A cancer's surprise origins caught in action

First demonstration of a cancer arising from a single cell

Source:Boston Children's Hospital

Summary : Researchers have, for the first time, visualized the origins of cancer from the first affected cell and watched its spread in a live animal. Their work could change the way scientists understand melanoma and other cancers and could lead to new, early treatments before the cancer has taken hold.

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Zebrafish, Danio rerio (stock image).

Credit: © mikhailg / Fotolia

Researchers at Boston Children's Hospital have, for the first time, visualized the origins of cancer from the first affected cell and watched its spread in a live animal. Their work, published in the January 29th issue ofScience, could change the way scientists understand melanoma and other cancers and could lead to new, early treatments before the cancer has taken hold.

"An important mystery has been why some cells in the body already have mutations seen in cancer, but do not yet fully behave like the cancer," says the paper's first author, Charles Kaufman, MD, PhD, a postdoctoral fellow in the Zon Laboratory at Boston Children's Hospital. "We found that the beginning of cancer occurs after activation of an oncogene or loss of a tumor suppressor, and involves a change that takes a single cell back to a stem cell state."

That change, Kaufman and colleagues found, involves a set of genes that could be targeted to stop cancer from ever starting.

The study imaged live zebrafish over time to track the development of melanoma.

All the fish had the human cancer mutation BRAFV600E -- found in most benign moles -- and had also lost the tumor suppressor gene p53.

Kaufman and colleagues engineered the fish so that individual cells would light up in fluorescent green if a gene called crestin was turned on -- a "beacon" indicating activation of a genetic program characteristic of stem cells. This program normally shuts off after embryonic development, but occasionally -- for reasons not yet known -- crestin and other genes in the program turn back on in certain cells.

"Every so often we would see a green spot on a fish," says Leonard Zon, MD, director of the Stem Cell Research Program at Boston Children's and senior investigator on the study. "When we followed them, they became tumors 100 percent of the time."

The cell that caused melanoma

When Kaufman, Zon and colleagues looked to see what was different about these early cancer cells, they found that crestin and the other activated genes are the same ones turned on during zebrafish embryonic development -- specifically, in the stem cells that give rise to the pigment cells known as melanocytes, within a structure called the neural crest.

"What's cool about this group of genes is that they also get turned on in human melanoma," says Zon, who is also a member of the Harvard Stem Cell Institute and a Howard Hughes Medical Institute investigator. "It's a change in cell fate, back to neural crest status."

Finding these cancer-originating cells was tedious. Wearing goggles and using a microscope with a fluorescent filter, Kaufman examined the fish as they swam around, shooting video with his iPhone. Scanning 50 fish could take two to three hours. In 30 fish, Kaufman spotted a small cluster of green-glowing cells about the size of the head of a Sharpie marker -- and in all 30 cases, these grew into melanomas. In two cases, he was able to see a single green-glowing cell and watch it divide and ultimately become a tumor mass.

"It's estimated that only one in tens or hundreds of millions of cells in a mole eventually become a melanoma," says Kaufman, who is also an instructor at Dana-Farber Cancer Institute. "Because we can also efficiently breed many fish, we can look for these very rare events. The rarity is very similar in both humans and fish, which suggests that the underlying process of melanoma formation is probably much the same in humans."

Zon and Kaufman believe that their findings could lead to a new genetic test for suspicious moles to see whether the cells are behaving like neural crest cells, indicating that the stem-cell program has been turned on. They are also investigating the regulatory elements that turn on the genetic program (known as super-enhancers). These DNA elements have epigenetic functions that are similar in zebrafish and human melanoma and could potentially be targeted with drugs to stop a mole from becoming cancerous.

A paradigm shift for cancer?

Zon and Kaufman posit a new model for cancer formation, going back to a decades-old concept of "field cancerization." They propose that normal tissue becomes primed for cancer when oncogenes are activated and tumor suppressor genes are silenced or lost, but that cancer develops only when a cell in the tissue reverts to a more primitive, embryonic state and starts dividing. They believe this model may apply to most if not all cancers, not just melanoma.

The study was supported by the National Institutes of Health (R01 CA103846), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (K08 AR061071), the Ellison Foundation, the Melanoma Research Alliance, the V Foundation and the Howard Hughes Medical Institute. Leonard Zon is a founder and stockholder of Fate, Inc. and Scholar Rock.

Co-authors on the study were Christian Mosimann (University of Zürich), Zi Peng Fan (Whitehead Institute and MIT), Justin Tan (Genome Institute of Singapore), Richard White (Memorial Sloan Kettering Cancer Center), Dominick Matos (Massachusetts General Hospital), Ann-Christin Puller (University Medical Center Hamburg-Eppendorf, Germany), Eric Liao (Harvard Stem Cell Institute and MGH) Richard Young (Whitehead Institute and MIT), and, at Boston Children's Hospital, Song Yang, Andrew Thomas, Julien Ablain, Rachel Fogley, Ellen van Rooijen, Elliott Hagedorn, Christie Ciarlo and Cristina Santoriello.

Story Source:

The above post is reprinted from materials provided by Boston Children's Hospital. Note: Materials may be edited for content and length.

Journal Reference:

C. K. Kaufman, C. Mosimann, Z. P. Fan, S. Yang, A. J. Thomas, J. Ablain, J. L. Tan, R. D. Fogley, E. van Rooijen, E. J. Hagedorn, C. Ciarlo, R. M. White, D. A. Matos, A.-C. Puller, C. Santoriello, E. C. Liao, R. A. Young, L. I. Zon. A zebrafish melanoma model reveals emergence of neural crest identity during melanoma initiation.Science, 2016; 351 (6272): aad2197 DOI:10.1126/science.aad2197

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Cancer riddle solved: How cancer cells form tumors

Summary : Using real-time recording of cellular movement, biologists have discovered how tumors form. Cancer cells extend cables and grab other cells. As little as five percent cancerous cells are needed for tumor formation, they suggest, stating that their findings could lead to more precise cancer testing.

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Cancerous cells "recruit" cells into tumors by extending a bridge of sorts and reeling in both healthy and cancerous cells. The UI researchers documented the phenomenon for the first time in real time and in 3-D.

Credit: David Soll laboratory, University of Iowa

Cancer is a mysterious disease for many reasons. Chief among the unknowns are how and why tumors form.

Two University of Iowa studies offer key insights by recording in real time, and in 3-D, the movements of cancerous human breast tissue cells. It's believed to be the first time cancer cells' motion and accretion into tumors has been continuously tracked.

The team discovered that cancerous cells actively recruit healthy cells into tumors by extending a cable of sorts to grab their neighbors--both cancerous and healthy--and reel them in. Moreover, the Iowa researchers report that as little as five percent of cancerous cells are needed to form the tumors, a ratio that heretofore had been unknown.

"It's not like things sticking to each other," said David Soll, biology professor at the UI and corresponding author on the paper, published in the American Journal of Cancer Research. "It's that these cells go out and actively recruit. It's complicated stuff, and it's not passive. No one had a clue that there were specialized cells in this process, and that it's a small number that pulls all the rest in."

The findings could lead to a more precise identification of tumorigenic cells (those that form tumors) and testing which antibodies would be best equipped to eliminate them. Soll's Monoclonal Antibody Research Institute and the Developmental Studies Hybridoma Bank, created by the National Institutes of Health as a national resource, directed by Soll and housed at the UI, together contain one of the world's largest collections of antibodies that could be used for the anti-cancer testing, based on the new findings.

In a paper published last spring in the journal PLOS One, Soll's team showed that only cancerous cells (from a variety of cancers, including lung, skin, and aggressive brain tumors known as glioblastomas) engaged in tumor formation by actively soliciting other cells. Like evil-minded envoys, individual cancer cells extend themselves outward from the original cluster, probing for other cells in the area, the researchers observed. Once it detects one, the extended cell latches on and pulls it in, forming a larger mass. The activity continues, the cancerous extensions drawing in more and more cells--including healthy cells--as the tumor enlarges.

"There's nothing but tumorigenic cells in the bridge (between cells)," Soll said, "and that's the discovery. The tumorigenic cells know what they're doing. They make tumors."

The question is how these cells know what to do. Soll hypothesizes they're reaching back to a primitive past, when these cells were programmed to form embryos. If true, perhaps the cancerous cells--masquerading as embryo-forming cells--recruit other cells to make tissue that then forms the layered, self-sustaining architecture needed for a tumor to form and thrive.

Think of a Death Star that's built up enough defenses to ward off repeated attacks. Or, less figuratively, how bacteria can conspire to create an impenetrable film on surfaces, from orthopedic implants to catheters.

"There must be a reason," Soll said. "You might want one big tumor capable of producing the tissue it needs to form a micro-environment. It's as if it's building its own defenses against the body's efforts to defeat them."

In the AJCR paper, the researchers compared the actions of human breast tissue cells (MoVi-10') to a weakly tumorigenic, parental breast cancer cell line (MCF-7). First, they found that over a 50-hour period, MoVi-10'-only cells grew more in density, primarily by joining together, than did MCF-7.

Also, in all instances, regardless of the ratio of MCF-7 to MoVi-10' cells in the cluster, only MoVi-10' cells reached out and drew in other cells--including healthy cells--to the growing mass.

"The results here extend our original observation that tumorigenic cell lines and fresh tumor cells possess the unique capacity to undergo coalescence through the active formation of cellular cables," the authors write.

The finding lends more weight to the idea that tumors are created concurrently, in multiple locations, by individual clusters of cells that employ the cancer-cell cables to draw in more cells and enlarge themselves. Some have argued that tumors come about more by cellular changes within the masses, known as the "cancer stem cell theory."

Soll's team also discovered that the Mo-Vi10' cells move at 92 microns per hour, about twice the speed of healthy cells. That's important because it helps scientists better understand how quickly tumors can be created.

Story Source:

The above post is reprinted from materials provided by University of Iowa. The original item was written by Richard C. Lewis. Note: Materials may be edited for content and length.

Journal Reference:

Joseph Ambrose, Michelle Livitz, Deborah Wessels, Spencer Kuhl, Daniel F Lusche, Amanda Scherer, Edward Voss, David R Soll.Mediated coalescence: a possible mechanism for tumor cellular heterogeneity. Am J Cancer Res, January 2016

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