude with questions needing answers:
* Could there be a circular phenotype that avoids arrest and becomes dormant?
* Could such a cell be mechanically filtered out?
* Could this cell be targeted?
Paper co-authors are Scott and Peter Kuhn, the Department of Cell Biology, Scripps Institute, La Jolla, Calif.
- Jacob Scott, Peter Kuhn, Alexander R. A. Anderson. Unifying metastasis — integrating intravasation, circulation and end-organ colonization. Nature Reviews Cancer, 2012; DOI: 10.1038/nrc3287
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