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Cancer’s First Step

A single mutant cell breaks free of its neighbors in the early stages of cancer development.

By | February 8, 2012

image: Cancer’s First Step Epithelial cells Wikimedia Commons, John Schmidt

Epithelial cellsWIKIMEDIA COMMONS, JOHN SCHMIDT

Normal, healthy tissues regularly suppress the growth of tumors, preventing cancerous cells from proliferating and metastasizing. Yet how this process happens on a molecular level has largely remained a mystery. Now researchers have presented one model of how the local environment regulates and prevents the expansion of a single mutant cell into a tumor.

The finding, published this week in Nature, confirms past studies that show cancer is not simply a product of the buildup of DNA mutations in a cell, but rather is dependent on the architecture of a cell’s local environment.

“It’s definitely an interesting phenomena,” says Douglas Brash, who studies skin cancer at Yale University and was not involved in the research. “This paper affirms that cancer is not a cell autonomous process; that the neighborhood really matters.”

Past experiments demonstrated that embryos can suppress tumors. In one classic study, for example, injection of a tumor-causing virus rapidly induced tumors in the wings of hatched chicks but not in 4-day-old chick embryos. But there have been few experiments examining the phenomenon on a molecular level in tissue culture.

Joan Brugge and Cheuk Leung at Harvard Medical School used a 3D cell culture of human mammary epithelial cells to examine what happens to a single oncogene-expressing cell in a tissue-like environment. The researchers used viral vectors to over-express oncogenes, which had been previously associated with epithelial cancer, one at a time in single cells in the 3D structure. Overexpression of Myc, a master transcription factor, or mutant activated AKT1, which perturbs cell checkpoints, did not result in the proliferation of the cell. “We found that majority of the oncogenes were unable to proliferate as single cells in the context of a normal, growth-arrested structure,” says Brugge.

But cells that overexpressed ERBB2—a cell receptor encoded by a gene that is amplified in 30 percent of breast tumors—moved into the center of the tissue culture, an open space called the lumen. There, freed from its normal neighbors, the single mutant cell began to proliferate.

Through additional experiments, the researchers found that ERBB2 expression affects extracellular matrix proteins, disrupting local cell-matrix attachments and allowing the cell to break free and move into the unrestricted space of the lumen. When the ERBB2 cell’s ability to move to the lumen was blocked, it remained next to neighboring cells and was no longer able to proliferate. They also found that simply by weakening cell-cell connections in the tissue, mutants expressing other oncogenes that were previously benign, including activated AKT1, were able to move into the lumen and proliferate. “The geography of a mutant cell’s neighbors is affecting whether the mutant cell moves to a different part of the tissue,” says Brash.

Next, Brugge plans to investigate how mature neighboring cells prevent single mutated cells from proliferating and if other factors in the environment, such as immune cells, influence the fate of the mutated cell. “We want to understand the nature of the suppressive effect of normal mature structures,” she says.

C. Leung et al., “Outgrowth of single oncogene-expressing cells from suppressive epithelial environments,” Nature, doi:10.1038/nature10826, 2012.

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Avatar of: Kay_U

Kay_U

Posts: 9

February 9, 2012

How can this work (on cell culture models) be accepted in Nature as a breakthrough? It was already shown several times over decades that the microenvironment influences a tumorigenic phenotype of cells. This includes the mammary epithelial niche. It has also been shown that oncogene-expressing cells modulate the proliferative capacity of adjacent normal cells that can adapt a tumorigenic phenotype. Just have a look at these two papers below where these phenomena were described in IN VIVO models. So, tell me, what is really new and paradigm shifting in that Nature paper? That this study was done at Harvard, is that it? Re-inventing the wheel?

Booth et al. (Feb. 2011) The normal mammary microenvironment suppresses the tumorigenic
phenotype of mouse mammary tumor virus-neu-transformed mammary tumor
cells. Oncogene  PMID:20890308

Kisseberth and Sandgreen (2004) Polyclonal development of mouse mammary preneoplastic nodules. Cancer Research PMID: 14871812   
"... suggesting that hyperplasia formation can be the result of non-cell
autonomous local tissue microenvironmental influences on groups of
cells, rather than clonal progression of a single initiated cell."

Avatar of: juliosc

juliosc

Posts: 2

February 9, 2012

Very interesting, the comments...

Avatar of: Dr. Jonas Moses

Dr. Jonas Moses

Posts: 26

February 9, 2012

As "Kay_U" observes, this is not new work. Beatrice Mintz was doing this, back in the 1960's. Also, see:

1) Folberg R, Arbieva Z, Moses J, Hayee A, Sandal T, Kadkol S, Lin AY, Valyi-Nagy K, Setty S, Leach L, Chévez-Barrios P, Larsen P, Majumdar D, Pe’er J and Maniotis AJ:
Vasculogenic Mimicry Patterns Dampen the Invasive Uveal Melanoma Cell Genotype
and Phenotype. Amer. J. Pathology (Oct 2006)
2) Maniotis A, Valyi-Nagy K, Karavitis J, Moses J et al.: Chromatin organization measured by AluI
restriction enzyme changes with malignancy and is regulated by the
Extracellular Matrix and the cytoskeleton. Amer. J. Pathol. (Apr 2005)
3) Gordon R, Karavitis J, Moses J, Valyi-Nagy K, and Maniotis AJ:
Differentiation waves versus positional information of morphogen gradients:
which is cause and effect? Information Processing in Cells and Tissues,
Morphomechanics of the Embryo and Genome, Lausanne, Switzerland , 2003.
4) Maniotis AJ, Karavitis J, Garcia C, Boddipali V, Moses J, et al.: “Intrinsic
differences in sequestration of DNA and proteins reveal how genomes within
normal and cancer cells are differentially organized…â€쳌 - ASIP 2004
5) Maniotis A, Moses J and Gordon R: “Role of interchromosomal sequences in genomic organization and signal processingâ€쳌 - ASIP 2004

6)Oh...I could go on, but...what's the point? Evidently Nature has decided to ignore the work of others, apparently in the absence of anything novel?

Respectfully,

Dr. Jonas Moses

Yet another of the score of cancer researchers who have reported these findings, over the years. Why did not of our publications end up in Nature, as "breakthrough research?" Hmm...

Avatar of: divinehealth

divinehealth

Posts: 1

February 10, 2012

I've heard that Glutathione is the only detoxerfier intracellularly being the only endogeneous antioxidant, and that it address the integrity of the cell within the cell mebraine. I've heard it is a main factor in dealing with inflammation at the beginning stage where cancer starts.

Appreciate any response on this.

Thank You!

Avatar of: Guest

Anonymous

February 12, 2012

Showing at the molecular
level how a single mutant cell breaks free from tissue constraint seems to be a
whole different kind of things than describing an observation of tissue
influences.  It looks pretty cool.

Avatar of: Guest

Anonymous

February 12, 2012

Showing at the molecular level how a single mutant cell breaks free from tissue constraint seems to be a whole different kind of things than describing an observation of tissue influences. It looks pretty cool.

Avatar of: Narsimha Valmiki

Narsimha Valmiki

Posts: 1457

February 15, 2012

hh

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