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Cancer's Big Sleep: Senescence May Be Potential Target for Cancer Therapies

Jeanne Erdmann

Clinicians and scientists agree that the best cancer cell is a dead cancer cell. Yet, even with current treatments, some cancer cells seem to elude apoptosis, the programmed cell death process intrinsic to normal cells. Scientists say that the ability to escape apoptosis likely represents one of the hallmarks of every tumor cell. But what if, instead of being sent to a programmed death, cancer cells could be shuttled to senescence, a permanent "sleep" where the cells would remain alive but be rendered incapable of dividing?

The study of senescence has already provided critical insights into tumor biology. Now scientists are asking whether anticancer treatments should target senescence rather than apoptosis. Would this strategy permanently abate cancer, and could it effectively be applied in cancer therapies?

Countdown to Senescence

Just as people have a limited lifespan, cells age and die as well. This cellular aging mechanism is called replicative senescence. As cells age, their replication rate slows, and a number of subtle changes occur in the nucleus and in gene expression. These internal clocks eventually signal "old" (or senescent) cells to stop dividing and enter replicative senescence.

Although senescent cells take on a new shape—they flatten like a pancake—they remain alive and metabolically active. Scientists can subject laboratory cultures of senescent cells to radiation or oxidative stress, and the senescent cells will not become cancerous or undergo apoptosis.

Scientists say that replicative senescence helps maintain the proper number of cells in the body and also acts as a "lifeline" against cancer by limiting the number of times a cell divides. Until the early 1960s, though, scientists believed that laboratory cultures of normal and cancerous cells could divide indefinitely if culture conditions were perfect. Leonard Hayflick, Ph.D., proved them wrong. In his experiments, Hayflick noticed that, as weeks passed by, normal fibroblasts took longer and longer to cover the bottom of the flasks.

"In subsequent weeks, that time increased to the point where there were no mitoses at all and the cells just sat there," said Hayflick, professor of anatomy at the University of California at San Francisco School of Medicine. Even though Hayflick fed the fibroblasts for a year, the cells remained alive without dividing, he said. His 1961 paper proved that normal cells have a limited capacity to divide and that cancer cells are predominantly able to continue dividing indefinitely.

In recent years, scientists have reported that "young" cells—those not cultured for a long time—could reach a phenotype that resembles replicative senescence. That observation prompted scientists to wonder whether senescence could also play a role in the cell's response to stress. Today, some scientists view senescence as an endpoint reached by both cell division and as a response to stressors such as mitogenic stimulators, radiation, or chemotherapy. How, then, can scientists turn this biological cousin of apoptosis against cancerous cells?

The Cancer Neighborhood

Sending all cells in a tumor to senescence is probably unrealistic for many reasons, and it would be difficult to design a therapy that reached each cell, explains Clemens Schmitt, M.D., professor of hematology and tumor biology at the Max-Delbrück-Center for Molecular Medicine at Humbolt University Berlin in Germany. Because senescent cells remain alive and metabolically effective, scientists do not know whether these cells could influence cancerous or noncancerous cells in the surrounding tissue. Apoptotic cells are chopped up by proteases and eaten by macrophages. Senescent cells remain in tissue indefinitely. Scientists also do not know what effect the presence of senescent cancer cells might have.



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Clemens Schmitt

 

In addition, the cancer neighborhood includes cancerous and noncancerous cells in different stages of cell division, some of which might have already acquired mutations rendering them immune to senescence and apoptosis. In that scenario, the senescent cells could stimulate the mutated cancer cells to grow.

Schmitt sees additional problems. Although senescence is considered irreversible, what if epigenetic mechanisms produced in the tumor vicinity silenced genes needed to maintain senescence and signaled the cells to begin dividing again? "This is a condition in which it's rather unlikely to acquire normal mutations, but it's still not impossible," said Schmitt.

On the positive side, pre-clinical experiments in Schmitt's laboratory demonstrate that senescence can be helpful. In work published in Cell in 2002, Schmitt and his colleagues studied the response to the chemotherapy drug cyclophosphamide in a model of primary murine lymphoma. His transgenic mice are prone to B cell lymphomas that mimic some of the genetic features of human follicular lymphoma, said Schmitt. The mice overexpress the oncogene myc, which steers cells toward apoptosis in response to chemotherapy. One group of myc-transgenic mice was also engineered to favor senescence and block apoptosis. When these mice received cyclophosphamide, the scientists found the tumor cells had entered a senescent-like state comparable to that of Hayflick's replicative senescent fibroblasts. In these mice, survival times also lengthened.

In people, chemotherapy helps keep follicular lymphoma at bay for many years, said Schmitt. Could this long remission in humans reflect a tumor with a large number of senescent cells? Indeed, this observation led Schmitt to hypothesize that senescent cells in human follicular lymphoma could be the mechanism supporting long remissions.

For now, that's a hypothesis. The study of senescence has mostly taken place in laboratory cell cultures, so connecting the dots has been difficult.

One way to help fill in the blanks is with mathematical models, which can provide guideposts to help predict what would happen if the balance of tumor cells were tipped toward senescence. In a recent paper published in The Journal of Theoretical Biology, Amancio Carnero, Ph.D., and Juan Poyatos, Ph.D., mathematically described the outcomes as combinations of cells in different stages of replication battle for dominance during tumor progression. One model showed that a high population of senescent cells mixed with genetically unstable cells could tip the balance toward tumor growth, a situation that correlates with the exponential rise of cancer with age, said Poyatos, Ramon y Cajal fellow at the Spanish National Cancer Institute (CNIO) in Madrid. "This sort of approach is still lacking in cancer research," he wrote in an e-mail.

Targeting Senescence

Robert Arceci, M.D., Ph.D., of the Sidney Kimmel Comprehensive Cancer Center and the Johns Hopkins School of Medicine in Baltimore, is looking for small molecules that target senescence pathways. For example, if scientists could locate and identify cancer stem cells, small molecules could "therapeutically exhaust" these early cells by sending them into senescence.



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Robert Arceci

 

"We don't want to make people grow old prematurely, but we'd love to be able to make tumors grow old faster and then stop growing," said Arceci.

A recent study by Arceci found a mechanism that brought on premature aging in mice. He and his colleagues found that knocking out the proliferation associated SNF-like 2 gene (PASG) led to smaller than normal mouse pups. In a matter of months, their hair turned gray, and they suffered age-related problems such as osteoporosis and soon died of old age. Also, said Arceci, the cells in their organs underwent senescence unrelated to telomere shortening.

The PASG gene (pronounced "passage"), helps methlyation, which is a process of modifying chemical groups to maintain the structure of DNA. Cells need PASG to grow and mature, said Arceci. Most adult tissues do not express PASG, but the hematologic cancers and solid tumors Arceci examined expressed a lot of it, he said. These high levels of PASG may occur as normal cells transform to cancer, or PASG could prevent apoptosis. Either way, the time between low and high levels of PASG expression could offer scientists a treatment window.

Arceci said the mice died too young to determine whether they are more susceptible to cancer, but he suspects that is the case. To test that hypothesis, he and his colleagues are developing a conditional knockout of the PASG gene that would give the mice a lifespan proportional to that of humans.

Another hurdle to senescence research is the difficulty of identifying senescent cancer cells in humans and then proving that chemotherapy triggers senescence in human tumor cells. "There are some data in the literature suggestive of this, but the tissue markers are crude," said Scott Lowe, Ph.D., professor and deputy director of the Cold Spring Harbor Laboratory Cancer Center in New York. Lowe and his colleagues are searching for markers that would identify cells on the pathway to senescence. He likens senescence to apoptosis because both are cell-cycle checkpoints with endpoints that occur in response to cell damage. Additionally, signals that trigger apoptosis in one cell type will induce senescence in another, said Lowe. Markers could help sort through these observations.

For starters, Lowe and his colleagues applied the principles they learned while studying apoptosis to stress-induced senescence. That approach led them to heterochromatin, a stable form of chromatin, which is the assembly of macromolecules that help pack DNA. The heterochromatin silences genes involved in growth and cell division and "locks" the cells into senescence. "I think this is a smoking gun for a great model. But it falls short of formal proof [that heterochromatin formation is] really the engine driving this process," said Lowe.

He and his colleagues are now looking for the components that make up this "engine" and complete the mechanism. Finding markers for the heterochromatin phenotype will reach beyond the ability to understand senescence in the context of cancer biology. "For me, I get excited about the process, because you can see that senescence could play such a broad role in pathology but we really don't have the tools yet to find out for sure," said Lowe.


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