Proteins that both hinder and spur cancer progression may not be as uncommon as previously thought
Cancer researchers are identifying an increasing number of proteins that have a dual nature when it comes to cancer -- they may initially promote the development of tumors, but in the long run make them less aggressive, or vice versa.
|Image: Wikimedia commons|
"There's just so many different things going on [in cancer] that it's not at all surprising to me that you come up with examples of proteins that hurt and help," cell biologist linkurl:James Bear;http://www.med.unc.edu/cellbio/faculty-research/bear of the Lineberger Comprehensive Cancer Center at the University of North Carolina School of Medicine told The Scientist
NEDD9, for example, is a scaffolding protein that supports tumor cell invasion and metastasis in many types of cancer. Accordingly, mice lacking the NEDD9 protein show delayed development of mammary tumors in mouse models of the disease. Late last year, however, linkurl:Erica Golemis;http://www.fccc.edu/research/pid/golemis/ of the Fox Chase Cancer Center and her colleagues showed that once tumors do develop in these mutant mice, they are hyper-aggressive compared to the tumors in mice with working copies of NEDD9.
This is not hugely surprising, Golemis said, given the range of critical signaling pathways known to depend on NEDD9, such as those that control proliferation, migration, and the cell cycle. "This protein has got multiple functions [and] multiple partners," she said. "When you take it out, you're not going to be affecting any one of these pathways, you're going to be affecting all of them."
Similarly, some researchers have demonstrated that the WAVE protein, which helps initiate the reorganization of the actin cytoskeleton, facilitates cancer, while other groups have looked at the same protein and found the exact opposite, Bear said -- that WAVE tends to inhibit tumor progression.
In addition to having different effects at different time points in cancer progression, proteins may function differently depending on their level of activity. "I think it probably is a common thing," said mouse geneticist linkurl:Norman Sharpless,;http://genetics.unc.edu/faculty/sharpless also of The Lineberger Comprehensive Cancer Center at the UNC School of Medicine. "It stands to reason there are a lot of biological processes where there's sort of a sweet spot in terms of being a cancer -- too much activity not so good, too little activity not so good either."
DNA repair proteins, for example, are necessary for tumor growth, as the cancer cells must still be able to replicate their genetic code, but a slight dysfunction in certain repair proteins could promote tumor development, as a cell must accrue a series of mutations to become tumorigenic. So some mutations to repair proteins will encourage cancer, but mutations that shut down those same proteins will also shut down cancer. "A modest decrease in DNA repair function leads to increased genomic instability and cancer, whereas more complete defect in DNA repair is toxic to proliferating tumors," Sharpless said.
A complete loss of ATR, for example, which plays a role in sensing DNA damage and activating repair pathways, is often toxic to cells, but "reduced levels may be oncogenic," he said. The same story is true for DNA ligase IV, a critical component of the non-homologous end joining pathway that repairs double-strand breaks.
Despite these examples, there are relatively few documented cases of individual proteins that both help and hurt cancer progression. One problem in identifying such two-faced proteins may stem from the fact that these opposing effects are rarely demonstrated in the same research paper. As a result, different methodologies often apply to the different findings, making direct comparisons next to impossible. Many studies investigate different tumor types, for example, said Bear, or employ different end points, such as tumor size, metastatic burden, or cellular proliferation.
"They are all honestly a reflection of cancer progression, but it's difficult to compare sometimes between papers," he said. "You really have to have a very detailed understanding of exactly what the researchers are reporting."
Furthermore, scientists say, there is little incentive to embark on the difficult task of investigating the effects of a particular protein under all possible conditions in search of such opposing effects, because such a complicated picture is often unattractive to journals and funding agencies.
Download Flash player to listen to a conversation on publishing complex biological researchOncologist Erica Golemis, PLoS Biology editor Theodora Bloom, and former BMJ editor Richard Smith discuss the best way to present cutting edge science.
Golemis, for example, who is a fan of complex, highly nuanced stories, found that reviewers often are not. "We tried to put our data about the tumor-promoting effect of NEDD9 loss together with the tumor-slowing effect, and the reviewers hated it," she said. "They kept saying, well, then the gene can't be that important. The editors essentially told us we had to split the results."
Thus, there may be many more two-faced proteins out there, but only one side of them has been revealed so far by research. "I'm guessing this kind of preference for a simple story may be hindering investigation of the issue," Golemis said. "It's probably going to be a more complicated picture."
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