How do you identify a cancer cell versus a normal cell?

Please read my article entitled free energy measurement distinguishes normal from cancer cell offering a new perspective for curing cancer, published on 10/12/13. That is exactly what I discuss.

In evidence-based medicine, only a pathologist appears to be really trained to say - with the look through the microscope on a putative tumor section: malignant or not malignant.

This is an interesting point that tissue rather than single cells is normally used to define cancer and normal cells.

Maurizio Pea

Assuming the term carcinoma in a broad sense, as a synonym of malignancy , it is certainly true that different characters show us the evolutionary potential of a tumor.

Sincerely,

Maurizio

Of course the pathologist has to look for several charakteristik signs of individuals cells in a cancer tissue, many of them probably established hundred years ago. I am not a certified pathologist, but morphology of cells, nuclei, nucleoli and atypical mitoses, help the pathologists in their decision. Antibodies andother stainings of cancer related mutations (FISH) can help to differentiale between Cancer types and Tumor Stages. This is usually Important to help the other clinicians to choose the best treatment. Often half of the tumor Mass includes normal cells which include immune cells and blood vessels, some of them can be typical for specific Tumor types. But this is 100 Year Old knowledge. It appears to be hard to find a Single tumor stem cell within a tumor Mass of more differentiated Tumor cells. It may just Look to normal.

Kindly please read two other articles of mine: 1- entropyomics as the blueprint of the logic of normal cell division. 2- Bioenergetics the foundation of the future of cancer therapeutics. I dissect more on this issue in these 2 articles. Yes indeed this is the only point of separation of a normal cell from a cancer cell. A cancer cell is a cell in which the entropy has irreversibly increased and escaped to infinity in such a way that whatever finite measures taken by the so called malignant stem cell compartment not only would not be able to reverse it but add further to the depth of catastrophe. Indeed this basic lack of understanding of normal cell and cancer cell is the biggest un noticed handicap in biology. People are racing to cure cancer without understanding what a cancer cell really is!! All the other definitions described by others are subjective.

@Manuel

I would not call this a "standard" assay. Your view can be used in many cell culture assays, for example by inducing tumor cells with oncogenes or chemical carcinogens. But this is, in my understanding, never used for checking human cancer cells. Human tumor cells, in contrast, are not very easy to culture as cell cultures.

@Kambiz

I understand that you are proud of your recent publications on bioenergetics, but you should not expect to get too much positive feedback from established scientists. I recommend you to mention this as a hypothesis, but would not expect to convince many cancer researchers or scientists. I guess, those bio-energetic papers have no impact factor. Nevertheless, you added something on your publication list, and many scientific breakthroughs were against the mainstream. But this does not imply being against the mainstream will be a future breakthrough. Sorry, your hypothesis should - at this point - not really used as scientifically or even medical standard or accepted.

My understanding of cancer etiology is that genomic instability that causes multiple mutations and phenotypes including the Warburg effect, growth on soft agar plates, and loss of some checkpoints. Are there cancers without genomic instability?

There are many cell lines with a broad range of mutations, as well as a huge spectrum of chromosome numbers within the cell line - supporting the idea of genetic instability. As I mentioned before, (but I could be wrong - others may comment this, please), I do not see genetic instability as a prerequisite of a cancer cell. Since only very few and limeted mutations are needed to make a cancer cell, I can imagine (i.e. I do not know), that there are very stable cancer cells, which do not use more than the few mutations. Of course, there are mutations, which then may start a hyper-mutation scenario, but that may represent only a part of all cancers, or a very late stage.

Given that one would like to be able to identify and hopefully kill cells undergoing metastasis, can anyone list any clinically approved tests at the cell level for cancer?

The occurrence of metastases appears to be a late event in tumor progression, but we should be careful with correlations and assumptions, even if commonly accepted. More than two decades ago the model fo accumulating mutations from benign adenomas to malignant colon carcinoma suggested mutations in the p53 gene as late event (Vogelstein and others). I had access to frozen brain tumor samples and started by myself to check if early stages of astrycytomas can have p53 mutations as well, and not only late stage of astrycytic brain tumors (Glioblastoma) - and found those mutations in a large amount of low-grade astrocytomas. Concerning the capability of tumors to metastasize, there are different views possible: one interesting one would be, that the tumor stem cell already - as a stem cell - has a great migratory potential, i.e. all the necessary tools to migrate to distant sites of the body, perhaps, comparable to a lymphocyte. That is why I stopped 20 years ago my successful, but very boring, genetic work on dead tumor mutations, and applied for some stipends for Harvard and Stanford (and finally got three), to check for the potential steps involved in lymphocyte-homing-like steps for cancer cells, not only the lymphomas (and found them). On the other hand, many metastasis researchers became more and more convinced that just the bigger size of tumor cells is the major factor for getting stuck in the blood stream. I meanwhile favorize the idea that tumor stem cells can have the big migration potential, including metastasis, although later mutations may change or incrieas this potential. It seems some of the accepted theories currently change even in the clinical management of metastasized tumors.

Dear john, Robert and Thomas, I never said Warburg effect causes cancer!! Rather I believe Warburg effect is a reflection of the events which have led to cancer, the center piece of which is the breakdown of the homeostasis governed by the fine interplay of second law of thermodynamics with the living cell. In addition my proposed treatment strategy is not aiming at reversal of Warburg effect either!! rather it is aiming at reversal of the distorted energetics of what seems to be the master regulator complex of the cancer cell. This could be achieved either through modification of the histone code or by shuttling nanotubes as depicted in my article. Thomas, I do understand that the degree of sophistication of technology needed to achieve this goal is so immense that it would give you the feeling of a strange theory. I also agree with Robert that many of the scientific breakthroughs have arisen out of what many scientists had considered strange and weird. I simply believe that in order to understand a sick fish, we first need to understand a normal fish. I go one step further and would say that in order to understand the normal fish we need to understand the ocean, i.e: the universe. For that reason and in order to make the matter somewhat more awkward for Robert , I would refer him to another article of mine: Zero geometry Zero space time the seeds of the final theory. My dear friends I wish solving the problem of cancer could have been an easier task. Unfortunately the easier way is an illusion.

The cell cytoskeleton and cancer

It has been known for a long time that malignant transformation and neoplasm are correlated with significant changes of the cellular cytoskeleton . Already more than a decade ago Dr. Hurtley hypothesized in his editorial for Science that “changes in the cytoskeleton are key, and even diagnostic, in the pathology of some diseases, including cancer”. Since systems biology has taught us that everything is connected with everything the central question is whether these cytoskeletal changes are just an indirect consequence of other tumor biological changes or are a functional prerequisite for tumor progression? From a systems biology perspective the door handle can be accidentally misinterpreted as the most important part of a car’s engine since it has to be opened first. Cell biophysics has a more stringent view point and divides a cell into functional modules. The cytoskeleton is one of the most essential modules that stabilizes and organizes a cell as well as provides the machinery for cell motility and mechanotransduction4. If the cytoskeletal alterations in a tumor are necessary they have to trigger biomechanical changes that impact cellular function.

Many diseases, the same changes from a material science perspective

Cancer, the big “C” word, is not just one disease but many diseases which differ widely in their causes and molecular biology. This is in part also the reason why cancer is perceived as such a deadly plague despite the truths behind the historical connotations of cancer are increasingly overturned by advances in medical therapy and screening. Nevertheless in all cancers malignant neoplasm, i.e. uncontrolled growth (division beyond the normal limits), invasion (intrusion on and destruction of adjacent tissues), and metastasis (spread in the body via lymph or blood), occurs. Thus we experience these diseases as one regardless that a prognosis is sometimes substantially better than for diseases such as heart failure. Recent results indicate that these three malignant processes require changes in a tumor cell’s active and passive biomechanics. Thus biomechanical changes can be a general prerequisite for malignant neoplasm independent of the peculiar molecular manifestation of cancer.

Increased cell proliferation

Biophysical methods to measure cellular stiffness, adhesion, and forces based on scanning force, particle tracking, and optical trapping techniques provide quantitative data on the single cell level, but have a rather limited through put holding back their applications in clinical trials. Undoubtedly, malignant transformation causes cell softening for small deformations. This has been clearly shown first for cell lines and then for tumors (breast and oral cavity). For breast tumors with respect to normal cells from breast reductions the distribution shifts to more soft cells. This shift can be attributed to a great part to the fact that during mitosis the actin cytoskeleton is greatly reduced. Furthermore, cell dedifferentiation may contribute to actin down regulation. Since actin filaments act like sparsely distributed elastic rods that stabilize a tent cell stiffness is highly sensitive to a reduction in these filaments. Thus cell softening is a good marker for increased cell proliferation and can help to detect early dysplasia. Cell softening can also have side effects that increase aggressiveness. The weakened actin cytoskeleton enables microtubules to penetrate through the cortical actin layer to form microtentacles that greatly foster metastasis for breast tumor cells circulating in the blood stream.

Tumor invasion

At first sight cell softening is contradictory to the observation that tumors are rigid masses and that palpation is used to screen for breast cancer at home. Moreover this apparent weakness of tumors would hinder their invasiveness. A cell confined by a tissue matrix can only divide if its stiffness exceeds the opposing rigidity of its direct environment. A simple experiment designed by Helmlinger et al demonstrates to what extend tumors can grow in a rigid environment. Tumor cells divide and form small spheroids confided in agar gels, which do not permit them to dissolve the gel or to migrate through it. Tumor growth ceases when the agar gel surpasses a stiffness of 104 Pa, which significantly exceeds the mechanical strength of the reduced actin cortex. However, cytoskeletal filaments inherently strain harden, i.e. stiffen, at larger deformations and thus compensates the weak linear elastic strength of the actin cortex. Intermediate filaments such as vimentin, which expression levels increase with tumor size, are perfect candidates to support the pressure against the normal tissue matrix generated by dividing tumor cells. Vimentin and keratin have been implicated in neoplasm for a long time, e.g. breast tumor cells that express vimentin as well as keratin are particularly aggressive, but their function for the disease remained unclear. From a biomechanical perspective intermediate filaments could be a quintessential prerequisite that tumor can expand against a rigid tissue matrix.

Metastasis

It is commonly thought that not all tumor cells participate in metastasis and that a process similar to the epithelial-mesenchymal transition (EMT) is required. EMT is characterized by loss of cell adhesion, down regulation of E-cadherin expression, and increased cell mobility. In embryonal development it is essential for mesoderm and neural tube formation. On the other hand the formation of a metastatic tumor could be a nucleation process and micrometastasis may take place right from the start after a malignant lesion has formed. Nevertheless, malignant cell lines that represent different levels of metastatic aggressiveness show significant biomechanical changes and indicate that cytoskeletal changes foster metastasis. Cell softening can increase individual cell speed for lamellipodial motion of malignantly transformed fibroblasts25 and breast cancer cell lines. However, all cells, even endothelial cells, can migrate and metastatic cells are not consistently faster than normal cells. A front of a normal breast cell line clearly moves faster than a malignant breast cell line. Moreover, cell motion is strongly collective throughout the advancing cell sheet and the cells are not able to overcome the cell boundary. Conceivably, it is the capability to move individually across a tumor’s boundary that is essential for metastasis, which agrees with the differential adhesion hypothesis in developmental biology. If all cells are motile liquid-like tissue-spreading28 and cell segregation phenomena arise from differences in intercellular adhesiveness and stiffness that act on a boundary between different cell types similar to a surface tension. The barrier that cells feel when they try to leave their cell boundary can be lowered by reducing cell adhesion as can be seen by adding small amounts of trypsin. Changes in cadherin expression also modulate through nonlinear instabilities30 tumor cell adhesion, but metastatic cells cannot simply reduce adhesion since they need traction to move. Interestingly, also cells such as fibroblasts with a pronounced ability to contract easily overcome cell boundaries and move individually and not collectively. In breast tumor samples small amounts of cells can be found that actively contract when an external force tries to gently stretch them. These could play a key role in metastasis since contraction can prestrain and thus stiffen the cytoskeleton, which reduces a cells ability to form adhesive contacts with other cells. Moreover, contractile tumor cells migrate significantly better through the extracellular matrix.

Potential oncologic impact

Initial clinical data indicate that cell softening can be used to screen for oral cancer. At the annual dental exam cytobrushes of suspicious lesions can be analyzed for an increase in soft cells symptomatic of augmented cell proliferation in early dysplasia. Cancer screening has become one of the most powerful tools in reducing tumor mortality as exemplified by the cervical PAP smear exams. For oral cell probes sole visual inspection as in PAP smears does not suffice and biomechanical measurements may fill this void. If differences between cellular compartments cause a surface tension tumors spread more easily within the developmental compartment where the malignant cells stem from because the normal cells from this compartment are more similar. Resection of cervix carcinomas performed under this premise has reduced mortality from 15 % to 2 %. From a therapeutic perspective the biomechanical changes during tumor progression may lead to novel abortive treatments by altering tumor cells’ biomechanical properties. These drugs would not be a cure that kills cancer cells, but would strongly hinder neoplasm. Since these possible treatments would be relatively mild therapies they may be a option for older patients that no longer take surgery and cytostatics well.

@Josef Käs

You pointed to some quite interesting aspects of tumor cell mechanics. I have seen you developed a laser-stretching of cells, which may have some advantages over AFM-based force spectroscopy. With checking just some of your abstracts, it seems tumor cells appear to be softer, but I wonder compared to what? What would be the correct cell to compare a tumor cell with, probably a normal cell in the surrounding tissue, but better would be the normal stem cell or precursor cell of that tissue, which may not be available. I remember another paper almost a year ago with AFM, where there was a signature of difference between tumor tissue (not single cells) and normal tissue, but I guess, all this is not restricted to cancer, but may also happen in many inflammatory reactions and other diseases.

It will be interesting to see, if all cancers behave similar (I do not know, so I am sceptical). I could imagine there could be a big difference on mechanic elasticity as in normal tissues, for example, comparing bone tissue with brain tissue.

Your approach may (or already did) get into clinical applications of supporting diagnostics, help with the choice of treatment and prognosis of patients.

Chapter Single-Molecule Studies of Integrins by AFM-Based Force Spec...

@Robert Eibl

We are currently finishing several clinical trials (breast, cervix, oral cavity, and brain). With the exception of brain we observed in all carcinomas an increase in softer cells with respect to normal epithelial cells, also with respect to benign tumors. The first cell softening seems to correlate with inreased cell proliferation. Futher cell softening correlates with metastaic agressiveness and goes along with increased cell contractility. The metastatic tumor cells thrive to find an ideal combination of cell softness and contractility to migrate through the body. Since neurons and glial cells are already too soft we find cell stiffening.

@Josef Käs

Interesting to see such a softening in tumor progression for several tumor types, although obviously not all (there could be differences in brain tumors). As there are so many tumor types, it will be interesting to see, if there are characteristic changes. I was thinking (about a year ago), for example, measuring within the patient such differences of questionable tumor tissue vs. benign alterations, like ulcera, adenomatous polyps, inflammations. There may be other methods to come out in the next years, measuring similar aspects of tumor cell mechanics and elasticity, but it will be difficult to find the right balance to support diagnostics. I could imagine that a gastric ulcer or a benign adenoma would not be such different to make a reliable probability decision of benign vs. malignant. So, my idea of testing such things in a patient is quite useless as long as a biopsy is relatively easy and the microscopic result so much clearer and reproducible.

I am still wondering about the best controls for any of such tumor mechanic studies, since 1) human tumor cells are hard to grow in cell culture and may not represent the tumor; 2) growing normal cells may also not represent the tissue they are derived from (although this may be a reasonable control); 3) whole tumor parts (malignant as benign) contain many different normal cells, blood vessels, stroma - they could be much contirbute to differences in elasticity just depending on the amount of blood vessels; 4) bone metastases in radiographies can be calcifying or decalcifying, maybe there is a broad range; 5) how about lymphoma tumor cells (should they also be softer as the already migrating normal counterparts, the lymphocytes?).

It definitely will be very intersting for me to read your future publications in this field!

Hello john, Robert, Thomas and Josef, with all due respect I believe definition of cancer cell is totally different than description of cancer cell. This forum started with john's fascinating question of definition of a cancer cell versus a normal cell 3 days ago. Definition of an entity or event should clarify the nature of that event or entity at its deepest root. By stating how the cell looks under light or electron microscopy or how stiff its cell membrane is, we are just looking for different ways to describe what we see in front of us. My contribution to bio medical sciences is that for the first time I have come up with the real definition and not the description of cancer cell and normal cell, which everything else including the design of future cancer therapeutics depend upon. As I mentioned before, cancer cell is a cell in which the entropy which is inversely related to free energy is at the highest level above and beyond any finite compensatory measure to reverse it back to its lowest level as dictated by the limits of the second law of thermodynamics. My publications would give you a more detailed view in this regard. The answer to Thomas' question of what master regulator complex of the cancer cell is, is that there are mathematical models which could decipher a handful of proteins and protein- protein interactions out of an estimated 300,000 PPI/ protein- protein interactions( the hair ball) that determine the functionality of that particular cell, which is most probably the target of malignant transformation. In case of colon cancer stem cell, it seems as though WNT pathway is the one and in case of prostate cancer cell, the androgen receptor shuttling proteins. Dear Thomas it is not fair while with all your honesty and decency you state that you do not know what master regulator complex means, you allow your self to make firm statements against my theory which indeed I have presented the first series of measurements in its proof in my latest publication

@Kambiz

It is always OK to come up with any hypothesis, but to get it discussed and accepted by others on a scientific level, you should get it published in a peer-reviewed journal with a high impact factor.

Any useful hypothesis related to cancer should allow predictions being tested to become a theory and broaden our understanding. Finally, any new treatment or prevention of cancer better than the current standard will support such a theory.

@Josef Käs and others in this conversation:

On the softening of tumor cells: Is softening unique to tumor cells? Or do normal cells also soften when they go through the cell cycle or move (e.g. chemotaxis) ? Is softening a cause or effect of transformation?

Hello Robert, and Thomas, many times in the history of science when some one comes up with a revolutionary idea and a new finding that is against the currently accepted way of thinking, he or she gets attacked by others in the field because the revolutionary idea is creating discomfort for the inside box thinkers in that field. One example is Haig particle, among many others. What is interesting to me is that none of you critically read my articles in this regard and all of you except for John found different reasons to attack my revolutionary idea and definition of cancer cell and the proposed treatment modality based on those basic principles and definitions. Our problem in biomedical sciences field of today is that there are a lot of proud champions that are racing for cure of cancer without having come up with the basic understanding of the mechanism of initiation of mitosis in a normal cell!! And definition of normal cell and cancer cell. I wish you a lot of success in your field of research.

@Sumantran:

In most normal physiological processes in your body cell stiffness does not change or stiffening ocurrs, e.g. as you grow older your cells become stiffer. Cell dedifferentiation can cause softening. The observed cell softening is independent of cell cycle. In cell cycle no stiffness changes can be observed besides in the moment when the cell is dividing. The cancer cells soften already in the primary tumor without any cues. Nevertheless cells that have left the tumor experience further softening triggered by the tumor microenvironment. Softening is definetly not a cause. However it is a necessary change that cancer can become a systemic disease.

Hello Kambiz, I agree in one point of yours - and it was me who mentioned it here before: there always have been really crazy ideas in the history of science and medicine, which later became the mainstream and accepted knowledge. But let's face it, just having an idea, which is against current knowledge, really does not mean, it will automatically become a mainstream idea or accepted in the scientific world. It is not me who has to prove your ideas are wrong, it is you who should proof your hypothesis to others - you should not suggest you have any scientific proof for your hypothesis. And since you use the word "energy", which is also used by many disproven (although very different) non-scientific approaches, it makes it even more difficult for you to get your ideas accepted by others. Just claiming your are right, may not help.

I also had a "crazy idea", more than 10 years ago: I wanted to see, if the postulated model of lymphocyte arrest in the blood stream, which was known to be mediated by VLA4 integrin receptors and immediately triggered by a chemokine, especially SDF-1, via the chemokine receptor CXCR4, could be evaluated on the single-receptor level on a living cell. After initial results showing the proof of concept, i.e. that indeed one can measure VLA4/VCAM-1 receptor binding and rupture of single bonds between two living cells (lymphoma cell or melanoma cell and endothelial cells), I further modified the system to measure as the first in the world the physiologic activation of this integrin from a low-affinity to a high-affinity.

Unfortunately, my idea and year-long, unpaid work was so good, that the questionable Leopoldina members gave my project to someone else to promote him on my project to a full paid professorship. This appears to be really crazy - but there is no way to control German universities and scientifically misbehaving professors - Leopoldina chemists and physicists are just too big to fail.

Meanwhile my "competitors" used my material, collaborations, secret tricks in the lab to confirm my findings, which no real cell biologist could beleive ten years ago, that it would be possibl to measure functional forces between adhesion receptors and their physiologic activation on a living cell.

So, I guess, if your hypothesis appears to be useful for others, they may try it - my guess is, your hypothesis is wrong, but I do not need to proof it, you or others have to make conclusions which would fit into your hypothesis...

@Josef Käs Thanks for the helpful answer. If stiffening does happening with ageing (and you say it is not at the cell level), then where does it happen? Is it all in the ECM (extracellular matrix) ? Also, are there some biochemical changes which uniquely mark this type of stiffening in cancer cells?

@Mohr

Thanks, but AGE is also found in normal cells, senescent cells, and other diseased cells (for e.g. retinal cells of diabetics). So, AGE is not unique to a stiffened cancer cell. That is why I asked about ECM changes-because there is some literature on alteration of collagen and glycans in stromal tissue around certain tumors

@Venil

I thought the hypothesis above was less on putatively stiffening, but on softening Cancer cells during Tumor progression; Many Tumor cells and/or surrounding tissues can produce enzymes which can degrade ECM, for example, MMPs, collagenase. Some Tumors may produce both, their ECM and enzymes which may softening the tissue. I expect similar Mechanismus in some inflamed tissues - so it will be hard to find parameters typical for Cancer tissues - but they could exist, perhaps as suggested somewhre else, a Signature in elasticity.

@ Venil Sumantran: Sorry, it seems that I have been not clear enough. I am talking about the mechanical properties of cells and for cells we have that stiffness increases with patient age and decreases with tumor staging.

Dear John,Thomas and Robert, could you please read the article entitled: Differential network entropy reveals cancer system hall marks. It was published in scientific reports in Nov 2012. Please keep in mind that genes that drive cell proliferation are attempting to decrease the entropy. That is exactly what I have mentioned in one of my publication.

Dear Thomas, quite unfortunately you have not read my articles carefully. If you do so, you would realize that I have mentioned the futile attempt of cancer cell to maximize its free energy and minimize its entropy by undergoing rapid cell division. Kindly please read the referece article that I sent you earlier today as well as my articles carefully so that you would become able to communicate on clear grounds.

Dear Kambiz, I am sorry, but I think it is OK that we all follow our own favourit ideas. You invested some time in your publications and sometimes the reviewers are not the best or critical enough; maybe you can address some of the points in future publications. I am in similar situation, that only a few former collaborators just overtook my project and now got millions of funding - so, I guess, my ideas, years of unpaid work as a guest-PI on my exclusively developed project in a physics lab can not be that wrong...

But may be I am just too allergic to words like "energy" and "cancer" - this is too close to many disproven treatments. But since many clinics even offer questionable treatments for otherwise fully treated tumor patients, you may get some support from non-physicists, although it may not be yet that evidence-based or widely accepted.

Dear Robert, John, and Thomas, It is critically important for our scientific society to come up with a very clear explanation of the behavior of the normal cell before embarking on dissection of abnormal examples such as cancer. Albert Einstein says: I want to know how god thinks, the rest is detail. In our field of biomedical sciences we have made ourselves too busy with dissection of details, so much so that we get offended if someone asks what the mechanism of initiation of normal mitosis is. Almost everyone would immediately respond, it is clear, cell is created with the machinary to replicate and the most efficient ones get selected out. I say living cell is like a fish in an ocean. In order to understand the fish we need to understand the ocean and the laws that govern the ocean. Universal laws do not stop at the ocean, they extend to the fish. In other words there is only one set of universal laws that run both, and we should not take anything for granted. These statements and thoughts are the foundations of my publications. I have tried to explain what we observe as normal based on those principles . I do understand the difficulties and the challenges that we have ahead of us. At times they seem insurmountable, but that is what evolution is all about, moving forward and overcoming these difficulties , being brave enough to admit to our illusions and to look at an old problem from a new point of regard, raising new questions and exploring new opportunities.

Thanks to J.Kas and R.Eibl. But, there is no misunderstanding. Based on earlier chat, I assumed that stiffness decreases (and softening increases) in tumor cells. I asked about biochemical correlates for this change in softening/stiffening, and AGE was 1 answer. I replied that AGE is not specific to stiffening of cancer cells ( decreased AGE would mean softening). SO, my question still remains. What marker measures the specific loss of stiffening / gain in softness for a cancer cell? It is complex, because aging is also related to cancer ! All the more reason for getting specific markers. I hope this is clear.

Christer Ericsson

Somebody must have correlated progression of Epithelial to Mesenchymal Transition (EMT) and cellular softness? It would seem perfectly as expected that the relatively stiff (for mechanical integrity of the epithelium) epithelial cells need to become more "soft" in order to be able migrate/invade as they become malignant.

Christer Ericsson

The bottom line is that there is NO general cancer cell marker. How could there be? On the other hand cancer is a sort of biomedical readout of the multiple underlying molecular changes that the cancer cells certainly can "read". If we only put our cellular glasses on and "read" the molecular changes the same way as the cell does, we will be able to distinguish cancer cells from other cells. The problem is, of course, that the underlying panorama of molecular changes are different not only from type of cancer to type of cancer, but also that there are multiple sets of changes even for a given type of cancer. In the end we will be able to first inventory the total panorama of changes, and then identify the "necessary and sufficient" - "driver" - mutations within those panoramas. But it may take some time...

Hi dear Thomas, I hope you receive this message in good health. Could you kindly please enumerate the flaws one by one. That would enable me to address your questions. Kindly please keep in mind that at times what some might consider flaws, are indeed the flaws generated in their neuronal network, simply because a new concept might contradict their preconceived notion of reality itself

In looking over the answers and thinking more about what distinguishes cancer and normal cells, I am thinking that perhaps genetic instability might be as close to a general cancer hallmark as anything. This could be assayed by levels of endogenous DNA damage or rates of genetic mutation.

For me, the reason to consider how to distinguish cancer at the cellular level is that we would wish to attack cancer at the cellular level to get a complete cure

Thomas - when you say as few as two mutations are these two mutations proposed to cause the tumor or the actual number of genetic changes in the cancer cells? My understanding is that tumor cells have large numbers of genetic changes - do you have citations for the few change examples?

Paula Figueroa-Arredondo

@JohnTainer Monogenic hereditary causes of cancer are examples of one gen only cause of cancer, such as Retinoblastoma (Rb-). One gen can be enough, the requisite is that this only one gene should be altering cell cicle and apoptosis.