Turning Cancer Cells Back To Normal Than Killing Them

Using the latest gene sequencing tools to examine so-called epigenetic influences on the DNA makeup of colon cancer, a Johns Hopkins team says its results suggest cancer treatment might eventually be more tolerable and successful if therapies could focus on helping cancer cells get back to normal in addition to strategies for killing them.

In a report published June 26 in Nature Genetics, the investigators focused on a particular epigenetic biochemical signature known as methylation, which silences genes. Although not part of a gene's central DNA sequence, it is copied when a cell divides, perpetuating its activity.

By comparing the epigenomes of eight human tissue samples -- three from noncancerous colon tissue, three from colon tumors and two from polyps (early-stage colon cancer) -- the team found that in all the colon tumors the defining characteristic was a universally "chaotic" pattern of methylation. In noncancerous tissue, they found methylation occurring in well-defined places, either as small "islands" of methylation or huge methylated "blocks" that collectively encompassed at least a third of the genome.

"In the cancer tissue we saw that the once-precise boundaries of the islands had shifted or disappeared altogether, and the start and end points of the sites appeared unregulated," says Andrew Feinberg, M.D., M.P.H., professor of molecular medicine and director of the Center for Epigenetics at the Johns Hopkins University School of Medicine's Institute for Basic Biomedical Sciences. "We also saw a loss of methylation, presumably increasing the randomness of gene function within them."

"What seems to define cancer at the epigenetic level may be simple and common, namely chaos that seems to be universal," he adds.

The researchers noted that cells in their normal colon tissue samples stayed methylated at around the 80 percent level for large (and previously unexamined) blocks of the epigenome. By comparison, cells from colon tumors comprising those same huge blocks had no such stability and were much more variable in terms of methylation levels.

Feinberg says the findings could mean that current efforts to simply identify methylation markers as signals of cancer or targets of cancer therapy may be misleading or worse, won't do the job at all. An alternative would be a new method that detects epigenetic chaos universally in any cancer epigenome.

The team designed a custom test to compare about 20 noncancerous tissue samples to 20 samples from each of a variety of tumors as they investigated thousands of methylation sites for colon, breast, lung, kidney and thyroid cancers. They found that, here again, methylation was well-regulated in the normal tissues, almost always occurring within a limited range of variability. However, in the very same specific places of the epigenome characterized by chaos in colon cancer cells, all the other cancerous tissues examined by the team showed distinctly variable and "chaotic" levels of methylation variation.

"Maybe the big lesson learned from our observation of this universal chaos is that we may need to think not so much about just killing cancer cells, but also about ways of helping cancer cells figure out how to be what they're supposed to be, and re-educate them so they can stay truer to their normal identities," Feinberg says.

From the cancer cells' "perspective," Feinberg says, the chaos is helpful, endowing tumors with the ability to turn genes on and off in an uncontrolled way, and making cancer cells adaptable enough to live in all different kinds of environments, spread and thrive in foreign tissue.

"The regions of epigenetic chaos where methylation appears wildly variable in at least five different common cancers are -- not so coincidentally -- the very same as those that during normal development are important in controlling cell differentiation, or what particular cells are supposed to be, like normal colon cells," Feinberg says.

"The same epigenetic malleability that permits human cells with the same DNA to become different tissue types during development also confers vulnerability," adds Rafael Irizarry, Ph.D., a professor of biostatistics in the Johns Hopkins University Bloomberg School of Public Health, who with Feinberg, led this study. "The epigenome has these regions where change is easy in order for some cells to become kidney and others, brain and spleen, for example, but that very vulnerability to change may ultimately lead to cancer. Targeting those regions might help the cells become more normal."

Because the new study also identifies regions of the genome that appear to control this epigenetic chaos, Feinberg and his team say it may prove potentially fruitful in revealing new targets for cancer therapy or prevention.

This study was supported by the National Institutes of Health.

In addition to Feinberg and Irizarry, other authors from Johns Hopkins are Kasper Daniel Hansen, Winston Timp, Hector Corrada Bravo, Sarven Sabunciyan, Benjamin Langmead, Oliver G. McDonald, Bo Wen, Yun Liu and Eirikur Briem. Additional authors are Hao Wu of Emory University, and Dinh Diep and Kun Zhang of the University of California, San Diego.

Kasper Daniel Hansen, Winston Timp, H├ęctor Corrada Bravo, Sarven Sabunciyan, Benjamin Langmead, Oliver G McDonald, Bo Wen, Hao Wu, Yun Liu, Dinh Diep, Eirikur Briem, Kun Zhang, Rafael A Irizarry, Andrew P Feinberg. Increased methylation variation in epigenetic domains across cancer types. Nature Genetics, 2011; DOI: 10.1038/ng.865.

Source: Johns Hopkins Medical Institutions, via EurekAlert.

5 comments:

Arnold Glazier, MD said...

The Hopkins data are consistent with an enormous amount of scientific evidence that cancer is an unpredictable, stochastic evolutionary process characterized by the potential for nearly unlimited genetic and epigenetic diversity.

The data from large-scale gene sequencing studies are very clear. To quote, Dr. Bert Vogelstein from John Hopkins, “Each cancer in each patient is different from any other cancer in any other patient. That’s mind boggling and challenging.” Furthermore, as discussed by Dr. Lawrence Loeb, in a recent Nature Reviews Cancer article, each cancer cell in a patient is also generally different with thousands of unique genetic alterations. The number of different genetic types of cancer cells that could evolve is estimated to be at least 10 to 68,000 power. That’s the number 1 followed by 68,000 zeroes. The extreme diversity and randomness of epigenetic alterations further compounds the chaos and complexity of cancer. http://www.curecancerproject.org/beta/media/number_types_cancer_cells.pdf

Although the genetic and epigenetic complexity of cancer is nearly unlimited, tumor cell evolution is constrained. A malignant cell will result, if and only if, the genetic and epigenetic alterations cause normal cellular machinery to carry out the processes of proliferation and invasiveness.

All malignant cells use normal cellular machinery to carry our proliferation and invasiveness. An exception has never been reported, and we can be confident that a malignant cell that violates this rule will never evolve. There is not sufficient time for the evolution of extensive new functional machinery. The complexity of the requisite interdependent biochemical processes is too great, the joint probabilities are too small, and the human life span far too short for a tumor cell to evolve extensive new functional cellular machinery.

The constraints to tumor cell evolution impart a simplicity to cancer: The nearly unlimited genetic and epigenetic complexity of the disease becomes irrelevant. What matters is the normal cellular machinery that could carry out malignant behavior. This normal cellular machinery is fixed, finite, encoded in the normal human genome, and is essentially the same for all types of cancer.

For example, MMP-2 and MMP-14 are involved in invasiveness. The pattern or combination of MMP-2 and MMP-14 (proteins and/or mRNAs) was found to be overexpressed in 32 out of 32 breast cancers, 14 out of 14 lung cancers, 26 out of 26 thyroid cancers, 15 out of 15 glioblastomas, 18 out of 18 prostate cancers metastatic to bone, 102 out of 102 bladder cancers, 10 out of 10 melanomas, 24 out of 24 colon cancers, 18 out of 18 head and neck cancers, 17 out of 18 ovarian cancers, 23 out of 24 oral squamous cell carcinomas, and 23 out of 27 pancreatic cancers. Many other normal proteins and patterns of biomolecules related to invasiveness are similarly overexpressed in a wide range of cancers.
For details see Table 3: http://www.curecancerproject.org/beta/media/Overview

For a detailed discussion of tumor cell evolution and the requirements for cure or control of cancer, please read or listen to the three-part New Cancer Mentality interview series, Cancer in the Post-Genomic Era: Where do we go from here? What will it take to prevent, cure, or control cancer? The interviews are at http://newcancermentality.blogspot.com/ a transcript can be downloaded at http://www.curecancerproject.org/beta/media/transcript.pdf
An Overview on the Requirement for the Cure of Cancer is at:
http://www.curecancerproject.org/beta/media/Overview on Requirements.pdf
Thank you. Arnold Glazier, M.D.

John said...

Very extensive explanation and information...thanks Dr. Glazier.

Guantes De Latex said...

This is a good blog about health. I am really eager to read with this type of blogs.

Botiquin De Primeros Auxilios said...
This comment has been removed by a blog administrator.
Eating disorder said...

Gold medals aren't really made of gold. They're made of sweat, determination, and a hard-to-find alloy called guts.

Translate