In
my previous blog post I mainly addressed the issue of factors that affect
circulating tumor cell count in blood samples. As previously mentioned, this
could lead to an under or overrepresentation of the cumulative CTC total within
the patient. As such, it is important to account for these factors during
quantification and ultimate prognosis using CTCs. In my previous post I focused
more on the factors of clustering and filtration. The factors that followed,
such as cloaking had to do with molecules from within the circulatory system
masking CTC presence and as a result prevented accurate analyses to the point
where it was deemed another factor in distorting CTC measurement. However one
of the factors that was in the article mentioned, but was never given a greater insight to is
G in the image below labeled “(partial) EMT”.
The
above image is from the article “Circulating Tumor Cells” by Vicki Plaks and
was also shown in my previous post. Within these factors is (partial) EMT which
was vaguely addressed by the article in a generalized manner.
Afterwards I found an article titled “The Basics of Epithelial-mesenchymalTransition” that highlighted EMTs and the process that it encompasses. The
article showed that epithelial-mesenchymal transition (EMT), was actually the
process in which an epithelial cell that normally interacts with the membrane
that it is on, undergoes biochemical changes that allows
it to gain mesenchymal cell properties. This essentially means that the cells gain
enhanced migratory capabilities and overall seem to gain cancerous cell-like
qualities, such as increased invasiveness in the organism.At this point, the possible skewing of data in a theoretical sense was realized; if these epithelial cells are being released from the initial carcinoma site, then these cells are more than just the new characteristics they have acquired: they are also products from the irregular cancerous growth.
The additional loss of traits that define the tethering potential in normal epithelial cells to the underlying structures could adversely affect CTC count because now the number of site that are used to target CTCs has substantially decreased. As a result, it is believed that the release of epithelial cells that were within proximity of the initial outgrowth of may fulfill the criteria to be detected by popular detection methods such as the CellSearch system, which according to this article by Terence W. Friedlander, is reliant on the implementation of antibodies that are directed against the epithelial cell adhesion molecule (EpCAM), which is expressed on cells derived from the epithelium. However the process isn't solely associated with more targets, but also potential loss of these transmembrane proteins leading to less targets for the CellSearch system. This, alongside the previous accepted assumption that neighboring cells that haven't necessarily gained the function of cancerous cells in that general region, may still have a manner of being quantified and accounted for by the CellSearch system. This could result in an overrepresentation of the current metastasizing potential of the cancerous growth.
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Above are two images from Raghy Kalluri's article and they mainly serve to show the general process of EMT. As read in the article, it seems that though the general steps within the process are known, it is unclear as to what dictates this process with respect to the carcinomas genetic information. There is one particular point within this section in the article that caught my attention and that was when it stated, "...activation of an EMT program has been proposed as the critical mechanism
for the acquisition of malignant phenotypes by epithelial cancer cells." and that made me question how EMT results in the acquisition of these phenotypes. After continued research, it seems that this is largely an assumption made by deductive reasoning without any convincing concrete evidence that supports it. Yet another topic of interest that I researched more into was what dictated the determining of a location where irregular growth resulting in a cancerous outgrowth would begin. However, like many other sections of research within this complex area of study, this too didn't lead to any significant findings indicating a pathway or factor that dictates this function. I personally believe the most reasonable assumption that can be made at the moment is that it seeks the location where it will most likely experience optimal to its proliferation. The manner it does so however, is beyond the research I have made.
With the current limited knowledge, I believe that the future of CTC analysis lies in developing a manner of analyzing CTCs that is reliant on mutations that arise because of the previously mentioned EMT process. I largely believe that this is would be a more accurate manner of targeting and defining CTC cells because analysis of transmembrane glycoproteins is quite circumstantial in that it relies heavily on the presence of surface protein targets. Genome targeting, however would focus on more specialized characteristics that occurs within a structure that all active tumor cells have. There is however, issues with this form of analysis, the first being the manner of making markers that target for these mutated forms of genetic information within the tumor cells that are likely to undergo EMT and enter the bloodstream, while not affecting normal cells that are proximal to the tumor site.
Interestingly enough, this is where we come back around to Plak's article. As shown in the first image, box J shows a panel labeled "single-cell 'omics'." After going back through Plak's article once more it seems that prevalent research has been done in terms of targeting these tumor cells through their genome. However, the main recurring theme that keeps on affecting CTC count and hinders many advances in cancer research is the fact that cancer is not static and there is not a set recurring characteristic amongst all cancers that allow them to be targeted at a molecular level. Overall, I personally believe that CTC quantification, as with other procedures within the cancer field that we have identified in class, is taking an approach that is too "static" and isn't paralleling the dynamic nature of cancer as a whole. Accepting the fact that treatments will most likely continue with their static nature, I believe that it is necessary to modify the set static form of analysis in order to better identify a dynamic nature. However, such a process is easier said than done, but noting that the continuous progress in the field has shown promising results, it wouldn't do the research justice to say that continual funding for improvement in CTC analysis is an inefficient use of resources.
With the current limited knowledge, I believe that the future of CTC analysis lies in developing a manner of analyzing CTCs that is reliant on mutations that arise because of the previously mentioned EMT process. I largely believe that this is would be a more accurate manner of targeting and defining CTC cells because analysis of transmembrane glycoproteins is quite circumstantial in that it relies heavily on the presence of surface protein targets. Genome targeting, however would focus on more specialized characteristics that occurs within a structure that all active tumor cells have. There is however, issues with this form of analysis, the first being the manner of making markers that target for these mutated forms of genetic information within the tumor cells that are likely to undergo EMT and enter the bloodstream, while not affecting normal cells that are proximal to the tumor site.
Interestingly enough, this is where we come back around to Plak's article. As shown in the first image, box J shows a panel labeled "single-cell 'omics'." After going back through Plak's article once more it seems that prevalent research has been done in terms of targeting these tumor cells through their genome. However, the main recurring theme that keeps on affecting CTC count and hinders many advances in cancer research is the fact that cancer is not static and there is not a set recurring characteristic amongst all cancers that allow them to be targeted at a molecular level. Overall, I personally believe that CTC quantification, as with other procedures within the cancer field that we have identified in class, is taking an approach that is too "static" and isn't paralleling the dynamic nature of cancer as a whole. Accepting the fact that treatments will most likely continue with their static nature, I believe that it is necessary to modify the set static form of analysis in order to better identify a dynamic nature. However, such a process is easier said than done, but noting that the continuous progress in the field has shown promising results, it wouldn't do the research justice to say that continual funding for improvement in CTC analysis is an inefficient use of resources.
References
Kalluri, Raghu, and Robert A. Weinberg. "The Basics of Epithelial-mesenchymal Transition." Journal of Clinical Investigation 119.6 (2009): 1420-428. Web. 4 June 2014.
Plaks, V., C. D. Koopman, and Z. Werb. "Circulating Tumor Cells." Science 341.6151 (2013): 1186-188. Web. 4 June 2014.
