About 160 years ago (precisely in 1849) a Physcian thought that a few cells from a malignant tumor got shed off from the tumor and somehow entered the blood vessels, there by reaching other places and organs in the body.
If those cells could survive and get planted, grow and proliferate in other places, a metastasis was created.
This is the most important feature of a malignancy and in about 90% of the cases is the cause of death. As a historical rememberonce, the pathologist had seen a few abnormal cells in an organ of a cancer patient.
These cells in circulation were named; “circulating tumor cells (CTC)” and for all practical purposes, these cells looked alike the original tumor cells in those times.
There had been a lot of laps of time after which only, the importance of it became more clear, in terms of tumor behavior, clinical response and progression.
Further studies and correlations down the line proved that the more advanced and big the primary tumor, circulating tumor cells were larger in member and, usually produced more drug resistance and frequent metastasis.
This lead to the imagination that these circulating tumor cells have to be precisely identified, and treated so that there is no relapse of tumor. For tumor treatment, it also became important to study there CTCs in depths. Therefore the separation and isolation of these group of tumor cells became important. The first imagination taught the scientists to classify and separate there CTCs on the basis of physical properties like size, shape, later by electrical charge and magnetic attraction so on. A number of filters were designed and this lead to first separation, none the less crudest. In recent past the techniques of separation banked upon magnetic chips on which millions of surface antigens were coated, the blood was made to pass over them, which attracted cells containing antibodies.
The epithelial cell surface marker, the most important being Epithelia Cell adhesion molecule (Ep-CAM) antibody was used for this purpose. However, not all the tumor cells or CTCs were sensitive to Epithelia Cell adhesion molecule (Ep CAM) antibodies and Epithelia Cell adhesion molecule (Ep-CAM) without technologies were developed.
As the characterizations, separation and isolation techniques were being perfected on one side, the other areas of emphasis and researches were in the line of personalized medicine, by culturing these cells to chose precise and responsive medicine. Still other line of investigation were towards charactersing these CTCS, for molecular biology features, DNAs etc. This became essential because the CTCs of a single tumor were found being heterogonous. True to expectation, the analysis showed that the cells of even same tumor were different at molecular level. This implied using different approach for treatment by either mixed or different drugs.
Therefore a simple looking innocently detached tumor cell that is a CTC was not at all that simple. Not only these had capacity to be actively moving, breaking the cell barrier but also endothelial barrier and entering the blood vessel, Moreover this cell was having all the armamentarium to disguise as to cheat on immune system to avoid engulfment from macrophages and T- lymphocytes and to ward off the effects of chemoperaputic agents.
These cells, in presence of appropriate response, through signaling pathways, got converted into myo-ephithelial cells via Myo - epithelial - transmission. Thus this myo- epithelial transmission cell was capable of moving easily within the solid tumor mass. It also got all helps from tumor “microenvironment” but at present the process is still not fully clear.
Why this cell was not killed when it reached to a new environment or a different organ as mets. What caused it to attach there? How and what helped it to find a new NICHE?
Not all the things are still clear and the research is going on and on. The difficulties were not limited to these single cells circulating mets, but scientists discovered that some mets CTCs travelled as cluster of these cells. These cluster contained not only tumor cells but associated mesenchyme, platelets, leucocytes etc as well. These clusters, although could not pass very minute and narrow vessels (microvasculatures), but of course, wherever they could move, had more chances of survival.
It was helpful to both, the intrinic attack by the innate immune system, and also from the chemotherapy.
Thus, now we also have the CLUSTERS of CTCs. These cluster of CTCs have different behavior, composition heterogeneity etc.
All present, the isolation of CTCs, precise characterization of these cells and molecular biology studies are going on single cells CTCs as well as on the clusters of circulating cells. Many truths are emerging indicating that we can surmount these difficulties and once achieved, the future appears bright.
*M V Surekha
**Vishnu Vardhan Rao
Department of Pathology & EM, *Food Toxicology, **Biostatistics
National Institute of Nutrition, Hyderabad, India
Department of Human Kinetics and Health Education
University of Lagos, University Road 101017 Akoka, Yaba, Lagos State., Nigeria
Jitendra Kumar Saxena**
Raj Kumar Singh***
*Department of Biochemistry, ****Department of Forensic Medicine and *****Department of Pathology.
Era’s Lucknow Medical College & Hospital, Era University Lucknow, U.P., India–226003.
**Division of Biochemistry
Central Drug Research Institute, Lucknow, U.P., India-226003.
***Department of Biochemistry
TSM Medical College, Opposite Amausi RailwayStation, Lucknow, U.P., India-226008.
Department of Anatomy
College of Health Sciences, University of Ilorin, Kwara State, Nigeria.
*Department of Chemical Pathology
University of Ilorin, Kwara State, Nigeria.
**Department of Anatomy
Bowen University, Iwo, Oyo State, Nigeria.
***Department of Anatomy
College of Health Sciences, Osun State University, Osogbo, Nigeria.
Department of Surgery
Era's Lucknow Medical College & Hospital, Sarfarajganj, Lucknow-226003
Jitendra Kumar Saxena*
Raj Kumar Singh**
Mrinal Ranjan Srivastava***
*Department of Biochemistry
Central Drug Research Institute, Lucknow, U.P., India-226003
**Department of Biochemistry
TSM Medical College, Opposite Amausi Railway Station, Lucknow, U.P., India-226008
Department of Community Medicine, ****Department of Pathology
Era's Lucknow Medical College & Hospital, Lucknow – 226003
Department of Radiation Oncologist & DNB
Mahavir Cancer Sansthan, Khagaul Road, Phulwari Sharif, Patna, Bihar 801505
Department of Obstetrics and Gynecology
Institute of Reproductive Medicine, HB-36/A/3, Sector-III, Salt Lake City, Kolkata - 700106
Department of Biochemistry, *Department of Physiology
Era's Lucknow Medical College & Hospital, Lucknow, U. P., India-226003
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