Word Cloud By Danielle Smolyar
Reporter/curator: Prabodh Kandala, PhD
New Georgia Tech research shows that cell stiffness could be a valuable clue for doctors as they search for and treat cancerous cells before they’re able to spread. The findings, which are published in the journal PLoS One, found that highly metastatic ovarian cancer cells are several times softer than less metastatic ovarian cancer cells.
This study used atomic force microscopy (AFM) to study the mechanical properties of various ovarian cell lines. A soft mechanical probe “tapped” healthy, malignant and metastatic ovarian cells to measure their stiffness. In order to spread, metastatic cells must push themselves into the bloodstream. As a result, they must be highly deformable and softer. This study results indicate that cell stiffness may be a useful biomarker to evaluate the relative metastatic potential of ovarian and perhaps other types of cancer cells.
ust as previous studies on other types of epithelial cancers have indicated, Sulchek also found that cancerous ovarian cells are generally softer and display lower intrinsic variability in cell stiffnesss than non-malignant cells.
Sulchek’s lab partnered with the molecular cancer lab of Biology Professor John McDonald, who is also director of Georgia Tech’s newly established Integrated Cancer Research Center.
“This is a good example of the kinds of discoveries that only come about by integrating skills and knowledge from traditionally diverse fields such as molecular biology and bioengineering,” said McDonald. “Although there are a number of developing methodologies to identify circulating cancer cells in the blood and other body fluids, this technology offers the added potential to rapidly determine if these cells are highly metastatic or relatively benign.”
Sulchek and McDonald believe that, when further developed, this technology could offer a huge advantage to clinicians in the design of optimal chemotherapies, not only for ovarian cancer patients but also for patients of other types of cancer.
Abstract of the study:
The metastatic potential of cells is an important parameter in the design of optimal strategies for the personalized treatment of cancer. Using atomic force microscopy (AFM), we show, consistent with previous studies conducted in other types of epithelial cancer, that ovarian cancer cells are generally softer and display lower intrinsic variability in cell stiffness than non-malignant ovarian epithelial cells. A detailed examination of highly invasive ovarian cancer cells (HEY A8) relative to their less invasive parental cells (HEY), demonstrates that deformability is also an accurate biomarker of metastatic potential. Comparative gene expression analyses indicate that the reduced stiffness of highly metastatic HEY A8 cells is associated with actin cytoskeleton remodeling and microscopic examination of actin fiber structure in these cell lines is consistent with this prediction. Our results indicate that cell stiffness may be a useful biomarker to evaluate the relative metastatic potential of ovarian and perhaps other types of cancer cells.
Ref:
1. Georgia Institute of Technology (2012, October 10). Squeezing ovarian cancer cells to predict metastatic potential: Cell stiffness as possible biomarker. ScienceDaily. Retrieved December 8, 2012, from http://www.sciencedaily.com/releases/2012/10/121010131556.htm
2. http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0046609
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Ovarian cancer is known for its aggressiveness. it’s enough that few cells will remain in the pelvic after surgery in order to cause recurrence and metastases. How then, can one be confident on using such system to predict prognosis?
Comparative gene expression analyses indicate that the reduced stiffness of highly metastatic HEY A8 cells is associated with actin cytoskeleton remodeling and microscopic examination of actin fiber structure in these cell lines is consistent with this prediction.
The results suggest either of two approaches. Atomic Force Microscopy is not normally used by pathologists in diagnostics. This brings me back to 1966, when I was doing electron microscopy on placenta as a medical student, and then I had to make my own glass knives. The instrument was large and the technique was not suitable for anything other than research. But EM gained importance in Renal Pathology. It has not otherwise been used.
A. So the first point related to microscopy is whether AFM has feasibility for routine clinical use in the pathologists’ hands. This requires:
1. suitable size of equipment
2. suitable manipulation of the specimen
3. The question of whether you are using overnight fixed specimen, or whether the material is used unfixed
4. Nothing is said about staining of cells for identification.
5. Then there is the question about whether this will increase the number of Pathologist Assistants used across the country, which I am not against.
This would be the end of “house” trained PAs, and gives more credence to the too few PA programs across the country. The PA programs have to be reviewed and accredited by NAACLS (I served 8 years on the Board). A PA is represented on the Board, and programs are inspected by qualified peers.
There is no academic recognition given to this for tenure and promotion in Pathology Departments, and a pathologist is selected for a medical advisory role by the ASCP, and must be a Medical Advisor to a MLS accredited Program.
The fact is that PAs do gross anatomic dictation of selected specimens, and they do autopsies under the guidance of a pathologist. This is the reality of the profession today. The pathologist has to be in attendance at a variety of quality review conferences, for surgical morbidity and mortality to obstetrics review, and the Cancer Review. Cytopathology and cytogenetics are in the pathology domain.
In the case of tumors of the throat, cervix, and accessible orifices, it seems plausible to receive a swab for preparation. However, sampling error is greater than for a biopsy. A directed needle biopsy or a MIS specimen is needed for the ovary.
B. The alternative to the first approach is the identification of biomarkers that are related to the actin cytoskeleton, perhaps in the nature of the lipid or apoprotein isoform that gives the cell membrane deformability.
I disagree with Dror Nir about the aggressiveness of ovarian tumors. They are terrible to deal with because they metastasize along the abdominal peritoneum and form a solid cake. It is a problem of location and silence until it is late. Once they do announce a presence on the abdominal wall, there is probably a serous effusion.
Marguerite M Pinto and Larry H Bernstein were the first to publish on the use of CA125 with CEA in the serous effusion to assist in the diagnosis of ovarian cancer.
In addition, they conducted a study with Dr. Martin Rosman and showed the the half-life of disappearance of CA125 was predictive of a 30 month remission post surgery.
There may not be a magic bullet. Perhaps we can have a dragnet!
Dr. Prabodh,
Thank you for this post on cell stiffness as a biomarker for the prediction of malignancy.
Histological properties, as cell deformity and softness, now identified as predictors of malignancy may expedite diagnosis and treatment. The bioengineering and molecular biology methods, used in AFM, can be performed in one lab per city, having all speciments obtained via biopsy or MIS been trasferred for AFM testing in one central lab equipped with the mechanical tools as above.
At the cellular level, alteration in actin cytoskeleton remodeling and actin fiber structure, I assume would be detectable by Calcium levels which can be obtain in the lab, cytoskeleton remodeling is microscope observable.
Now that cell stiffness is identified as biomarker, methods for measurement of
Alterations in actin, as above, need be harnessed to be used for malignancy prediction.
Thansfer of this discovery to other types of Cancer is very important in thecontext of efficacy dimensions of diagnosis formation and unification of the universe of knowledge on histopathology of Cancer.
In our forthcoming e-Book on Cancer:
Dr. Prabodh, since my folioing two instructions are inspired by your owh post, may you please contact Dr. Williams, our Senior Editor of this effort, requesting your ownership as Editor for as lease one of the following:
we need to have:
1. A Chaper on Biomarkers derived from discoveries in Genomic Research.
2. Another Chapter on Biomarkers derived from discoveries in application of Bioengineering, Mechanics, Nuclear Medicine, Statistical physics, innovations in PET, and other BioMed derived approaches, as applied to the study of Cancer.
Dr. Larry,
Thank you for your comment above, it has three parts, thus, please edit it as such, starting with the last one, ending with the first one, as a historical reflection.
Method of knowledge exporition in Comments is equally important as the structure of of any post. We are in Online publishing, Comments are RealTimeScientific Discourse, often to be embedded in new posts as ideas belonging to an Author.
Dr. Larry and Dr. Williams, jointly, please author a new post for the Cancer e-Book, on Actin, actin fiber, calcium and cytoskeleton modification in Cancer cells morphology and histopathology.
Thank you, all, please continue, as above.
I can’t edit a post written by someone else. The WordPress format does not permit my entry. I’ll try to copy and paste to a separate post.
I requested that you will edit your own COMMENT above, just above mine.
I did not mean the POST itself, YOU OWN comment per my instructions, above
[…] Squeezing Ovarian Cancer Cells to Predict Metastatic Potential: Cell Stiffness as Possible Biomarker (pharmaceuticalintelligence.com) […]
PUT IT IN CONTEXT OF CANCER CELL MOVEMENT
The contraction of skeletal muscle is triggered by nerve impulses, which stimulate the release of Ca2+ from the sarcoplasmic reticuluma specialized network of internal membranes, similar to the endoplasmic reticulum, that stores high concentrations of Ca2+ ions. The release of Ca2+ from the sarcoplasmic reticulum increases the concentration of Ca2+ in the cytosol from approximately 10-7 to 10-5 M. The increased Ca2+ concentration signals muscle contraction via the action of two accessory proteins bound to the actin filaments: tropomyosin and troponin (Figure 11.25). Tropomyosin is a fibrous protein that binds lengthwise along the groove of actin filaments. In striated muscle, each tropomyosin molecule is bound to troponin, which is a complex of three polypeptides: troponin C (Ca2+-binding), troponin I (inhibitory), and troponin T (tropomyosin-binding). When the concentration of Ca2+ is low, the complex of the troponins with tropomyosin blocks the interaction of actin and myosin, so the muscle does not contract. At high concentrations, Ca2+ binding to troponin C shifts the position of the complex, relieving this inhibition and allowing contraction to proceed.
Figure 11.25
Association of tropomyosin and troponins with actin filaments. (A) Tropomyosin binds lengthwise along actin filaments and, in striated muscle, is associated with a complex of three troponins: troponin I (TnI), troponin C (TnC), and troponin T (TnT). In (more ) Contractile Assemblies of Actin and Myosin in Nonmuscle Cells
Contractile assemblies of actin and myosin, resembling small-scale versions of muscle fibers, are present also in nonmuscle cells. As in muscle, the actin filaments in these contractile assemblies are interdigitated with bipolar filaments of myosin II, consisting of 15 to 20 myosin II molecules, which produce contraction by sliding the actin filaments relative to one another (Figure 11.26). The actin filaments in contractile bundles in nonmuscle cells are also associated with tropomyosin, which facilitates their interaction with myosin II, probably by competing with filamin for binding sites on actin.
Figure 11.26
Contractile assemblies in nonmuscle cells. Bipolar filaments of myosin II produce contraction by sliding actin filaments in opposite directions. Two examples of contractile assemblies in nonmuscle cells, stress fibers and adhesion belts, were discussed earlier with respect to attachment of the actin cytoskeleton to regions of cell-substrate and cell-cell contacts (see Figures 11.13 and 11.14). The contraction of stress fibers produces tension across the cell, allowing the cell to pull on a substrate (e.g., the extracellular matrix) to which it is anchored. The contraction of adhesion belts alters the shape of epithelial cell sheets: a process that is particularly important during embryonic development, when sheets of epithelial cells fold into structures such as tubes.
The most dramatic example of actin-myosin contraction in nonmuscle cells, however, is provided by cytokinesisthe division of a cell into two following mitosis (Figure 11.27). Toward the end of mitosis in animal cells, a contractile ring consisting of actin filaments and myosin II assembles just underneath the plasma membrane. Its contraction pulls the plasma membrane progressively inward, constricting the center of the cell and pinching it in two. Interestingly, the thickness of the contractile ring remains constant as it contracts, implying that actin filaments disassemble as contraction proceeds. The ring then disperses completely following cell division.
Figure 11.27
Cytokinesis. Following completion of mitosis (nuclear division), a contractile ring consisting of actin filaments and myosin II divides the cell in two.
http://www.ncbi.nlm.nih.gov/books/NBK9961/
This is good. I don’t recall seeing it in the original comment. I am very aware of the actin myosin troponin connection in heart and in skeletal muscle, and I did know about the nonmuscle work. I won’t deal with it now, and I have been working with Aviral now online for 2 hours.
I have had a considerable background from way back in atomic orbital theory, physical chemistry, organic chemistry, and the equilibrium necessary for cations and anions. Despite the calcium role in contraction, I would not discount hypomagnesemia in having a disease role because of the intracellular-extracellular connection. The description you pasted reminds me also of a lecture given a few years ago by the Nobel Laureate that year on the mechanism of cell division.
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