October 15, 2012 (Vol. 32, No. 18)

New Strategies Aimed at Putting End to War Richard Nixon Declared Four Decades Ago

In The Art of War, Sun Tzu advises, “Know your enemy and know yourself and you can fight a hundred battles without disaster.”

As the federal “war on cancer,” slogs on toward its 42nd year in December, researchers from Israel and the U.S. have applied that advice by suggesting that their foe should be studied for its similarities to bacteria. Specifically, the research team says cancer shows similarities to the sociality and collective survival strategies seen in bacteria, presenting potentially “a valuable model system to inspire new hypotheses and investigations useful for developing novel therapies.”

“Perhaps we are entering a new era of biological cyber warfare, in which we will learn to enlist bacteria in conjunction with the immune system to defeat cancer precisely on account of its ‘social intelligence,’” the researchers said.

The team presented its call for a “cyber war” on cancer in a recent paper in the September issue of Trends in Microbiology. Co-authors noted that, while understanding of cancer biology has improved over recent decades, researchers remain baffled by questions regarding the deadliest traits of malignancy: metastatic colonization, dormancy and relapse, and the rapid evolution of multiple drug and immune resistance.

“Our guiding hypothesis is that cancer’s collective capabilities are key concepts for understanding tumor dynamics; one cannot successfully proceed under the assumption of uncoordinated genetic instability of individual cells,” the researchers posited. “The emerging picture is that of cancer, the primary tumor, and the metastases combined, as a multiclonal society of smart communicating cells endowed with specific traits for successful cooperative behaviors.”

Cancer metastasis, for example, can thus be seen as a programmed response in which the primary tumor deliberately fashions cells to colonize foreign territories: “Rather than being an independent clone mutated from the primary tumor, the metastatic cells could be variant members of the society with assigned tasks.”

How completely the primary tumor controls the metastases is not yet known, the paper’s corresponding author—Eshel Ben-Jacob, Ph.D., who focuses on the social behavior of bacteria, as well as network neuroscience and system level immunology, as a professor of physics at Tel Aviv University and senior investigator, Center for Theoretical Biological Physics (CTBP) at Rice University—told GEN last week.

A key reason why is because researchers have yet to nail down the extent of communication within cancers. Recent research has shown, for example, that primary tumors communicate with circulating tumor cells (CTCs), though it has yet to be shown whether communication occurs from the CTCs to primary tumors.

“That’s a very important part of the puzzle,” Dr. Ben-Jacob said. “I assume that there should be, because if you look in biology, it’s always two-way communication.” When asked why he feels that way, he responded, “We call the CTCs ‘spying cells’ and know that, prior to metastasis invasion, ‘spying cells’ are sent to explore the body (using repulsive signals such as MMP1/collagenase-1 to assist their navigation), and return (using attractive signals such as IL-6 and IL-8). It appears that the cells return with important information, as the process has been shown to accelerate tumor growth, angiogenesis, and stromal recruitment.”

He said the absence of knowledge into CTC-tumor communication “is disturbing, because it either doesn’t exist, which is very hard for me to believe, or that people simply didn’t look into it.”

Also not yet known, Dr. Ben-Jacob said, is how malignancy traits such as metastases and cell dormancy and relapse vary from cancer to cancer. A decade of genome sequencing data has revealed that variability by showing tumors to be multiclonal, rather than monoclonal like a single-cell bacterial colony.

Recent research has also found that, when primary tumors are exposed to hypoxia and other types of stress, they secrete exosomes—nano-sized lipid vesicles containing pieces of RNA, DNA, or both. The exosomes are capable of inducing changes that enhance metastasis, such as changing the acidity of the environment of the tumor while increasing toxicity for immune cells. The RNA and DNA pieces can be transferred between distant cells through the exosomes, and through gap junctions between, and natural nanotubes connecting, cells closer to each other.

“All this sounds like an enterprise which is programed, and not just a collection of accidental, opportunistic cells that decide to leave the tumor and just take their chance that they will arrive or not,” Dr. Ben-Jacob said.

As the co-authors noted, the most common form of communication within cancers is chemical signaling, though it is also carried out through mechanochemical interactions in which cells can affect other cells; and intercellular calcium waves are believed to help regulate cellular responses such as transition to dormancy, apoptosis, and autoschizic cell death.

Co-authoring with Dr. Ben-Jacob were Donald S. Coffey, Ph.D., at Johns Hopkins University School of Medicine; and Herbert Levine, Ph.D., co-director of the Center for Theoretical Biological Physics at Rice University.

Their paper proposed four hypotheses for future research:

  • Primary tumors aid cells in both leaving from and returning to the main neoplasmic cell mass.
  • Information from nascent metastatic outposts is conveyed back to the primary tumor, both by returning cells or emitted signals.
  • Cell transitions into and out of dormancy are collective decision-making processes, akin to the sporulation pathway in Bacillus and the mating pathway in yeast.
  • Cellular rates of genetic and epigenetic exploration are coupled to signaling pathways sensitive to the local microenvironment, both at the single-base pair mutation level and at higher levels.

Dr. Ben-Jacob said he is now focusing in part on the mechanism for cancer cells entering into dormancy and relapse, especially an early stage of metastasis focused on the interplay between metabolism and signaling. Other areas of future research that are of interest, he noted, include how DNAs and RNAs intended to fight bacteria instead end up protecting tumors from the immune system; as well as how bacteria interact with tumors and the immune system.

Scientists hope to enlist bacteria in conjunction with the immune system to defeat cancer through its “social intelligence”. [Kheng Guan Toh/ Fotolia]

AACR Report

The “cyber war” paper by Dr. Ben-Jacob and colleagues came out days before the nonprofit American Association for Cancer Research (AACR) issued a report detailing progress, and many challenges, for researchers battling cancer.

As noted in “AACR Cancer Progress Report 2012,” an estimated 577,000 Americans will die from the disease this year; another 13.7 million Americans are cancer survivors. FDA approved eight new drugs for cancer, plus new cancer indications for three previously approved drugs, between September 2011 and August 31, 2012. Since then, the agency approved Choline C 11 Injection, an intravenous Positron Emission Tomography imaging agent for prostate cancer developed by the Mayo Clinic.

While researchers have found targets for which to develop drugs against some forms of cancer, other forms of the disease have no similar driver gene.

“Seventy percent of all cancers are caused by mutations for sure, but we just can’t tell what the driver is. Worst case might be, there isn’t a driver. The tumors are driven by some sort of a committee of minor players which together cause the disease. And that will I think make things more complicated for us, and require more research and new ways of analyzing those kinds of tumors,” AACR President Frank McCormick, Ph.D., said during a September 12 presentation.

AACR argues for increased funding of NIH and its National Cancer Institute, at a time when they and other nondefense agencies face “sequestration” or across-the-board 7.8% budget cuts on January 2 unless Congress and President Obama agree how to reduce $1.2 trillion in spending over 10 years. The outcome won’t even begin to emerge until after Election Day.

Until then, and especially afterward, researchers and cancer-funding advocates like AACR should give serious credence to the social-community view of the disease expressed by Dr. Ben-Jacob and colleagues, as a promising research avenue likely to speed up the march toward the conquest of cancer envisioned by President Richard M. Nixon more than four decades ago.

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