Going Rogue : How does a cancer spread to become metastatic?
Why do cells that are tightly packed or neatly arranged in rows (epithelia), come loose and become insidiously mobile? The answer lies in a basic developmental process known as EMT, short for epithelial to mesenchymal transition.
❑ During EMT, cells no longer know which way is up (i.e., lose their polarity), break off their cell-cell junctions and extend pseudopodia or foot-like processes that help them move. In the image below, colon cancer cells were caught in the act of rearranging their junctional proteins (in red and green) to become amorphous, drug-resistant and invasive. Even more dangerous, these cells acquire stem cell properties, allowing them to seed new cancers. In short, cells lose their mature, differentiated form and recapitulate their origins.
❑ But EMT, and its reverse process MET, are normal features of embryo development, leading to formation of the neural tube, heart valve and other organs. Also, during wound healing, skin cells at the edge of the wound undergo EMT, reverting back by MET after the wound is closed. Understanding what triggers these changes, and how they may be controlled, is key to cancer therapy.
❑ This explanation is in response to the more sensationalistic title, New theory uncovers cancer’s deep evolutionary roots , shared on G+. The theory “promises to transform the approach to cancer therapy, and to link the origin of cancer to the origin of life and the developmental processes of embryos”. Choose between breathless science (http://goo.gl/yDsys) or the rational explanation here 🙂
Wiki entry for EMT: http://goo.gl/2U806
Reference (open access): Chronic oxaliplatin resistance induces epithelial-to-mesenchymal transition in colorectal cancer cell lines. Yang et al. http://www.ncbi.nlm.nih.gov/pubmed/16857785
#ScienceSunday
madame scientist's not-so-mad musings 
great yaar…
I choose rational science!
another breathless headline put into its proper context Thanks Rajini Rao a public service on G+ Sharing
I will opt for the rational explanation. Once again, Rajini Rao thank you for bringing clarity to sensationalism.
Thanks, all. The science is still pretty darn cool, even without bogus claims.
Interesting post! The focus of my research is B-catenin, but in this case it’s B-catenin activation, which also contributes to tumorigenesis. It is one fascinating protein!
Akinola Emmanuel , good to know! We’ve just started looking at changes in E-cadherin when our calcium transporters are upregulated in breast cancers. Trying to keep everything straight (integrins, catenins, cadherins, etc.).
My biology Prof. said one time that normal cells divide across three planes corresponding to the x, y, and z axes. Cancerous cells divide on all the other planes, not in alignment with the above stated axes.
Is this similar to what you say that cells no longer know which way is up?
Jim Carver , yes, I think so. Cancer cells lose polarity and no longer divide along one plane only (if they were in a sheet).
Thanks for the non-sensational explanation, Rajini Rao!
Hyder Noori , there are natural inhibitors of EMT as wells as drugs that can be targeted to signaling pathways that control this. Surgery helps with the primary tumor only; once the cancer has become malignant (metastasized), it’s difficult to track and remove.
Rajini Rao Thanks. you know your posts are complex and it takes a little while to get up to speed. I usually have the read the header three times and do some more research. 🙂
Rajini Rao Fascinating. I’m looking primarily at T cell development, but the upregulation of B-Catenin we see is very similar to what is seen in other human leukemias so the downstream effect of B-Catenin activation is our key interest.
With so many friends and relatives having died from one form of cancer or another I still hope a cure is soon found
Grat rajani
Jim Carver , thanks for making the attempt 🙂
My two “take home” points are (1) cancer cells hijack a normal developmental process to spread out of the original tumor, and (2) this idea is well-developed and under active study- not quite earth shatteringly new.
“Pseudopodia” – wow!! Any acquisition of ‘pseudo’ over the period becomes destructive!!
Kriti Gangwar , fortunately I do enjoy writing. But my time is mostly spent writing research papers and grant applications, which quickly start to sound wordy and dense 🙂
R Prakash Prakash , you like that word? 🙂
Pseudopodia or “false feet” are pretty much the way all cells move.
My bad understanding 😦 . I got carried away by the first paragraph in OP, which I construed like this – the cells acquire false feet in the process of going rogue!
No you are right, R Prakash Prakash ! These cells have no business acquiring “false feet” (unlike lymphocytes/white blood cells that do need them to patrol our body looking for germs). When they change from stationary to mobile, they “go rogue”.
Thanks Rajini Rao you tutor so well. For once, I can pat myself 🙂
I dnt know how it spread but we did some donation for a research to find out and finish it
How u got any idea????
Thanks Rajini Rao … Excellent use of graphics and text to explain a complex phenomenon without talking down to the reader.
Best way to kill any cancer is to eat lots and lots of fried or raw garlic with mild cayenne powder & lots of ginger 😉
I edited a cover picture from Clinical Cancer Research: it is so pretty and striking isn’t it, Alan Kotok ? Thanks!
Buster Zinger , can I substitute fiery hot cayenne for the raw garlic? I’m afraid I’ll live longer but nobody will come near me 😉
Rajini Rao What? It’s back to cooking school? Okay, I’m in. Let’s take a lightly sweetened with glycerol tincture of cinnamon, infused with devilish Basil, covered in turmeric and laced with garlic oil.
Simmer ever so lightly and imbibe with a large glass of red wine in the morning. Repeat until drunk…or when you don’t care. Witch ever comes first. Follow up the next day with a doctor, because you’re gonna need that sob now! ;D
Jim Carver , it’s always cooking school on my posts, right? 🙂
Is it okay to start on the large glass of red wine first?
The rational explanation leaves me breathless Rajini Rao 🙂 (I am amazed that we understand the processes to that extent). Thanks for sharing
Rajini Rao Ab-so-lutely, every body knows the creative chemistry proceesess begin and end with wine. So many drunken accidents have led to major discoveries that it’s outstanding. Many a poor chemist would be destitutionalized without said extrapolations and would surely have been in the drink, if it weren’t for the help.
Ren and Roy are chemists and they are doing an experiment after a stint at the wine-tasting bar.
Ren: You put benzene in my alcohol.
Roy: So? You put alcohol in my benzene.
Ren: I was linking that alcohol with a nitrogen atom.
Roy: So we’re…BOOM
The Ren and Roy Memorial Museum opens on Friday.
Interesting! After reading the link, I can see cancer patients an an Atkins diet, stuffed in hyperbaric chambers.
Jean Liss You can see that can you? Funny, because I don’t.
Rajini Rao thanks for this interesting post!
Jim Carver from the ASU article..
“Davies and Lineweaver predict that if cancer cells are saturated with oxygen but deprived of sugar, they will become more stressed than healthy cells, slowing them down or even killing them. ASU’s Center for the Convergence of Physical Science and Cancer Biology, of which Davies is principal investigator, is planning a workshop in November to examine the clinical evidence for this.”
Jean Liss
Why you tell me this? I’m the most organic person on here.
But to tell you the truth…that sounds like crap.
And no link? I don’t know if I’m that enthused about it to even search for it.
Cancer cells do well in hypoxia and prefer to use glycolysis in place of aerobic respiration. On phone now, but can discuss later.
One article is not a theorem. I would be willing to entertain something if the poster has something to offer.
Maybe there are multiple mechanisms how cancer cells become metastatic. There is a recent paper that cancer cells sometimes merge with white blood cells in metastasis, is it common? Jess O’Brien reported it, the paper is here http://www.plosone.org/article/info:doi%2F10.1371%2Fjournal.pone.0066731
Jean Liss I went back and re-read this thread. You haven’t posted anything with a link and made your first vague comment at (my time) 2:22
I really don’t know wtf you are talking about. There is no basis…talk all you want but you have to have something that we can get a handle on.
Jim Carver let it go. I know what Jean is referring to and will respond later. OK?
Rajini Rao K
#TheRationalExplanation – it’s made of win (lol)
Actually I think the theory from Paul Davies is not so ridiculous at all, it is based on the nearly 100 year old Warburg Hypothesis http://en.wikipedia.org/wiki/Warburg_hypothesis . He has written a number of papers about it. David Basanta , Jacob Scott and Artem Kaznatcheev work on mathematical models that may shed some light on the evolutionary aspects and processes at work. In the end it could be that Davies is not completely wrong.
Jochen Fromm , thanks for that PloS One article: very unusual finding, I’ll have to read it and get back to you. Davies hypothesis re. glucose consumption and hypoxia is not ridiculous at all, on the contrary, it is quite well known. The Warburg hypothesis is the corner stone of cancer bioenergetics. Neither are Davies’ ideas on cancer cells recapitulating their embryonic form anything new. My point is that it is well studied and actively researched (there is even a Wiki page on EMT). I get the sense that he is a physicist on a journey of self discovery 🙂
Rajini Rao possibly. Why not explore every possible alley on the road to a solution of the problem? The article from Paul Davies in question is here http://livasperiklis.com/2013/07/01/httpwp-mep29tmj-4hw/ I like the idea that the hallmarks of cancer somehow correspond to the major evolutionary transitions. Wonderful idea. There are older articles from Paul Davies and Charles Lineweaver about the idea that some forms of cancer are a fallback to the dawn of multicellular life as well, one is from 2011.
Sorry Jim Carver , I followed the link in Rajini Rao ‘s post to read the “breathless science” behind what this post was about. Sorry, links are hard to cut and paste on phone.
Jochen Fromm , my point is that it is an old idea. Well known. That is exactly what EMT is: a de-differentiation and recapitulation of embryonic state as explained in my post. It is also linked to the evolution of multicellularity. It is not Davies’ idea at all, and I’m not sure why he is passing it off as a Eureka moment. Maybe for him it is, from outside the field, but not for us.
Great job on clarifying the basics. Science is cool dnough without sensationalism. I have to say though that while the theory of EMT is an old old news, there is quite a bit of controversy over whether it actually occurs in vivo. Meaning do tumor cells dedifferentiate ( like they do in tissue culture) or are there tumor stem cells that are present within the initial tumor at a very low abundance and then escape to seed at distant sites. There is a really cool pancreatic cancer paper that I am blanking on the author. Was in Cell about 8-10 months ago. They showed that pancreatic cancer metastasis if you will can be established even before the primary tumor forms and those metastatic cells express EMt/ stem cell markers. Was thought to explain why pancreatic cancer is so deadly. I will look for the article and send it your way.
Natalia Mitin , thanks, please let me know if you find it. Are the cancer stem cells in the niche sufficient to drive metastasis?
Yay! Awesome debunking post!
A couple of factors I wonder about are:
What about surrounding cells and their interactions with the surface of a cancerous cell (size and shape matter to cell function). Work in the 90s showed liver cells lost function when grown in a flask, but kept function when grown in collagen sandwiches. They also studied the extent you could alter the shape of the cells by culturing them on printed silicon wafers.
What are the individual changes to the DNA ( implications to packing, gene function apoptosis pathways etc…) Many of the factors involved in embryology.
So I find it cool work and having more sets of eyes on the problem (even if some of it is old hat information) may help produce a new approach to therapy.
Rajini Rao, here is the link to the pancreatic cancer metastasis paper I mentioned. It’s behind a paywall. Let me know if you don’t have access and I will send you a pdf
http://www.ncbi.nlm.nih.gov/pubmed/?term=EMT+and+Dissemination+Precede+Pancreatic+Tumor+Formation
Natalia Mitin , thanks (I have Univ. subscription, but the paper is open access via PubMedCentral). It’s a sobering finding that metastasis does not have to be the final stage in cancer progression but can occur any time, and before tumors are observed. The paper also reinforces that EMT transitions are more plastic and heterogenous than text book versions. A great read, thanks!
You are very welcome Rajini Rao. I think from a clinical perspective (I am not an MD), regardless of how we think EMt occurs, having cells expressing EMt markers in your tumor is never good news. If you want to read more on cancer and EMt and stem cell like characteristics, I would recommend looking up papers from Charles Perou at UNC. Especially his recent ones on triple negative breast cancers and claudin-low subtype. Those cancers are the deadliest breast cancers and frequently occur in much younger women.
I’ll take a look, thanks! By the way, I just realized that my Hopkins colleague Steve Leach, was one of the senior authors of the pancreatic cancer paper you linked me to 🙂
That’s too funny. Small world. Take care and thank you again for dedicating your time to this community.
This discussion is so beyond my educational background, BUT I am so thrilled to see how your amazing intellect is being used to help people like me who’s lives have drastically changed because of the “C” word. People like you and the students you teach may someday find that cure! Blessings to you and folks like you Rajini Rao. That means you too Chad Haney!
Thanks Mary W. You give us motivation from your courage.
So these headlines give us scientists a “teaching moment,” which is good, I guess. G+ scientists help cut through #sciencemediahype
Thanks for the tag, Scott Sneddon , a great idea. It’s also given me an idea for a new category in the Science on Google+ community. Right now, the community is filled with reshares of popular news without much original commentary or critique. We are trying to get more engagement, critical thinking and outreach.
I don’t really use the communities very much (the Cytometry Community has been the most useful so far) but I’d definitely contribute to that category on Science on G+.
My overall feeling is that there’s so much excellent science being done, where really elegant approaches are being taken, and truly subtle and wonderful things are being discovered that it rubs me the wrong way when the work is so thoroughly misrepresented in attention-grabbing headlines and posts. I think truth-checking these headlines is a service to those of us actually doing science, as well as to those who follow these stories because they are interested in science.
Ji
Damn I love a smart girl
Pray god can intervien trust the one who made us kendg
Why do polyps and other tissues like polyps have like almost a magnet set for cancer??
I’m not sure what you mean Andrew Russell Cancer can be in many tissues that aren’t like polyps. If anything, I’d say glandular tissue, like breast, prostate, ovaries, etc. is more predisposed for cancer. If you can elaborate, I’ll try to answer.
I was trying to decipher the question, too. Polyps are proliferating tissue so perhaps more prone to switching from benign to cancerous? I’ll have to look them up.
Adhesion molecules
Oncogens
Andrew Russell From WebMD
“Colorectal cancer usually begins as a polyp. The word “polyp” is a nonspecific term to describe a growth on the inner surface of the colon. Polyps are often non-cancerous growths but some can develop into cancer.
The two most common types of polyps found in the colon and rectum include:
Hyperplastic and inflammatory polyps. Usually these polyps do not carry a risk of developing into cancer. However, large hyperplastic polyps, especially on the right side of the colon, are of concern and should be completely removed.
Adenomas or adenomatous polyps. Polyps, which, if left alone, could turn into colon cancer. These are considered pre-cancerous.”
Several years ago I saw a great paper presented at a colon cancer symposium where patients were followed and their polyps were removed and genetically analyzed. It was really interesting to see that they would start as hyperproliferative (upregulated EGFR I think), but not cancerous (that is, genetically stable), and then they would eventually go through a phase (over several years in the same patient) where they would accumulate other mutations, including deletion of checkpoint control and eventually p53 deletions. At that point the polyps would become cancerous, but it took the accrual of several mutations. Eventually the polyp/tumor “population”would converge, in that it would be taken over by a population of single clonal origin. It would eventually diverge at that point, as most tumors do.
So yes, polyps.
Thanks, Scott Sneddon , for the clear explanation. It certainly makes sense. Another gateway to cancer is prolonged inflammation, which also triggers proliferation.
Rajini Rao the role of inflammation in cancer has been a long-term research interest of mine, going back to the days when people thought I was crazy for looking at it. So glad to see that the role is better understood now.
The relationship between polyposis becoming cancer and GIRD and acid reflux was what really made the connection for me.
I was indeed thinking of GI inflammation, ulcers (H. pylori infection) and the link to gastric cancer when I made that comment. We are looking at ion transporters that alter lumenal pH in the endosomal pathway and increase surface expression of EGFR and other proteins to promote proliferation in glioblastomas. Just putting together the data for a paper now.
I was working on a project involving tumor senescence and immune response which has an indirect connection to inflammation. I’m need wrap things up at work or I’d elaborate more. Oh, and I need more tea.
Oh, it’s well past tea time for me. Sipping something red that activates my ADH 🙂
I still have my drive home before yeast activated beverages.
Rajini Rao please share the paper when you’re able. We (Sharp Edge Labs, Inc. , and our lead-biologist Qi Yan ) have been quite involved in developing tools for measuring endosomal pH and we’d be very interested to learn more about the work. It’s a fascinating area.
Scott Sneddon , I will be delighted. In a paper that should be out hopefully soon, we used dual FITC/Alexa Fluor-labeled Transferrin to measure endosomal pH. We work with endosomal Na+/H+ exchangers (NHE6/9) that alter the lumen pH and trafficking.
I guess I should work up a post on paraCEST agents and pH imaging.
E cadherin staining looks really cool, i tried it once for rwpe1 prostate epithelial cells and didn’t work
Jay Wagh , E-cadherin staining works well for us. Could be your antibody. Or, if the cancer cells have undergone EMT, E-cadherin levels go down (as in MDA-MB-231 cells, a metastatic breast cancer line).