Glossary

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Benign Circulating Epithelial Cell
([|Plaks], et al. 2013)
 * Benign circulating epithelial cells** are epithelial cells in the bloodstream that are not associated with the tumor development. However they have similar properties to CTCs in that they are traveling cells that have flaked off into the bloodstream from their original environment. Furthermore they also have epithelial cell adhesion molecules that allow them to be targeted by the CellSearch system. Thus, their presence can result in a false positive for CTCs and erroneously inflate the CTC count.

CellSearch
The **CellSearch** system is the only validated assay that has been cleared by the U.S. Food and Drug Administration as an aid to monitor patients with metastatic breast, prostate, and colon cancer. It has also been shown to have prognostic value in patients with cell lung carcinoma. It utilizes anti-EpCAM-coated magnetic beads in order to extract CTCs from a blood sample, after which they are fixed or stained and then manually counted. However, this system can only be used on EpCAM-positive cells. For cancers without these membrane markers, less efficient identifiers must be utilized, such as size, shape, or genomic markers. This has greatly limited CTC studies in other cancer types. ([|van de Stolpe], et al. 2011)

Circulating Stem Cells
([|Plaks], et al. 2013)
 * Circulating stem cells** (CSCs) are cells which hold stem cell properties within a cancerous cell. As is true with CTCs, there is some debate as to what exactly defines a CSC. Some have suggested that they are actually a subdivision within the CTC grouping. Furthermore, like benign circulating epithelial cells, they will also sometimes be detected through the same means as CTCs. Their confusing status can result in the skewing of measurement data.

Cloaking
The **c****loaking** of CTCs pertains to the masking of CTCs in the bloodstream via platelets or coagulation factors. Because CTC detection is dependent on epithelial markers, their covering could disguise a CTC and reduce the overall CTC count. ([|Plaks], et al. 2013)

Clustering
([|Plaks], et al. 2013)
 * Cl****ustering** is related to filtering, in the bunching of CTCs in the blood vessels. The bundling of CTCs not only causes their flow to be more difficult, but the overlapping of CTCs can create the false appearance that the group is actually just one CTC. Thus, the CTC count can be erroneously reduced.

EpCAM
Epithilial cell adhesion molecules (EpCAM) are a type of membrane protein that mainly function by binding to the EpCAM on other cells in order to hold both cells together. In normal tissue this allows for cellular adhesion. However in cancerous cells, this allows certain CTCs to dock at distil tissues and form a metastatic tumor. EpCAM molecules can be utilized to detect certain CTCs because these proteins are generally absent from cells in the blood. ([|van de Stolpe], et al. 2011)

EMT


In **epithelium-mesenchymal transition (EMT)**, epithelial cells lose their polar nature and have biochemical changes that constitute the loss of adhesion and ultimately leaving the site from their original site. It is this process that ultimately allows tumor cells to leave their initial site and as a result, they are able to enter the bloodstream. The figure above shows a general idea as to the process that occurs. It starts with the presence of otherwise normal epithelial tissue. After carcinoma development in situ, abnormal cell proliferation is observed and causes sufficient production that cells begin to lose the adhesion to the basement membrane that held them in place. This is followed by intravasation, the movement of metastatic cells from their initial epithelial position to the blood vessel. Thus, the tumor cell has effectively entered a new pathway that will increase the tumor's potential to metastasize. Once at the new site deemed suitable for growth, mesenchymal-epithelial transition occurs. This is essentially the reverse process of EMT and causes the extravasation of the CTCs. The possibility that this affects CTC detection is due to the loss of EpCAM on the membrane of the CTCs that are leaving the initial cancer site. Of all the factors that contribute to CTC analysis inaccuracy, EMT is one whose manner of affecting data accuracy is known, but the measurement of the effect is still something that isn't entirely defined. ([|Kalluri], et al. 1786)

Filtration
Perhaps one of the most common issues when attempting to attain a clear representation of CTC concentration within the bloodstream is the fact that the circulatory system is not solely comprised of defined pathways that are equivalent in size. The ability of CTCs to flow throughout the bloodstream is known as **filtration**. However, CTCs are significantly larger than normal blood cells. Because capillaries are especially small in comparison to veins and arteries, entrapment and clogging is prevalent. The subsequent sequestering of CTCs can interfere with their collection and counting. ([|Plaks], et al. 2013)

Heterogeneity
([|Plaks], et al. 2013)
 * Heterogeneity** is a highly significant factor, in that not all circulating tumor cells are alike across different cancers. Because there are very few properties shared amongst the CTCs of different cancers, besides their ability to flake off of the primary tumor and form metastases, it can be somewhat difficult to label what a CTC is. In this sense, it is also fairly difficult to determine a single method of measuring CTCs as one method will not necessarily work across all cancer types. This can result in inaccurate representations of CTC concentration in that the instrument of measurement could simply fail to detect the CTCs.

Seeding Potential
([|Plaks], et al. 2013)
 * Seeding potential** refers to further difference among CTC and their ability to cause proliferation and give rise to cancerous growth. Not all CTCs have the same potential to cause the development of cancerous growth at a location distal to the origin site. Some CTCs have almost no metastatic potential, while others can have above average metastatic potential. Despite the differences in their risk levels, these cells will be counted as the same, which skews the estimate of patient risk.