Sunday, May 4, 2014

Heterogeneity of the Circulating Tumor Cell

            Carlos Rivera and I are researching the correlation between circulating tumor cell (CTC) counts and the progression of the cancer. These CTCs are seed cells that have shed from the primary tumor and circulate through the bloodstream and are the primary means through which metastases spread. Furthermore, they are also fairly easy to collect as they only require a blood draw. Due to their utility, there has recently been a great deal of development in the study of CTCs as well as their application in treatment. However, one particular aspect that caught my attention in my research was their heterogeneity. One article that I found was helpful on the subject explained how a degree of heterogeneity was achieved through cytomorphological similarities between the CTCs and the primary tumor cell.

Heterogeneity due to Cytomorphology

            An interesting case report from the Departments of Cell Biology in the Scripps Research Institute attested to the unique features displayed by CTCs. The researchers sought to observe cancer cytomorphology in a patient diagnosed with stage III B non-small cell lung cancer and heavily utilized staining in the isolation and characterization of CTCs. It was expected that there may be some differences between primary tumor cells and CTCs in order to better prepare the CTCs for the environmental change. Figure 1 below displays the results with stained CTCs and cells from the primary tumor.


Figure 1. A.) The CTCs were labeled and identified through an immunofluorescent staining protocol. Cytokeratin is red, CD45 is green, and 4′, 6-diamidino-2-phenylindole is blue. B.) The same CTCs were characterized using a Wright-Giemsa stain. C.) Cells collected from the primary tumor 4 years prior to the CTC draw. The arrow points to the distinctive lobated nucleus.

            However, it was found that CTCs were cytomorphologically similar to the cells from the primary tumor from which they arose. Both were 2 to 4 times larger than neighboring white cells and had distinctive nuclei with occasional notching or lobation. The article also noted that in previously studied patients with breast and colon adenocarcinomas, the CTCs were also cytomophologically similar to the primary tumor. Although the CTCs from these samples were admittedly less well differentiated, traits such as cell size and shape remained relatively constant between specific CTCs and primary tumors. This suggests that different cancers should display identifiable CTCs. However, this case report only discusses the attributes of a few types of cancer. In order to better validate this conclusion, more tests must be taken. Furthermore, this report also only utilizes data from one patient. More tests would have to be done on multiple patients in order to ensure that CTCs are not patient specific as well. Lastly, there are methods other than cytomorphology for identifying CTCs such as through epithelial cell adhesion molecules (EpCAM). In order to better understand CTC heterogeneity, these other markers must be studied in detail. Nonetheless, the results of this report indicate exciting developments in the study of CTCs.

Practical use of CTC Heterogeneity

            CTC heterogeneity displays an interesting prospect for the study of cancer. While this should provide a noninvasive method for determining the type of cancer a person has, it also implies that multiple tests must be taken in order to reach this conclusion. Because the CTCs of different cancers have different characteristics, tests that are effective in detecting CTCs from one type of cancer, may not be nearly as effective for another. It is also unlikely that a single test could be created, due to the differences between cancer types. Furthermore, performing every test could prove improbable because numerous different tests could exist to correspond to various cancer types. This might be problematic for patient with multiple cancers, as while some cancers might be identified, others could go unnoticed. Therefore, I believe that while CTCs would certainly hold a great value in determining cancer type, it is best utilized alongside other techniques. Furthermore with prior knowledge of the patient’s condition, the heterogeneity of CTCs could be used to monitor the development of tumors for people with multiple cancers. Since the CTCs are distinct from one another, a CTC count could be used on a person with multiple cancers to monitor the development of each corresponding tumor.


Dena Marrinucci, Kelly Bethel, Madelyn Luttgen, Richard H. Bruce, Jorge Nieva, and Peter Kuhn
            (2009) Circulating Tumor Cells From Well-Differentiated Lung Adenocarcinoma Retain
            Cytomorphologic Features of Primary Tumor Type. Archives of Pathology & Laboratory
            Medicine: September 2009, Vol. 133, No. 9, pp. 1468-1471.