Cancer and Immune Cells Merge

Mouse colon cancer cells can fuse with macrophages, leading to changes in tumor growth.

By | December 16, 2013

WIKIMEDIA, RAMAMacrophages are usually the body’s protectors, engulfing pathogens and cleaning up dead cells and debris. But in some cases, cancer cells fuse with these immune cells to possibly become even more harmful, according to a poster presented yesterday (December 15) at the American Society for Cell Biology Annual Meeting in New Orleans. The researchers demonstrated that macrophages and mouse colon cancer cells spontaneously fuse when cultured together and noted altered growth in the hybrid cells compared to ordinary cancer cells, prompting speculation that hybridization could spur cancer progression.

The methodology is rigorous,” said Alberto Mantovani, an immunologist at the University of Milan’s Humanitas Research Institute who was not involved in the study. But he added that the cells fused in culture, not within mice. “We need to know whether this is real in primary tumors,” he said.

“I think it’s interesting if it’s true,” said Zihai Li, a cancer immunologist at the Medical University of South Carolina who was also not involved in the study. However, he noted that it remains unclear how important cell fusions are in human cancers.

German biologist Otto Aichel first proposed that cancer cells and white blood cells such as macrophages could fuse in 1911, according to John Pawelek, a cancer biologist at the Yale School of Medicine who studies cell fusion. Aichel hypothesized that hybrid cells would have both the proliferative powers of cancer and the migratory properties of white blood cells. The qualities that allow white blood cells to spread throughout the body could help cancers to metastasize.

Research since Aichel’s time has given tantalizing hints that immune cells do fuse with cancer cells. Nevertheless, “people are still skeptical,” that the mergers take place, said the poster’s lead author Alain Silk, a postdoctoral cancer cell biologist at Oregon Health and Science University.

Silk and colleagues cultured mouse colon cancer cells alongside macrophages, equipping the cells with fluorescent markers to track whether the two cell types merged. Silk was surprised to see that a small proportion of cells did indeed fuse. “When I initially decided to do this I thought, ‘I’m going to disprove this idea,’” he said. Hybrid cells—made up of female cancer cells and male macrophages—also had elevated chromosome numbers and combinations of X and Y chromosomes that indicated fusion had occurred.

Silk soon noticed a difference between parental cancer cells and the hybrids: While the original cancer cells growing at high density tended to lose adhesion to the plastic of the culture dish and clump together, the hybrid cells continued to stick to the dish’s bottom even at high density. Ultimately, the researchers grew the cells in 70 distinct microenvironments and confirmed that hybridization led to altered adhesiveness in some situations. The hybrid cells expressed some genes from each parent, as well as some genes expressed by neither parent cell.

Next, Silk’s team exposed the hybrid cells and their parent cells to cytokines, cell-signaling molecules that modulate immune system activity. In the presence of some cytokines, the hybrid cells showed a growth advantage. Finally, Silk and colleagues injected the hybrid cells into mice. They formed tumors that grew faster than tumors grown from non-fused cancer cells.

Silk considers his research a proof of principle, rather than a specific discovery of how cancer progresses. “It definitely supports the idea that fusion can result in phenotypic changes to cancer cells that enhance their growth,” he said. Cells within tumors must evolve, often through genetic mutation, in order for disease to progress. Cell fusion could be another tool cancer cells use to change and gain an advantage

It’s less clear which phenotypes of fused cells, if any, will be relevant in human cancers. One study, published earlier this year by Pawelek and colleagues, indicated that bone marrow-derived cells and cancer cells had fused in a human melanoma patient. The patient had undergone a bone marrow transplant to treat a prior cancer, and the telltale sign of fusion was that tumor cells had the genetic background of both the patient and the bone marrow donor. But it is generally difficult to determine whether human tumor cells, which often have elevated chromosome counts regardless, are the products of cell fusion.

Still, the idea that fused macrophages and cancer cells could play a role in human cancer is compelling. For one thing, “macrophages have the inherent capacity for fusion, and tumors are chock full of macrophages,” Silk said. Cancer cells also have a tendency to merge with each other. Tumor-associated macrophages have already been shown to promote cancer by secreting signals that spur cancer progression, independent of any cell fusion events.

Silk says that he and colleagues are now studying the hybrid cells’ behavior in the mouse bloodstream to see if they show enhanced abilities to survive in the circulatory system, exit blood vessels, or establish themselves in foreign tissues—all qualities necessary for metastases to take hold in new areas of the body.

“We think there should be more attention paid to [cell fusion] as another potential way that tumor cell evolution can happen,” Silk said.

A.D. Silk et al., “Spontaneous fusion with macrophages alters cancer cell phenotypes,” American Society for Cell Biology Annual Meeting (poster), 2013.

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Avatar of: lazar3345

lazar3345

Posts: 3

December 17, 2013

This a “chutzpa” to claim in 2013 that “tumor cell and macrophage fusion” is a new phenomena. In PubMed alone there are >1800 publication on  this subject matter. Already in 19721 it was published by Gordon S and Chen Z “Macrophage-melanoma cell heterokaryons’ J Exp Med. 1971 O1;134(4):935-46.

December 17, 2013

Lazar is 100% correct.  This is hardly a new discovery. And John Pawelek knows this full well.  

Here's the problem in a nutshell:  biomedical politics.  I learned this the hard way in the early 1980's when I "discovered" a similar phenomenon in living mice that had been injected with cultured "model" syngeneic lymphoma cells.  I then found a publication in the literature describing an observation IN A REAL PATIENT who had undergone bone marrow transplant treatment for leukemia and the cancer that "recurred" was from the donor marrow.  Not proof that it was due to fusion, of course, but certainly a strong hypothesis worth testing.  Further literature-delving revealed well-controlled studies from other labs on the fusion phenomenon. There was no ambiguity in some of those studies, unlike my own preliminary work for which a fusion hypothesis was still just a hypothesis and other hypotheses, such as viral etiology, still needed to be explored as well -- although that too was a big "no-no" taboo topic at the time.

The problem was that the experimental cancer community did not want to hear about the possibility of cell fusion (or viral etiology). One of the authors of the leukemia-patient papers who worked at my institution was politically afraid to even talk about his own earlier work with me (or anyone else), except to tell me he suspected it was a widespread clinical phenomenon that nobody wanted to touch with a ten-foot pole.  A few years later, still in the 1980's but when I was no longer doing cancer research, I communicated with John Pawelek, not about my own work, but providing him with my extensive bibliographical list of prior published work on the topic. 

The good news from this article, I guess, is that the time is now finally ripe for the biomedical community to think about things with open minds and respect for "novel" ideas.  If true, this is a welcome change indeed. But the true pioneers in this field, many of them either retired or perhaps even deceased by now, should get the appropriate credit for their work.  This is really important.  And giving credit, however belatedly, where credit is due is also important.  

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Avatar of: Dr. Jonas Moses

Dr. Jonas Moses

Posts: 18

December 19, 2013

This entire article is abolute bunk.

In 2003, I performed hundreds of experiments identical to this, creating multi-nucleated cells and hybrids -- between HUMAN cell lines... my initial lines, provided by ATCC and other labs, were MUM2B, MCF10a (among other tumor types) and various normal fibroblast and endothelial cell lines. And yes,...by the way... I have retained thousands of photos, from 2003, and am delighted to share them with anyone who wishes copies.

How is it possible that the work dozens -- if not hundreds -- of others have been performing, for years, is now a new and (even worse!) significant finding? What is the secret sauce to creating these hybrids, you ask? PEG. This process is well-known. What the authors failed to mention is that their result is actually a controlled artifact. Anyone, with proper tools, can create these hybrids, with human cells. It no more points to such a thing occuring, in vivo, than reading a statement on the Internet means that it must be a fact!

Shame on the authors for trying to pawn this off as good science, and shame on The Scientist for bothering to publish it.

With all due respect,

Dr. Jonas Moses

 

 

Replied to a comment from Dr. Jonas Moses made on December 19, 2013

December 20, 2013

There are plenty of reports in the published literature, going back decades, of cancer cell fusion or likely/possible fusion, in both cultures and in vivo, that do NOT rely on PEG.  If this work involved PEG-induced fusion in vitro, then yeah it's bunk.  But prior work over the past forty-plus years was not dependent on PEG-induced fusion, and that prior work MUST be acknowledged-- even if the authors of the abstract have to go to the library and do a -- gasp! --manual literature search.  

Avatar of: ASilk

ASilk

Posts: 1

December 23, 2013

This comment is written by Alain Silk, primary author of the poster referenced in this article, and presenter of this work at the ASCB annual meeting in 2013.

I am writing in response to comments posted here in order to clarify the science and significance of this work. I would like to thank those who have commented for drawing attention to important aspects of my experiments that were not apparent from the article, and also those who have called for recognition of others who have worked extensively to establish the study of cell fusion in cancer.

Firstly, the fusion we have been investigating between cancer cells and primary macrophages is purely spontaneous and not induced by PEG or other artificial means. We observe that hybrids of these two parental cell types arise in unperturbed co-cultures, in standard tissue culture media, over the course of 2-4 days of growth in standard conditions. These cells continue to proliferate in culture and retain chromosomes from both parental cell types for an extended period of time. It is important to note that the hybrids I have been studying are formed exclusively in vitro, and while some might consider cell culture itself an “artificial means” of inducing fusion, there is an extensive literature describing the spontaneous fusion of haematopoietic-lineage cells (and specifically macrophages) and other cell types (including tumor cells) in vivo, suggesting that studying the outcomes of spontaneous fusion in vitro is a reasonable way to try and understand the outcomes of spontaneous fusion in vivo.

Of course, the idea that different cell types can spontaneously fuse is not new, and neither is the idea that this might contribute to cancer. Indeed, it was more than 100 years ago that fusion between different types of cells was first proposed to cause changes in cellular behaviors that could lead directly to cancer. Since that time, many scientists have contributed to this idea, and we each rightly want recognition for our relative contributions. However, my primary concern is not with being recognized for this work (although that would be nice) but to more firmly establish the potential for heterotypic fusion to impact cancer outcomes. Our most recent work in this field (discussed in this article in the Scientist) is currently unpublished, and at the time of publication we will attempt to recognize appropriate additional contributors. Please note that due to space constraints the poster presented at ASCB 2013 highlighted only a selected set of previous publications, and space constraints will also necessarily limit the number of previous contributors we will be able to recognize in a published manuscript. Upon publication, I welcome any and all comments related to our attribution of credit and also our scientific methodology, results and interpretations of our data.

Finally, an important point raised in the comments to this piece has been the general reticence among cancer biologists to accept the possibility that spontaneous fusion of cancer cells with other cell types might contribute in some situations to cancer progression. One reason for this may be that much previous work has been aimed at demonstrating that fusion can occur, while less attention has been paid to demonstrating how it might change cancer cell behaviors. What heterotypic fusion might do in cancer (if anything) has been, in many cases, speculation. Our work builds on many previous efforts indicating that spontaneous heterotypic fusion can occur in cancer, but I believe we are the first to comprehensively study the phenotypic outcomes of spontaneous fusion between two defined cell types and demonstrate the specific cellular phenotypic changes that can be induced in cancer cells following fusion. Our most significant finding is that spontaneous fusion of cancer cells with another specific and defined cell type (macrophages) is sufficient to provide cancer cell subclones with a selective growth advantage under certain conditions. To the best of my knowledge this has not been previously directly demonstrated – although it may have been suggested through correlation. Since the outgrowth of subclones with enhanced fitness under specific selective conditions is the essence of cancer progression, I believe that our work now provides the most direct and convincing demonstration to date that cell fusion can act as a mechanism of cancer progression. Anyone working at the interface of cell fusion and cancer biology should be encouraged to see mainstream recognition of the possible contribution of fusion to cancer progression, and I am glad that at this time there is greater acceptance for these ideas. Hopefully both the scientific press and scientific journals will feature more stories and publications on this topic, benefiting all scientific contributors to the field, and more importantly those patients who will ultimately benefit from our contributions.

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