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Cancer Metastasis - Science topic

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...For research purposes to help others. If you are or know of anyone who is who would be willing to share his/her story, I would greatly appreciate the introduction! Thank you so much!!
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Has Mrs. O'Brien ever read my answer? Please let me know
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I am a newby on in vivo imaging. We are using IVIS imaging system to study breast cancer metastasis in vivo, but we really do not know how to quantify the images along time. As the time pass, of course, the primary tumor and metastases grow so we must change the adquisition parameters. I would like to know how to properly quantify to able to compare the different time points. Thanks a lot!.
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Hi Maria J. Garcia-Leon , I know this is an old thread but just want to clarify in case others have similar questions. I'm a field application scientist for PerkinElmer and this is what we recommend in our trainings:
1. Use auto settings. This setting will control the exposure time, binning, and f/stop to make sure your readout is between 600 and 60,000 counts (roughly the linear range of the detector). It's okay if these settings change over the course of your experiment. They should if your tumors are growing or shrinking!
2. Load your images together. If you want to look at your study images all together: In the Living Image software, go to File > Browse and select the parent folder that contains all images you wish to compare. In the browser, select the desired images and click "Load as Group." All of the images should open in a single window. To put them on the same color scale, go to the Tool Palette > Image Adjust > uncheck the "Individual" box.
3. Draw your ROI, the bigger the better. Like Valentine Comaills said, you can draw your ROI bigger than your tumor and can sometimes even draw a box around the whole mouse to quantify because with bioluminescence (unlike fluorescence), the background signal is almost nonexistent. The worst thing you could do would be to exclude pixels because you drew your ROI too small.
4. Quantify in total flux (photons/s). This is a calibrated unit that takes into account any changes you've made in exposure, binning, and f/stop over the course of your study.
*Tips: Image your tumor and control cohorts separately. Bright signals can obscure dim signals. Also, the method of noise subtraction is different with long compared to short exposure times so you sometimes end up with negative ROIs if you image them together. You can cover/remove bright mice and reimage to see less intense signals.
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I need an ID8 murine ovarian cancer cell line to study the peritoneal metastasis in C57BL/6 mice. To perform noninvasive imaging of cancer metastasis, I also need ID8 cell lines expressing either luciferase or GFP.
Please kindly let me if anyone can provide me the cell line. Thank you so much for your support.
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Santhosh Kalash Rajendrakumar - You might want to check with the Rankin Lab @ Stanford or Kathy Roby @ University of Kansas Medical Center. Not sure if they have cells with bioluminescent or fluorescent reporters but it couldn't hurt to ask.
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hello everyone,
I am looking for an easy way to predict breast cancer metastasis through CTCs from whole blood or serum. Any idea? methods? targets? THANK YOU
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In addition, some methods:
Regards,
Joachim
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Hello,
I am doing a cancer metastasis experiment both primary and experimental metastasis. I would like to know has anyone collected CTC from mice blood and how did you store it?
Regards
Tasnim
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I do collect CTCs from PDX mice blood at end point by collecting blood from the heart (terminal bleeding). This gives me around 1 ml of blood. I do RBCs lysis step followed by live immunostaining for the human marker CD298. Positive cells are then picked by a micromanipulator or a similar device.
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I am looking to develop a model for lung cancer metastasis in C57 mice. I used a tail vein injection method but the model did not work for me. Do you think an injection of saphenous vein can help me? Or should I look for another way? Thanks a lot
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It is unlikely that the route is the issue. It doesn't get much more direct than tail vein → heart → lungs. The more likely explanation is that your cell line cannot form mets when injected intravenously. The very best model at this is CT26 cells (BALBc) which produces about 250 mets when you inject 500,000 cells, so even in the best model, the ability to complete the entire process of forming a metastasis after IV injection is very very rare. Your model is likely not able to do it.
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I tried with Crystal violet but was not able to stain the colonies. It seemed that the stain could not penetrate the semisolid agar.
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(Similar as Gülsah Torkay says):
1. Remove carefully the media over soft-agar.
2. Wash with PBS and remove again.
3. Add 200 µl (p24 wells) of MTT 1 mg/ml in PBS.
4. Incubate overnight at 37°C
5. Remove carefully the MTT staining solution, wash with PBS, remove again and take photografs of wells.
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It has been known that certain foods increase the risk of certain cancers and some other foods reduce the risk of certain cancers. But can improved diet or diet modification help in curing advanced metastatic stage IV cancer ?
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Thank you all for your inputs. But my further literature search has suggested that cheap and non-toxic dietary interventions will play an important role in future treatment strategy of advanced metastatic cancers.
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This is about a different approach to fighting cancer basically cancer cells must have glucose to survive. Following a ketogenic diet, the glucose drops and then using the administration of diabetic drugs to drop and keep blood glucose levels below 60 mg the healing process should start.
I would like to ask if you know people who tried this diet approach as detailed as possible & in the first place can somehow affect the patient they are any circumstances for that?
Can be this a way to heel cancer ? Are there researches that confirm this process or is the book written without evidence and is everything in theory?
Regards,
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Thank you
I appreciate you replay.
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I am planning to do orthotopic injection of breast cancer cells (MDA-MB-231 and 4T1 cells) into the mammary fat pad of mice to observe cancer metastasis and tumor growth. In lots of references I see people used growth factor reduced (GFR) matrigel and mixed it with the cells. My question is what is the purpose of using GFR matrigel. Will it makes a different when using matrigel containing growth factor?
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You should not need to use Matrigel when injecting into the mammary fat pad - as others have said, 4T1 will grow almost anywhere without the additional ECM support. Depending on your experiment, matrigel can potentially confound your analysis. It can be difficult to determine that you have implanted into the mammary fat pad rather than sub-cutaneously near the fat pad, since the cells grow equally well in either site.
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Sometimes this can be accomplished by surgery, but the propensity of cancers to invade adjacent tissue or to spread to distant sites by microscopic metastasis often limits its effectiveness; and chemotherapy and radiotherapy can have a negative effect on normal cells
What do you think is the best way to treat cancer? do you know the side effects of the methods?
Do you have any information about methods such as radiotherapy?
Have you read an article about this?
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Surgery, chemotherapy, radiotherapy, PTT, PDT, and immunotherapy. Different therapy methods are applied to different patients. In clinic, surgery, chemotherapy and radiotherapy are still main ways. Recently, immnunptherapy has received tremendous attention from the researchers based on one's own immune system. But it have to be developed in the future due to limited response or autoimmune disorder.
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Is it possible to make and xenograft a subcutaneous tumor with MDA-MB-231, and then induce a gene knockout in the tumor in order to analyze relevance of this gene in metastasis. Which system of inducible knockout could I use?
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Yes it is possible to do in vivo knockouts. We've done MDA-MB-231 xenografts commercially (http://altogenlabs.com/xenograft-models/breast-cancer-xenograft/mda-mb-231-xenograft-model/) and we've also made in vivo transfection reagents (https://altogen.com/product/in-vivo-transfection-kits-peg-liposome-nanoparticle-polymer-lipid-tissue-targeted/) for, trivially, the in vivo based knockout of given genes. You should be careful though - inducible knockouts are only transient, and you'll either have to use systemic administration or have a clear way to deal with the transient nature of the knockout in your research.
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Australia's National Health and Medical Research Council (NHMRC) produced a sham review of Water Fluoridation in 2017 by deliberately ignoring over 3000 peer-reviewed scientific papers on Fluoride Toxicology. One important paper the NHMRC suppressed dealt with the mechanism by which Fluoride damages your teeth, with or without metal ions like Aluminium. Fluoride causes increased SATB1, a factor associated with Malignant Cancers and their Metastasis, with many relevant publications relating to Leukemia, Melanoma, Laryngeal and Nasopharyngeal squamous cell carcinoma, cancers of the Bladder, Breast, Cervix, Colon, Kidney, Lung, Ovary, Prostate, Uterus, and Liver.
A couple of papers: Zhang Y, Kim JY, Horst O, Nakano Y, Zhu L, Radlanski RJ, Ho S, Den Besten PK - "Fluorosed mouse ameloblasts have increased SATB1 retention and Gαq activity" PLoS One 9(8):e103994
Fluoride interferes with FoxP3
Zhang G, Zhou B, Han T, Wang M, Du X, Li Q, Wang J. 2012. Decreased percentages of CD4+CD25+ regulatory t cells and foxp3 expression in the spleen of female mice exposed to fluoride. Fluoride 45(4)357-364.
Observed increases in cancer incidence over four decades follow the roll out of Fluoridation and increased Dental Fluorosis. Surely it is time to ban Fluoridation worldwide?
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I agree, none of the articles talks about fluorosis, but the original question is: why if it has been shown that fluoride is toxic, it has not been banned, my answer is yes, Fluoride is toxic, but for produce the effects that are mentioned in the articles on which Dr. Pain is based, the doses are much higher than those used to prevent the caries process.
In some parts of my country, drinking water contains cyanide, but the doses are lower than those that produce toxic effects.
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What will be the best test in order to differentiate between Seminoma and Non Seminoma ?
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You may look the levels of tumor markets, if with elevated alphaphetoprotein, it does have a nonseminoma component; however gold standard for the diagnosis is pathology specimen result, so a biopsy should be done.
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a lot of data show that CXCL12 can promoter cancer cell migration
experiment process
1. coating matricgel(1:9 in seriumfreeDMEM) transwell-chamber (SPLinsert 8 um) put into the Cell Culture Incubator 6hours
2. count the cell 2*105 use the non-seruim DMEM wash twice
3. inside chamber add A549 cell combine CXCL12 cytokine (100 ng/mL)
outside chamber add 10% DMEM
4. put in bake Cell Culture Incubator 14 hours than fixing and staining
this is my problem "CXCL12 treatment migrated cell is lower than the control"
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Hi, if CXCL12 promotes cell migration, you have to put it outside the cell chamber. The cells have to migrate towards a stimuli.
If you put the stimulus in with the cells, they have nothing to migrate towards.
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I am working with antimetastatic compounds and would like to compare their activity with some other compounds. Maybe somebody know any approved drug from cancer metastasis? Or maybe somebody know good positive controls for migration and invasion assays in vitro or for both of them?
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Dear Vilma Petrikaite!
Here is my answer. Pleasecheck it and come back to me!
Sincerely Yours!
Dr. Bratko Filipič
________________________-
Abstract
In solid cancers, invasion and metastasis account for more than 90% of mortality. However, in the current armory of anticancer therapies, a specific category of anti-invasion and antimetastatic drugs is missing. Here, we coin the term ‘migrastatics’ for drugs interfering with all modes of cancer cell invasion and metastasis, to distinguish this class from conventional cytostatic drugs, which are mainly directed against cell proliferation. We define actin polymerization and contractility as target mechanisms for migrastatics, and review candidate migrastatic drugs. Critical assessment of these antimetastatic agents is warranted, because they may define new options for the treatment of solid cancers.
Keywords: solid cancer, metastasis, invasion, treatment, contractility, migrastatics
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Three Days ago, the world lost a young and brilliant mind Maryam Mirzakhani (2014 Fields Medal,  mathematics), died from metastatic cancer.
There are different methods which are under development, but why todays science can't be able to treat or delay the metastatic cells, I would like to ask which research line would be more promising in treating at least major types of cancer?
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I agree that we all have our biases.  My bias is that we need to move away from unilateral causality (genotype to phenotype) and targeted therapies to understanding cancer as a systemic disease.  Yes, certain genotypes can increase risk for certain types of cancer but one of the precursors of cancer is genome-wide epigenetic changes, indicating that multiple systems are involved.  The microenvironment changes gene expression on an ongoing basis.  The p53 tumor supressor gene has more than 10 different functions depending on the microenvironment.  That is why diet, carcinogens, etc., are so important.  With trillions of cells in the body and continuous turnover, we get mutations on a regular basis.  These are usually caught by DNA repair mechanism that repair strand breaks, base-pair mismatches and insertion / deletion mistakes; or by apoptosis, which id programmed cell death that happens when a cell starts to malfunction; as well as anoikis and immune cells that target and kill cancer cells. There is also a system of bioelectric currents stemming from ion channels in cell membranes and  microtubules within cells that are important in cancer initiation and progression. Cancer is not a disease of single cells, it is a disease of that results when the informational organization within and between cells and tissues breaks down.  As burden on the defense systems increases, the system's ability to respond appropriately to new onslaught weakens.  It's as if the body reaches a point of bifurcation where a tumor forms and co-opts the very mechanisms that previously defended against it (e.g., macrophages).  Targeting a single pathway when so many are involved (e.g. Akt signaling, Notch signaling, Hedgehog signaling, RAS signaling, Wnt signalling, etc., etc.), simply does not make sense. The current paradigm focuses on killing cells and is based on the same type of thinking that we use with antiobiotics to kill invading bacteria.  However, tumor cells are part of our own bodies, not foreighn invaders.  Killing them makes us sick - which is why chemotherapy is so devastating.
So what is the best treatment?  Currently that depends on the type of cancer.  But in general, I think we need a new paradigm that re-programs the body's own defense mechanism so that it can cure itself.
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Hi. I am studying the role of exosomes in cancer metastasis. Exosomes derived from cultured tumor cells could be isolated and was identified by various methods. I was wondering if it would be possible to increase or decrease a specific microRNA inside the isolated exosomes in vitro? The plan is to use the microRNA modified exosomes to investigate the downstream effects or mechanisms if that could be done. Thanks a lot.
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I'm skeptical about knocking out microRNA in exosomes. Instead, you can KO the miRNA in the tumor cell and the isolate the exosomes, run pcr to ensure the absence of the particular miRNA and proceed with the downstream analysis. 
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In orthotopic lung mouse model, 
Lets suppose primary tumor is at lung A and after 4 weeks we observe metastasis at lung B, how we can calculate the rate of metastasis  
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Hi Ghulam,
I recommend reading this for your query: https://www.ncbi.nlm.nih.gov/pubmed/25107893. Its wonderfully described by Poullis et al (2015) here. All the best !
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I am looking for Lung metastatic model for C57B6J mice. We inject LLC or B16F10 tail vein for experimental metastasis, but i want a model that tumor cell lines implanted in subcutaneous or intradermal so that metastasis can happen after several days. Suggestions are greatly accepted.
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HI Denise and Elmina, Thanks for your suggestion, I injected 500,000 to 2 million cells Subcutaneously, let see, how it goes. Thanks once again
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melanoma models in mice 
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Thanks Michael, will have a look
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Injecting C57Bl/6 mice with B16-F10 cells via s.c. and i.v. routes.  After primary tumor growth (in s.c.study) and pulmonary colonization (in i.v. study) we want to discriminate and isolate B16-F10 cells from the surrounding tissue, invading immune cells, etc. Is there a specific antibody (FC validated) that could selectively label the B16 melanoma cells?  This would keep us from having to label and gate out the various subsets of cells found in tumor tissues (stromal cells, immune cells, etc).  Any help would be appreciated.
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Interesting concept, Dr. Lange, but we chose a syngenic model specifically for the intact host immunity.  Conversely, transfecting the B16 cells to express GFP/RFP may be a viable option.  Thanks for the input.
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We have been trying to develop 4T1 breast tumor model in balb/c mice. We have been injected 10^6 4T1 cells suspended in 100 uL PBS into the mammary fad pad region, subcutaneously. After 10 days we see mass, in site of injection. The size of mass is approximately 5mm ×5 mm. After 20-days mass is completely regressed in some mice and in some other the size of mass aggressively diminished. in pathological examination, some of the small mass have tumor properties and are malignant. if these mass are tumor what are the causes of restricted or abolished growth of them? why these cell line can induce small tumors in some balb/c mice but not in all of them?
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thanks, dear Sajid for your practical advices.
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The metabolism of most tumor cells is essentially higher than it usually is in most somatic cells. It is reasonable to assume that the tumor cell is much more sensitive to incomes of oxygen and carbohydrates. So, under blocking of feeding arteries, tumor cells should die first. The time needed for this could be set experimentally. So, if the local circulation is recovered after this blockade, we can expect that most of the normal cells will recover too.
Certainly, in the case of not local tumors, special procedures have to provide brain circulation. 
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This is an interesting question and I don't know if anyone has researched this type of approach or how feasible it would actually be. I think there are multiple aspects of this approach that would need to be considered. The idea of reducing a solid tumour's blood supply has been around for quite some time. For example, Bevacizumab was the first angiogenesis inhibitor used to treat solid tumours, but as I mentioned I am not aware of an approach that would physically block blood supply. (Note: I would be interested to read about something like that so if anyone has papers, so please share any in your reply). There is also a lot of literature on the hypoxic micro-environments within solid tumours and the genotypes and phenotypes of the tumour cells that reside there. Some important considerations would be incorporating research that points to a cancer stem cell niche presence in the hypoxic areas of solid tumours, which are not only less accessible to pharmacological agents because of an already reduced vasculature, but for that reason are also more resistant to low oxygen levels, and perhaps more resistant than normally oxygenated 'normal' tissue.
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Can Chemo drug elicit abscopal effect ?
&
Lysing (In Vitro)  surgically excision tumor and admitting it back to the same patient who has multiple metastasis , will elicit abscopal effect ?
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Thanks for alerting me to abscopal effect! Wikipedia only mentions a role for immune cells being responsible for this effect.  If chemo or surgery activates immunity-then the abscopal effect can potentially happen. Usually, chemo and surgery are linked with opposite effect (increased chances for local tumors regrowing). 
Hope this helps.
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when cancer cells are inoculated in mouse circulation they will be immediately coated with fibrinogen ... in which it mediates there entrance into the different metastatic sites among them is the lung ...  now cancer cells associated protein inside the lung willbe in which form fibrinogen or fibrin 
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so the right thing is to search about fibrinogen in the tissue 
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i would like to see the fibrin that is associated with metastatic cancer cells and i would like to know which is the best stain that could be used to stain fibrin 
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For FFPE tissue sections you may use carstairs' staining:
Note: staining results depends on duration of fixation!
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brain cancer metastases from breast cancer
treatment of secondary brain cancer
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Nobody said that, Lapatinib is given as a single agent!! It's licensed to be given in combination with either Capecitabine or Trastuzumab (Herceptin).
In the case of hormone receptor positive and Her2 over-expression advanced breast cancer, Lapatinib is also LICENSED to be given in combination therapy with Letrozole (Femara) for postmenopausal women. 
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We know that postoperative adhesions limit the availability and distribution of intraperitoneal chemotherapeutic agents to all areas of peritoneal cavity. It has also been shown that fibrin traps tumor cells and these cells in return become protected from any form of chemotherapy. Still the data on early postoperative intraperitoneal chemotherapy shows improvement in outcomes, especially for ovarian cancer. What is the mechanism of effectiveness if we know the drug is not evenly distributed in the peritoneal cavity and is likely not reaching all tumor cells.
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You are wellcome Raza. Just for example - see at the attached table the peritoneal/plasma concentrations (midle row) as well as peritoneal/plasma AUC (right row) of some chemotherapeutic drugs in normothermic IP application.
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I am working on the effect of fenofibrate on the 4T1 breast cancer metastasis by using Balb/c mice as the animal model ... but I have a problem in how I could give the required dose of fenofibrate without harming mice since most fenofibrate solvents will be toxic to them ... and the main problem is the limited solubility of fenofibrate in its various solvents like (DMSO, DMF and ethanol), so that to reach the required dose of the fenofibrate ( 0.2 % Wt/Wt), we will need a high volume of the solvent in which it will exceed the lethal dose .. also if we dilute the solvent we will need to inject mice with a higher volume that will exceed the intraperitonial volume dose   ... SO I would like to ask kindly : 1 _ how we can give the required fenofibrate dose to  mice without affecting them by the solvent ??? 2_ if we want to give the drug by food how we can avoid the variation in the amount of food intake daily by mice ??? Your time to answer my question will be appreciated ^_^ Montaser Haddad
Your time to answer my question is really appreciated ^_^ 
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How about trying an oral gavage of suspension using a blunt L type gavage needle?
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I want to find a high expression and low expression colorectal cell line to culture
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What should I do before mouse experiment?
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A metastatic process is a 3D process occuring in an amazingly complex tumor microenvironment.
Any cell migration / invasion assays relating to "pure cancer cells forced to evolve in 2D dimension and prisoners of closed plastic dishes" have nothing to do with the actual 3D journey of metastatic cancer cells.
Here attached are various in vitro approaches that recapitulate some of the important aspects of an actual metastatic process.
Best regards
PS: I also added 3 reviews for those of you who would be interested by the metastatic journey. These are the first three articles here attached.
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I am trying to isolate single cells from mouse lung with B16F10 metastatic tumours. Typically, after enzymatic digestion, I filter the cells through 70um filter, followed by 40% Percoll to remove dead cells. Finally, I lyse RBCs using ACK lysis buffer and proceed to staining.
However, as soon as I begin to stain (surface and intracellular markers), the cells begin to clump heavily and I don't seem to get enough cells for flow cytometry in the end.
I am unable to identify the reason for the clumping. Is it because of the tumour cells sticking around or because of too many dead cells? - I see about 40% dead cells after trypan blue staining, even after the 40% percoll step (~3ml percoll for 10min)
Also, I want to know if 
1) Using a 40/80 Percoll gradient to separate tumour cells would help. I don't want to pool the lungs from different mice together, therefore is it advisable to layer the cells from one mouse only? I'm scared of loosing too many cells during this step. 
2) Mostly I can get a maximum of 3 X 10^6 single cells from one lung. Is that what is usually seen or do people get more cells?
3) Is it advisable to pass the cells through a 30um filter instead of 70um? This is assuming that the lymphocytes (my pop of interest) can pass through it while tumour cells can't.
Any help would be greatly appreciated. Thank you !
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I am currently isolating tumour cells from the lunges of patients with non-small cell lung cancer using bronchoscopy. I subject the cells to flow cytometry to evaluate their apoptosis with different treatments. I do not have such a problem; however, I do use DNAse and Collagenase D to digest the cells and then pass them through a 70 um filter. 
You do not necessarily need to eliminate the dead cells, instead you can use propidium iodide to determine the dead and the live cells in your analysis later. 
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Is metastasis something that every cancer cell can and will do at some point or are there genetic mutations or epigenetic changes are results in metastasis?
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A lot of good points raised but most exhibit a proclivity to the primary tumor "doing things" that subsequently result in metastases - we should also consider the roles played by the pre-cancerous niche and how the microenvironment where the  metastasis occurs facilitates the "seeding" of the cancer- so how would one weight the role of a traveling cancer cell against the role of the environment where the metastases ends up occurring?
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Dear all,
     Does anyone know if E0771 from C57BL/6 can metastasize to bone regularly? Or, are there other murine breast cancer cell lines from C57BL/6 background that give rise to bone metastasis easily?
Thanks for your help,
I-Chun
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We use the 4T1 murine cell line (http://www.atcc.org/products/all/CRL-2539.aspx) to induce bone metastasis in our Balb/c mice. Not sure if it would work in your mice (but since they're murine cells, they probably would). IC injection with 1x10^5 cells will result in visible osteolytic lesions (using xrays) in the hind femurs and tibias by day 14. The 4T1 cells are super aggressive, so keep an eye on those mice. They may have serious fractures by day 21. 
If you want to use MCF-7 or MDA-MB-231 cells, athymic mice are the most commonly used. Also, not all strains of these cells will readily form osteolytic metastasis (as per reported in the literature). The ones that do go to bone have been derived from bone-tropic subclones (like the ones Yibin Kang uses). 
Hope that helps!
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I see many papers doing cell migration assay and then testing metastasis in animal model. Isn't metastasis inside body rather than cell based assay. Do we get any information or hint about metastasis from cell based assay?
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Dear "JP",
From my own point of view, the response is actually "NO".
In vitro cell based-assay relating to cell migration or even invasion cannot predict the in vivo metastatic process. In vitro, one or only very few biological parameters are taken into account. In vivo, it is unfortunately another story (see the attached articles).
In contrast, in vitro cell-based assays permit to study the influence of a given compound on the migratory part of a cancer cell population, and studying it appart of cell proliferation or cell death (see the attached articles by Decaestecker et al., 2007; Debeir et al., 2008).
To efficiently combat a given cancer, you must decrease its proliferation rate (in subclones), increase cell death (in other subclones) and decrease (ideally blocking) cell migration and invasion (in still other subclones).
In vitro assays enable you to study the influence of various compounds on these distinct cancer components, while taking into acount the sole cancer component in a cancer. You must not forget the amazing complex story of the tumor microenvironment (see the attached articles).
You can also use 3D in vitro models which recapitulate much better the in vivo situation, while more difficult to use than 2D ones.
The story of trabectedin and plitidepsin is very interesting (see the article here attached).
Best regards
Robert 
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It appears to be often quoted in various papers and articles although I've not been able to find the original source (papers often reference secondary sources only) - any ideas?
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I am sending you a few sources where you will find this concept mentioned, but in my practice as an oncologist for more than 40 years I keep my own statistics where metastasis is the cause of death in 87% of cases. This concept has two exceptions: 1) head and neck squamous cell carcinoma where the main cause of death is local recidive and spreading and 2) hepatocarcinoma.
Mehlen P, Puisieux A: Metastasis: a question of life or death. Nat Rev Cancer.
2006; 6(6): 449–458.
Taketo MM: Reflections on the spread of metastasis to cancer prevention.
Cancer Prev Res (Phila). 2011; 4(3): 324–328.
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Among the array of cytoskeletal remodelling processes that a cell undergoes, surface phenomena such as protrusion formation (during migration and phagocytosis) demand an intricate coordination between the various molecular players involved. The significance of protrusion formation in cohort cell migration can be placed in a higher league. Considering its decisive role and the plethora of molecular players regulating the protrusion dynamics, what are the various parameters (biological and non-biological) that determine a stable cell protrusion 
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The Src kinase activation and phosphorylation of Cortactin may be useful parameters to determine the activity of invadopodia.
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Hi there my friends, I have 4 chemotherapeutic agents to treat cancer cells. However, I'm not sure what is the best way to give the treatment: whether the 4 drugs have to be given at the same time in the culture medium or separately otherwise. Please help me and thank you all very much in advanced .
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You should first test your compounds individually and precisely determine the IC10, IC25 and IC50 concentrations for each compoud and for each cell line.
Then, in a second experiments, you treat (or untreat = control) the cells either with the four drugs at IC10, or at IC25 or at IC50.
The purpose of this kind of study is to see whether for example with 4 x IC10 you can obtain a global growth reduction of > 50% or not.
Same think with the 4 x IC25.
If you succeed, this means that you are able to reduce by 50% the growth of your cell population of interest by at least 50% while you lower the toxic-side effects of each compound.
Best regards
Robert
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Is there any role of master regulator i.e Brain in metastasis of primary tumor?
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Dear Praveen,
Can you "reformulate" your question because I do not understand it.
Some cancers metastasize to the brain like melanomas because of neurogenic factors. Not far from half of the brain metastases are from melanomas.
On the reverse, the brain can influence the growth of some primary cancers outside the brain with respect to various types of neuropeptides, an example of which is the CCK / gastrin family of peptides or also neurotensine.
I am providing you with attached articles, but I actually do not know whether I am responding within the field of your question.
Best regards
Robert
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The role of autophagy in cancer metastasis seems to be complex. During early stages autophagy can play an inhibitory effect on metastasis. However, during advanced stages, autophagy acts as metastatasis promoter.
A recent review (Su et al, 2015) summarizes some of these aspects (see link). I am working in hepatocellular carcinoma, but my experience analyzing the relationship between autophagy and metastasis is limited.
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Sorry Jose, I have never  analyzed the role of autophagy in cancer metástasis.
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Is this evidence-based,or only experimental model? 
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You should address your question to Florence Lefranc, MD (neurosurgeon and neuro-oncologist), PhD who is registered on RG (florence.lefranc@erasme.ulb.ac.be).
Best regards
Robert
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Certainly many carcinomas (epithelial derived tumors) spread at least in part through the lymphatic system since lymph node metastases exist, and also are part of clinical prognostication. That in itself does not rule out direct dissemination to the blood. Is there any data on the relative contribution of lymphatic spread and direct blood spread? 
Since lymph node (local) metastases have prognostic value one would expect them to be part of the mechanism of disease, i.e. there would be a mechanistic progression from lymph node metastases to diatant metastases. Is this born out by clinical observation? Can it, and has it, be mimicked in animal models?
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 dear Christer, the one route of dissemination does not preclude the other and vice versa. Cancer cells have been identified in the blood of patients with practically all types of carcinomas (Clin Cancer Res. 2004 Oct 15; 10(20):6897-904.). Additionally, circulating tumor cells have been identified as an independent prognostic factor associated with detrimental prognosis eg in the setting of breast cancer (NCI J Natl Cancer Inst (2014) 106 (5)). on the other hand, lymphatic infiltration is a well established negative prognostic factor, associated with increased chances for metastatic relapse. these combined indicate, that both routes of metastatic dissemination operate not competing, but rather complementing each other as facilitators of metastatic relapse. hope that this helps. 
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We are looking for a mouse tumor cell line to do local tumor control study. We used 4T1 with small initial size (100-200mm^3) before. In a new project, we are going to increase the size to 1000 mm^3 when to start treatment and know it will take about >14 days. Because 4T1 has higher metastatic tendency and will die due to metastasis after inoculation, 4T1 is apparently not a good model  for our experiment. Our research aims to develop a new therapy for breast cancer, so we have to find a breast cancer cell line which can grow in mouse with intact immune system (not incompetent one, like nude mice). Thanks
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4T07 is another one non-metastatic mouse breast tumor line.
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we know that  EMT  is critical step for metastasis  ,then these metastatic cell require MET in establishment and stabilization of distant metastases. but what about cell lines taken from metastatic site , will they undergo EMT when inject intravenously and thus require MET in order to colonize metastatic site.?
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My opinion is that cells injected directly into the circulation do not require EMT as the early stages of metastasis has been bypassed. There is no reqirement for dissociation of tumor cells from the primary site or invasion or intravasation. They will require to extravasate once they reach the secondary site. Most tumor cells injected iv will die those that survive will implant in the target parenchyma. it is believed that epithelial type cells are more efficient at doing this than mesenchymal like cells, hence the reqirement for MET when cells go through the full metastatic cascade. Iif the tumor cells injected are largely epithelial like anyway MET transformation would not be needed. Poorly differentiated colorectal cancer cells for example tend to be more invasive but less metastatic to the liver when injected intra splenically than the more epithelial like well differentiated cells.  
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What is the exact role of fibroblasts of tumor tissues in promoting cancer metastasis? 
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PI3K-Akt signaling is crucial for progression and metastasis of malignant tumors, and it has been documented that the Akt substrate, Girdin, an actin-binding protein, which regulates cell migration, is expressed and activated by Akt phosphorylation in cancer-associated fibroblasts (CAFs). The cross communication between tumor cells and CAFs (also denoted as activated fibroblasts) plays a vital role in the regulation of tumor promotion and progression, angiogenesis, invasion and metastasis.  Fibroblast activation protein α (FAPα) is a transmembrane serine protease that is strikingly expressed in CAFs in more than 90% of human epithelial neoplasms. 
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I am studying the mechanism of a Serine/Threonine kinase to promote cancer metastasis. It will promote metastasis of cancer cells in vivo. But I can't find the target of the kinase to promote metastasis in vitro. So I am wondering whether I can use IP to get its whole substrates and then do mass spec. 
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Co-immunoprecipitation is a terrible way to identify kinase-substrate interactions (with some rare exceptions). The nature of the interaction is transient - that's the entire mechanistic quality of reversible phosphorylation. Moreover, the kinase is usually present in lower concentrations that its substrates and most kinases have a slew of target proteins. In other words, if interactions were stable, signal transduction would not work very well. So, what do we do?  We epitope -tag and massively over-express a protein kinase and a putative substrate and, lo and behold, find evidence for interaction by immunoblotting. This forcing of transient interactions can be very misleading and my bet is that the majority of papers that show such interactions are doing so in a non-physiological manner.
So, what to do to identify your kinase targets?  There are many methods but one you might want to check out is called BioID in which you tag your kinase with the biotinylation domain of birA and express this in the cells of choice.  You then purify biotinylated proteins via affinity binding to Streptavidin beads and identity them by mass spectrometry. Of course, this generates false positives too and will not detect all transiently interacting proteins, but it's a lot better than co-precipitation and has the enormous benefit of pushing you away from biases by looking under the lamp post.
There are a lot of recent studies of the approach, you could start here: https://www.researchgate.net/publication/260131454_BioID_A_Screen_for_Protein-Protein_Interactions
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Babak Rashidi et al. (2000) demonstrate that liver metastases from colon cancer are capable of remetastasizing to other sites ,1- however are there other tumors  may follow this course ?
2- If metastatic cells re – metastasize , Do they Follow the approach that's similar to the primary tumor or that of metastatic site (as they originate primarily from metastatic site).
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I agree with Daniil. And I do not think that the second metastasis is the same as the first.
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I am planning to flow breast cancer cells, in a buffer, into a device. What is the highest flow rate I could use if I want the breast cells to attract to the CXCL12 chemokine? Specifically, I am putting the CXCL12 on the side of the device and flowing the cancer cells in the middle. Will the force of attraction be strong enough to eventually have all the cancer cells on the side of the device with the chemokines?
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Your experimental design of CXCL12 on the side of the device and flowing the cancer cells in the middle seems to be artificial. Tumor tissue is composed of surrounding ECM (collagen and laminin etc. ) as well as cancer cells and cancer-associated fibroblasts (CAFs) with alpha-SMA. The bio-availability of chemokine CXCL12 should be evaluated with the consideration of factors other than tumor cells themselves. The blood vessel endothelial cells determine the permeability of CXCL12. Further, the stability (half-of-life period) of the chemokine in vivo cannot be predicted. The persistent secretion of paracrine manner is essential to evaluate the concentration in the serum and tumor tissue.
Why not check the expression of CXCR4 (CXCL12 receptor) before and after administration of CXCL12 in vivo model in the long term, since CXCL12-CXCR4 axis plays a negative feedback loop.     
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I am using patients derived xenograft to study genes regulating breast cancer metastasis to the lung. So I will need to collect human breast cancer cells from the mouse lung.
Thus I will need a protocol for lung dissociation and selection for only human cancer cells.
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It would be possible after making single cell suspension and gating through Human EGFR.
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I know of oncomine and TCGA. I am trying to see if a gene of my interest in involved in metastasis.
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Dear Gaelle, thanks for the update. I really appreciate it.
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In various literature reports, CXCR4 interacting with CXCL12 has been said to cause metastasis in breast and prostate cancers. In colorectal cancers, reports have stated that the cancer cells respond to CCL20, meaning they contain the CCR6 receptor. However, shouldn't these three cancer cell lines all have the same receptors, since they are all epithelial in origin?
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Hello Roy,
Well, recent reports have indicated that CXCR4 and CXCL12 axis also play important role in the metastasis of colorectal cancer (CRC) cells. CXCR4 expression has found to be high in CRC cells, though CXCL12 expression is very less (according to most of the published reports). However, cancer associated fibroblasts do have high expression for the CXCL12 ligand, suggesting inverse association between CXCR4 expression tumor cells and CXCL12 expressing fibroblasts cells. Moreover, liver has high expression for CXCL12, which possibly explains why it is the primary site for CRC metastasis. Not only liver, lung, adrenal glands and bone marrow also have high expression for CXCL12 under normal condition, which further make them a suitable choice for homing for CXCR4 bearing CRC cells.
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Circulating tumor cells (cancer cells that cause metastasis) respond to a variety of chemokines, causing it to travel through the bloodstream into specific organs. Which chemokines attract ONLY these cancer cells without having any effect on normal white blood cells?
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Currently, none
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resection of metastases or chemotherapy?
umbilical metastasis
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dear sebastian
resection of metastases has only the palliative role only if the patient has symptom., otherwise disease is in metastatic setting and according the NCCN ,surgery has only palliative role.
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Two big issues remaining for prostate cancer migration are cancer formation from hyperplasia and the way cancer to migrate. We may figure out if we can detect the beginning of different signaling of metastasis or lymphastasis.
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The subtype of VEGF expression pattern makes the difference of the metastasis depending on between blood vessels and lymphatic vessels. The interaction of the ligand VEGF-C and its tyrosine kinase receptor VEGFR-2 induces the formation of paraneoplastic lymphatic vessels and let tumor cells exhibit the distant metastasis via lymph node.     
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Perineural invasion is frequently observed in pancreatic cancers and they exhibit focal differentiation surrounding the peripheral nerves. Neighboring schwann cells lead to the differentiation of invasive tumor cells and the formation of the tubule-like structures. The nerve growth factors are responsible for this peri-neural invasion with differentiation?
The co-culture experiment in combination of schwann cells with pancreatic cancer cells in vitro leads to the enhanced migration potential as well as higher levels of differentiation molecule expression in a heterogeneous way. It is noteworthy that the co-culture system without cell-to-cell attachment cannot induce the same result, indicating the possibility that neither soluble growth factors nor exosomes containing micro-RNA cannot be the cause of the alteration of tumor cell phenotype. 
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Surely MMP is a likely candidate to promote the peri-neural invasion, but this is soluble in stromal fluids. Thus I do not think MMP can explain the cell-contact-dependent manner of peri-neural invasion and accompanied the focal differentiation of invasive tumor cells. 
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Or do they evolve ( gain or loose) depending of their micro environment?
Thank you for your inputs
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That's a very important but difficult question. And probably best studied with respect to epithelial (E) and mesenchymal (M) markers. I agree with Ruhul: micrometastasis are very frequently found and they are typically M, while in macrometastases E markers are expressed. The question is: are these M cells 1) becoming E via an mesenchymal to epithelial transition (MET, e.g. via INDUCTION by the microenvironment) or 2) are dissociated SELECTED E cells attracted to the micrometastases which basically may represent a good microenvironment themselves for the E tumor cells due to cooperation (Tsuji, Cancer Research 2009, Cleary, Nature 2014 )? The answer may strongly depend upon the tumor type. But for breast cancer we have a manuscript in preparation that stable MET and thus induction is much less likely than cooperation and selection - this is  supported by single cell data, fluorescent cell tracking, functional videomonitoring and importantly, patient data,
To answer your question about markers: multiple markers capable to discriminate the E from the M phenotype at the micrometastatic site should be used, which described the STAGE and level of aggressiveness with E markers relfelcting aggressive and M markers reflecting less aggressive.
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Although CTCs have a clinical impact in several tumor types like breast cancer or colorectal cancer, the role of CTCs in lung cancer remains unclear. However, I am planning a project in the area of CTCs in NSCLC and I'm on the search for the researchers who have experience with CTCs and are willing to participate. Feedback and opinions on the topic are also welcome.
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Some of our works may help you in the theme of ctc and liquid byopsies: 1) http://www.jthoracdis.com/article/view/1642/html Sobre Cytokeratin-based CTC counting unrelated to clinical follow up. 2) http://www.appliedcr.org.br/detalhe_artigo.asp?id=260 about=sobre : Circulating tumor cells: basic concepts and some clinical applications. 3) Thymidylate synthase expression in circulating tumor cells: A new tool to predict 5-fluorouracil resistance in metastatic colorectal cancer patients. http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1097-0215/earlyview
hope may help
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Hey,
I'm planning to use BrdU to label cancer cells in vitro, and inject the cell in vivo, in order to track the cell. For this, I want to know whether BrdU affects the biology of cancer cell or not..(especially metastasis)..I have done some searching on this, but I couldn't find any...
The only thing I found is a study which used cell tracker for this,[Mol Cancer. 2015 Dec;14(1):282] , These guys have done exactly what I am trying to do.
;however, as I know, fluorescent of cell tracker only lasts few weeks,,
That's why I am concerning BrdU
Q1. Would BrdU affect biological behaviour of cancer cells?
Q2. Does anybody know any study using BrdU-treated cancer cells for metastasis experiment?
Q3. Cell tracker vs. BrdU, for this experiment which one would you recommend ?
Thank you!
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Yes.  Because BrdU intercalates into DNA it can lead to DNA damage and consequently to changes in cellular behaviour.  For tracking cells long-term, your best bet is to use a fluorescent dye such as CFSE or SNARF that bind protein.  With each cell division after labelling, the amount of stain remaining is halved allowing you to estimate the rate of proliferation over time.  Labelling with either of the above reagents is totally straightforward, just be sure to wash away any unincorporated dye before proceeding with your experiments.  Good luck!
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Can be Bone, Brain, Liver, Kidney, Peritoneal zone and Adrenal Glands? These six because have the propriety of "encapsulate" the tumors? I hope your answers, Thanks.
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You have focused on the presence of capsule, but rather than that I think the vasculature is much more important to determine the possibility to let cancer cells form the distant metastatic tissue. For instance, the metastatic lesion in the lungs derived from sarcoma is quite common in the clinical settings. After all, lungs are composed of alveoli with numerous capillary blood vessels, where circulating tumor cells (CTCs) exhibit extra-vasation and colonized to the pre-metastatic niche with favorable kinds of ECM.
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I want to know names of the most commonly and commercially available drugs against cancer metastasis, can anyone help? 
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Not clear if you are looking for an (antimetastatic agent) or do you mean a drug which is used for the treatment of metastatic tumours? these are two different things.
For the first the answer is really none! Metastasis occures in many ways using different mechanisms depending on  tumour type. It will be interesting to have an (antimetastatic) agent or drug for all tumours and if you are interested deepening in the mechanisms of metastasis may help. Many doctors tried to use surgical controles of blood vessels for example. Not much success.
If on the other hand you mean a drug which can be used to treat metastatic tumours there are many depending on the tumour type. As in the first answer some treatment schedules are well established for e.g. metastatic breast cancer. May I add another example :Vemurafenab in metastatic melanoma. Success however is never 100% but there is a very good improvement in remission rates up to 50% sometimes.
Wishing you success.
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I am going to perform a flow cytometry assay in order to detect myeloid cells and melanoma metastatic cells in the lung. For myeloid cells I am going to use CD11b antibody conjugated Alexa 488 and for melanoma cells Tyrosinase antibody conjugated with phycoerythrin. I am wondering what should be the positive and negative controls for gating in this assay.
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Metastatic myeloid cells in the lungs?? It sounds complicated because of the kind of tissue (lungs have a high density of blood vesels which generates the posibility of contamination of blasts coming from the blood, in such a case different kind of cells could be CD11b including NK cells). It would be better if you could identified solid myeloid tumors (myeloid sarcoma) and not only cells in a fluid. In such a case you should perform the diagnosis of myeloid sarcoma as recommended by the WHO classification of lymphoud and myeloid neoplasms 2008. If you are planning to identify cells in a fluid, I think it should include at least CD34, CD45, CD117, MPO, CD33. CD13, CD15 markers in order to better identified populations of myeloid origin (mature or immature). But again, it depends on how specific you need it. It is difficult to talk about "myeloid metastases" in the lungs when many cells CD11b+ are coming normaly from the blood. But there are many publications about flow cytometry and the minumun panel required for myeoid lineage.
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KRAS,NRAS,BRAF wild type colorectal cancer can response the anti-EGFR therapy using cetuximab or panitumumab. However, in some cases such as Her2 or MET amplification there will be an resistant to anti EGFR therapy although tumor has  KRAS,NRAS and BRAF wild type genotype. If there is a polysomy in chromosome 17(Her2:CEP17 ratio 1, however there is a increasing number of chromosome 17 such as 3:3,4:4), using FOLFIRI+Cetuximab+Herceptin can overcome EGFR resistant in metastatic colorectal cancer?
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Very interesting discussion, I would just like to add besides the discussions above, one may also keep in mind the PI3K, MEK, AKT mutations that may be involved and molecules of other alternative or additional  pathways that may be involved in resistant metastatic colorectal carcnomas. The article below may be of help.
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What is the most advanced and reliable method or technique to track metastasized breast cancer cells in human body?  
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You can detect circulating epithelial tumor cells (CETC) in blood samples of cancer patients (also breast cancer patients) by fluorescent anti-EpCAM antibodies and fluorescence microscopy. The number of CETCs in blood or lymph fluid is correlated with the risk of relapse and metastasis formation.
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Prospective fate maps show that cells of different germ layers and different subdivisions within germ layers are partially segregated from one another in the epiblast and primitive streak. however , Gerhart et al (2007) demonstrate that the epiblast contains both multipotent cells and a subpopulation of cells that are stably committed to the skeletal muscle lineage before the onset of gastrulation .
Monte et al.[1983] suggest that pattern of metastatis in malignant melanoma may related to the embryological derivation of tissues involved.
could there is specific interaction between deifferent segregation in epiblast or they exposed to related factor that may explain organ - specific metastases ?
this make sense or there is something i understood wrongly ?
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“Seed and Soil Theory” is well-known to understand the preferential distant organ/ tissue in which the particular kind of cancer cells forms the metastatic foci. Further, the genetic/epigenetic alteration during the embryonic development is responsible for aggressive cancer development. The tumor involved in skeletal muscle is frequently childhood-onset such as rhabdomyosarcoma etc, but the distant metastasis to the muscle is not common among several kinds of tumors for precisely unknown reason.
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What is the role of Notch1 or SIRT1 pathway in breast cancer metastasis
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just a book chapter you might find helpful 
best 
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Is the migration procedure initiated within the metastasized cells or is there a chemo/electrical signaling from the ECM/endothelial cells/blood stream which recruits cells into the blood stream?
Of course cells should have the potential to migrate, but what it makes cells posses a response like migration?
In migration/cell invasion assays, I've seen that a "chemoattractant" is used. This means that metastatic cell lines, on their own, can't migrate. They need a cue to start moving towards the blood stream.
Any insight on the topic is much appreciated. 
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Hi Hanie... These are some thoughts regarding the question you asked.
Carcinoma cells acquire a mesenchymal shape through EMT (Epithelial-to -Mesenchymal Transition) that is when a cell starts to lose its epithelial characteristics and adopt a newly mesenchymal expression profile. Molecular-wise, cells will upregulate EMT markers such as Vimentin, N-Cadherin, Twist...etc and downregulate other genes, especially those pertaining to MET such as E-Cadherin.This will drive cancer cells to slowly detach from the basement membrane, as cells are no longer in close proximity to one another (also loss of gap junction, contact inhibition, and many other cell-to-cell junction), and give the cells the 'freedom' to invade locally. Indeed, cells can locally invade by digesting the ECM through a group of enzymes termed 'proteolytic enzymes' such as MMP2 and MMP9. That alone is insufficient for cancer cells to locally invade then leave their primary site, there is indeed a need of acquired motility associated with a rearrangement of the cytoskeleton: cancer cells will upregulate proteins involved in motility, such as Cdc42 or RhoA which drive 1. the remodeling of actin cytoskeleton, 2. a contractile force for cells to move, 3. invasive actin structures associated with an invasion status such as invadopodia. Because of the uncontrolled cell growth, there's definitely a lack of nutrient and oxygen which drive a state of hypoxia, if you take a tumor growth or foci, and you cut it, you would realize that cells in the core have undergone necrosis because of hypoxia. This phenomenon will induce cancer cells to increase the transcription of HIF1-alpha which drives the secretion of growth factors that enable 'de novo' blood vessels formation, a good example of these factors would be VEGF. Blood vessels will start to orient themselves towards a chemoattractant (VEGF) that is secreted locally, nearby the cancer cells. It should be noted here that blood vessels formed due to angiogenesis are generally leaky, and poorly structured as pericytes are loosely attached to them.  Moreover, the tumor microenvironment plays a crucial role in the process of invasion. In breast cancer cells for example, a very important member of the tumor niche is Cancer Associated Fibroblasts (CAFs) which promote invasion through secretion of local growth factors and cytokines that drive cancer cells to metastasize. Immune cells also play an important role in the supply of growth factors and cytokines as these are essential for the growth and survival of cancer cells. Now, when blood vessels reach cancer cells, a heterotypic interaction between endothelial cells and the latter cells take place: Cancer cells are indeed capable of transcribing connexin genes (mainly Cx43) to interact with the endothelial cells, and because gap junctions are one of the sources of molecular exchange between cells, cancer cells can cross the the endothelial layer (that is one proposed example of how cancer cells can cross and get into the bloodstream). A recent paper in Cancer Cell came out in April 2014 where it was shown that breast cancer cells secrete mir-105 that is capable of destroying the vascular endothelial barrier to promote metastasis. This suggests that there isn't a generalized theory on how cells get into the bloodstream, but many studies have particularly focused on that. The big question to ponder now: How can cells that have never been exposed to the blood environment i.e. blood pressure, pH change, immune cells,.. adapt so quickly (survive) and can invade into a secondary site? Many cells will die throughout the process, and few will make it and form foci. 
Hope this helps,
Patrick  
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Any further role for the radiologist in this case?
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I agree with Muhammad Shoaib Akhtar. Standard CSF cytology methods, using routine centrifugation followed by resuspension are often not useful for CSF tumor cell cytology. Even "cytocentrifugation", directly on a slide or coverslip, alters cytological features. I used, for critical diagnostic CSF cytology, a sedimentation method developed a long time ago by Prof. Suta (Praha university), followed by May-Grunewald-Giemsa staining. Even so, speed is of the essence: twenty minutes between CSF sampling and lab technique are a maximum. Preliminary results were given in : SUBERO A., FONCIN J.-F., LE BEAU J. : Diagnostic cytologique du liquide céphalo-rachidien par la chambre de sédimentation de Suta. Neurochirurgie (Paris) 1968 14 n°5, 627-634.
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there are studies show reciprocal interaction between cancer cell and stroma mediated by extracellular vesicles ( cancer cell release microvesicles affect stromal cells which in turn release microvesicles affect cancer cell) at primary tumor enviroment, in addition cancer cell release extracellular vesicles play a role in pre-metastatic niche formation .
but is there reciprocal interaction between primary tumor and pre-metastaticniche mediated by these vesicles ( i mean do cells in premetastatic niche also release extracellular vesicles affect primary tumor ?)
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What you proposed is an interesting idea. I think it is possible that cells in premetastatic niche release vesicles to affect primary tumor. However, there is currently no published evidence.
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We are using arteries from humans for myographical studies, but we have problems during contraction when we use phenylphrine (PE)? But, the arteries contract normally when we use KCl.
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All vessels are not equal when it comes to their ability to constrict to PE; some arteries are much more responsive to PE than others.  It depends on the amount of adrenergic receptor expressed on the smooth muscle cells, and on the amount of sympathetic innervation of the artery studied (although, I am not 100% sure that the level of sympathetic innervation directly correlates with the expression level of adrenergic receptors...).
In your context (cancer feeding arteries or umbilical cord), I am not so sure that PE is physiologically relevant, I would try other agonists.  I was quickly looking into the literature and found this paper where they show that arterioles within a prostate tumor do not constrict to PE:
I would try other agonists (ET1, AngII, 5-HT, PGI2 etc.) but your choice depends on your hypothesis, what is it that you would like to test on these vessels? Are you studying a pathway in particular or do you "just" want to see the overall contractile ability of these vessels?
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In their article and communications with the editor [1, 2] S. Halabi and coauthors reported on predictive significance of pain interference scores and pain intensity for overall survival in patients with castration-refractory prostate cancer (CRPC). Overall 317 men with CRPC included in the study, and the median survival times for patients with pain intensity score of 5 or greater was significantly shorter than in men whose pain intensity score was less than 5 (8.76 months, 95% CI 6.88-11.30 months vs. 18.15 months 95% CI 15.47-20.20months, P<0.001) by univariate analysis. After adjusting for other prognostic factors, pain intensity remained a statistically significant predictor of OS with adjusted hazard ratio of death 1.61 (95% CI 1.21-2.13, P<0.001).
However, data in the literature on predictive role of pain intensity for survival in patients with bone metastases from solid tumours are scarce.
1. Halabi, S., et al., Pain predicts overall survival in men with metastatic castration-refractory prostate cancer. J Clin Oncol, 2008. 26(15): p. 2544-9.
2. Klepstad, P. and S. Kaasa, Predication of cancer patients' survival by pain interference items is not the same as evidence that pain intensity is a survival predictor. J Clin Oncol, 2008. 26(25): p. 4215-6; author reply 4216-7.
 
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A recent paper in the Red Journal (Int J Radiat Oncol Biol Phys, "An Easy Tool to Predict Survival in Patients Receiving Radiation Therapy for Painful Bone Metastases" Sept 24, 2014, in press) by PG Westhoff et al. looked at predictors of survival in 1157 patients with bone metastases. Although pain intensity was a predictor in univariate analysis, it did not contribute to the multivariate model. Of baseline variables, Karnofsky performance status (KPS) was the strongest predictor of survival.
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Does anyone have experience regarding the difference in metastatic potential of B16-F10 and B16-F1 cells? How much longer would B16-F1 cells need to cause a substantial number of metastasis in the mouse lung when injected i.v.?
I found quite different statements in literature. Some showing almost no metastasis, some showing a huge number of metastasis after 2 weeks.
Thanks in advance!
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Dear Carsten,
I am afraid you are making a minor mistake in regard the concept of metastasis and colonization. When you intravenously inject the B16 cells you are bypassing important steps of the metastatic process, e.g. invasion and intravasation. If you are studying extravasation and colonization, the model of Lung colonization is a good option. The time of metastasis occurrence totally depends on the number of cells you inject. I use to inject 3x10e4 to 10e6 of B16-F10 cells intravenously, with good results at D+14 to D+21. By the other side, if you want to study the whole metastatic process, I recommend you trying to model a primary tumor (e.g. subcutaneous melanoma). I noticed good number of spontaneous metastasis (lungs, brain, liver) at D+42. Another option is assessing spontaneous metastasis through survival. For example, you inject B16-F10 subcutaneously and wait until D+14 to D+18. Then you surgically remove the primary tumor and observe the survival of your different groups. Unless the animal develop a local relapse, you can state that the mortality is due to spontaneous mets. About the other part of your question, the literature claims that B16-F10 is a more metastatic strain of B16, so I would recommend you to test them, in opposite of B16-F1.
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I am willing to do in vivo study (Xenograft) using 4T1 cell line (murine breast cancer cell line) and as I understand this cell line can highly metastasize to different organs. My goal of the study is to inhibit growth and not stop metastasis. So, even though the cell line grows very fast, it is not the suitable. Any help will be appreciated.
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I haven't had experience with this particular cell line, but have with other metastatic cell lines in orthotopic xenograft models. I would favor this type of model over one that doesn't involve metastasis, for many reasons. For example, if you are wanting to treat the animal with a compound/inhibitor after the tumors have already been established, then the model you are using may be good to see whether that agent can inhibit the growth of both the primary and metastatic tumors. If it does in fact inhibit the growth of metastatic tumors, this would be a great discovery and may be more clinically relevant for advanced breast cancer. Similarly, if you are trying to determine whether knocking down or over-expression of a gene could influence tumor growth, then this model should tell you whether the alteration influences engraftment or tumor growth, irrelvant of metastasis. And, if altering the gene doesn't affect primary tumor growth but does affect metastasis (which has happened in my experiments), then this is also valuable information and you may have found a new promoter or suppressor of metastasis. Win win!