It's been a fight that has been going on for four decades, but new technologies are allowing us to get a better understanding of how cancers work, reports Alex Philippidis in Streetwise's Life Sciences Report.

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 toward its 42nd year in December, researchers from Israel and the US 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
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, said the paper's corresponding author, Eshel Ben-Jacob, 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 at the Center for Theoretical Biological Physics (CTBP) at Rice University.

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—nanosize 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 programmed, 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.