by Playfuls Staff |
12th April 2007
A new study conducted at Howard Hughes Medical Institute proves that a concerted effort to “deactivate” 4 genes with abnormal activity could stop the proliferation of cancerous cells inside the body.[more]
Gene activation and cancerous cells spreading are two important pillars in understanding the mechanics and the dynamics of cancer. Since cancer is not a single disease (it is actually a class of diseases, each with its particular manifestations and causes) these two pillars are vital because they are involved in most forms cancers.
Cancer appears when an uncontrolled division of cells occurs and when those abnormal cells get the ability to spread, either by direct growth into adjacent tissue through invasion, or by implantation into distant sites by metastasis (where cancer cells are transported through the bloodstream or lymphatic system). Cancer may affect people at all ages, but risk tends to increase with age. It is one of the principal causes of death in developed countries.
Cell division or cell proliferation is a physiological process that occurs in almost all tissues and under many circumstances. Normally the balance between proliferation and programmed cell death is tightly regulated to ensure the integrity of organs and tissues. Mutations in DNA that lead to cancer disrupt these orderly processes.
The uncontrolled and often rapid proliferation of cells can lead to either a benign tumor or a malignant tumor (cancer). Benign tumors do not spread to other parts of the body or invade other tissues, and they are rarely a threat to life unless they extrinsically compress vital structures. Malignant tumors can invade other organs, spread to distant locations (metastasize) and become life-threatening.
In order to spread, some cells from the primary cancer must break away, travel to another part of the body and start growing there. Cancer cells do not stick together as well as normal cells. They also may produce substances that stimulate them to move.
There are three main ways a cancer spreads: local spread (the cancer grows directly into nearby body tissues), through the blood circulation (in order to spread, the cancer cell must first become detached from the primary tumor; it must then burrow through the wall of a blood vessel to get into the blood stream. This is a complicated journey though; most cancer cells do not survive it) or through the lymphatic system (this process is similar to the blood transportation).
Why exactly a cancer spreads the way it does is not yet fully understood (for example, some types of cancer behave in an unusual manner- prostate cancer moves to the bones), but it is believed that gene activation (or, generally speaking, gene regulation) plays an important part. Estimates are that only one in ten genes is active in a given cell at a given time, so these questions concerning gene activation are biologically significant.
Previous studies involving human tumor cells implanted in mice have shown that the abnormal activation of four genes drives the spread of breast cancer to the lungs. The new studies conducted by Howard Hughes Medical Institute researchers revealed that the aberrant genes work together to promote the growth of primary breast tumors. Cooperation among the four genes also enables cancerous cells to escape into the bloodstream and penetrate through blood vessels into lung tissues.
Although shutting off these genes individually can slow cancer growth and metastasis, the researchers found that turning off all four together had a far more dramatic effect on halting cancer growth and metastasis. Metastasis occurs when cells from a primary tumor break off and invade another organ. It is the deadliest transformation that a cancer can undergo, and therefore researchers have been looking for specific genes that propel metastasis.
The HHMI researchers discovered that two key proteins produced by genes inside breast cancer tumors can be inhibited using drugs that are already on the market, contributing to their decreased growth and proliferation. Researchers say that metastasis of breast cancer are already attacked with a combination of cetuximab (trade name Erbitux) and celecoxib (Celebrex).
The research team, led by Howard Hughes Medical Institute investigator Joan Massagué at the Memorial Sloan-Kettering Cancer Center, published its findings in articles in the April 12, 2007, issue of the journal Nature and in the online early edition of the Proceedings of the National Academy of Sciences on April 9, 2007.
Massagué had previously discovered that the spreading of breast cancer tumor cells to the lungs involves at least 18 genes with abnormal activity. By combining in vivo selection of human metastatic cells, transcriptomic profiling, and functional testing, his team had identified genes that selectively mediate breast cancer metastasis to either bone or lung. In their research, gene transfer and gene-silencing techniques had been used to demonstrate the contribution of these genes to the metastasis process. Some of these genes were found to serve dual functions, providing growth advantages both in the primary tumor and in the lung (but not the bone) microenvironment. Others were found to contribute to aggressive growth selectively in either the lung or the bone. Many encode extracellular proteins and are of previously unknown relevance to cancer metastasis.
In the more recent study published in Nature, Joan Massagué and colleagues from Hospital Clinic de Barcelona focused on 4 of these genes with abnormal activity. T hese genes, which code for proteins called epiregulin, COX2, and matrix metalloproteinases 1 and 2, were already known to help regulate growth and remodeling of blood vessels, said Massagué.
“Our understanding of the genes for these four proteins and their behavior in metastasis led us to hypothesize that they might be cooperating with each other in a way that would give an advantage to cells in the primary tumor,” said Massagué. “These same genes, we believed, might also be used for some related purpose in the target organ, the lung.”
“We found that depriving aggressive metastatic tumor cells of these genes decreased both their ability to grow large aggressive tumors in the mouse mammary gland and also the ability to release cells from these tumors into the circulation,” said Massagué. “The remarkable thing was that while silencing these genes individually was effective, silencing the quartet nearly completely eliminated tumor growth and spread.”
To test their idea researchers first “deactivated” the 4 types of genes in various combinations, using a method called RNA interference. RNA interference (also called "RNA-mediated interference", abbreviated RNAi) is a mechanism for RNA-guided regulation of gene expression in which double-stranded ribonucleic acid inhibits the expression of genes with complementary nucleotide sequences. Conserved in most eukaryotic organisms, the RNAi pathway is thought to have evolved as a form of innate immunity against viruses and also plays a major role in regulating development and genome maintenance.
Microscopic analysis proved that the formation of blood vessels typically seen inside the tumors- after inhibiting the 4 genes- was greatly reduced and that the vessels that did form allowed fewer cancer cells to escape into circulation.
“These findings provide a beautiful explanation for how the genes that we identified in breast cancer patients as being associated with lung metastasis manipulate blood vessels to give them an advantage both in the primary tumors and in the lung,” he said.
Referring to the two drugs used in clinical tests (Cetuximab- an antibody that blocks the action of epiregulin and is used to treat advanced colorectal cancer, and Celecoxib- an inhibitor of COX2 that is used as an anti-inflammatory, and is being tested in clinical trials against many types of cancer) Massagué said that “We found that the combination of these two inhibitory drugs was effective, even though the drugs individually were not very effective. This really nailed the case that if we can inactivate these genes in concert, it will affect metastasis.”
Although there is still a long road ahead before the revolutionary treatment becomes a reality, Massagué said that “there are already treatments to diminish the chance of metastasis in breast cancer, so such trials would have to be designed very carefully to understand how and whether the new drug combination would be of additional benefit.”
In the article published in the Proceedings of the National Academy of Sciences, Massagué and his colleagues explored how the entire group of 18 genes, called the `lung metastasis gene-expression signature' (LMS) influenced both breast tumor growth and spread to the lungs. Co-authors on the paper were from the University of Chicago, The Netherlands Cancer Institute, Veridex L.L.C., The Cleveland Clinic and the Erasmus Medical Center in The Netherlands.
“There has been an undeniable link between tumor size and growth and metastatic risk, but the molecules and mechanisms underlying this link have remained unresolved,” said Massagué. “The hypothesis we wanted to test was that these signature genes play a role in both primary tumor growth and metastasis to the lung.”
Massagué and his colleagues are now exploring the possibility of shutting down even more LMS genes, to see how they can effectively stop the spreading of breast cancer to the lungs. They also hope to discover whether the aforementioned genes are also involved in the metastasis sent to the brain, the bones or the colon cancer.
(the entire study can be found
here)
