When cancer cells proliferate in a primary tumor, they may start to grumble like impatient diners denied service at a busy restaurant. Eventually, the cellular grumbling, expressed via secreted molecules, becomes loud enough that some of the cells encourage each other to break away and seek sustenance elsewhere. Were this phenomenon known to Yogi Berra, he might have characterized it as follows: “Nobody stays there anymore. It’s too crowded.”
Of course, the primary tumor remains densely populated despite the outward migration of metastatic cells, which accounts, in part, for the continued emphasis on therapeutic approaches that try to limit tumor growth. Yet alternative therapies could focus on the tumor cells that become restless in crowded conditions and head for the exits.
Directly targeting metastasis looks more promising in light of recent findings produced by scientists based at The Johns Hopkins University. These scientists have discovered a biochemical signaling process that causes densely packed cancer cells to break away from a tumor and spread the disease elsewhere in the body. This process, the scientists report, may be disrupted by administering a combination of two existing drugs.
The new findings, which point to a way of slowing metastasis, are important, because 90% of cancer deaths are caused by metastasis, and anything that derails this activity could improve the prognosis for patients.
Details of the scientists’ work appeared May 26 in Nature Communications, in a paper entitled “Synergistic IL-6 and IL-8 Paracrine Signalling Pathway Infers a Strategy to Inhibit Tumour Cell Migration.” In this paper, the scientists explain why they decided to focus on the way the local concentration of secreted proteins increases with cell number: “We speculate that the contribution of proliferation-induced local crowding, accompanied by increased local cell density in the collagen-rich 3D TME [tumour microenvironment], may be a significant, yet largely unidentified factor that directly alters tumour cell migration.”
The scientists used a high-throughput multiplexing cell secretome profiling assay to demonstrate that only interleukin-6 (IL-6) and interleukin-8 (IL-8) are specifically increased with cell density. The scientists also found that IL-6 and IL-8 are necessary and sufficient to increase tumor cell migration in a cell-density-dependent manner with negligible feedback on cell proliferation. This effect, they noted, is specific to metastatic cancer cells. IL-6 and IL-8 have no effect on the migration of normal and nonmetastatic cancer cells.
“The effect,” the articles authors indicated, “likely involves the downstream signalling of WASF3 [Wiskott-Aldrich syndrome protein family member 3] and Arp2/3. “Simultaneous inhibition of IL-6/8 receptors decreases the expression of WASF3 and Arp2/3 in a mouse xenograft model and reduces metastasis.”
The Johns Hopkins team members cautioned that this treatment has not been tested yet on human cancer patients. Nevertheless, the researchers said the discovery contributes to a promising new focus for cancer research: disrupting the biochemical activity that prods cancer cells to spread through the body.
“We found that it was not the overall size of a primary tumor that caused cancer cells to spread, but how tightly those cells are jammed together when they break away from the tumor,” said lead author Hasini Jayatilaka, Ph.D. “At a fundamental level, we found that cell density is very important in triggering metastasis. It's like waiting for a table in a severely overcrowded restaurant and then getting a message that says you need to take your appetite elsewhere.”
One of the study's senior authors, Denis Wirtz, Ph.D., said no commercial drugs are now being produced specifically to inhibit metastasis because drug companies believe the best way to stop cancer from spreading is to destroy the primary tumor from which it originates.
“The pharmaceutical companies view metastasis as a by-product of tumor growth,” said Dr. Wirtz. “Our study looked more closely at the steps that actually initiate metastasis. By doing this, we were able to develop a unique therapeutic that directly targets metastasis, not the growth of the primary tumor. This treatment has the potential to inhibit metastasis and thus improve cancer patient outcomes.”
The two key drivers of metastasis, Dr. Wirtz said, are cancer cells' tendency to reproduce at a rapid rate and their ability to move through surrounding tissue until they reach the bloodstream, where they can then hitch a ride to spread the disease to other parts of the body.
By studying tumor cells in a three-dimensional environment that resembles human tissue, the researchers were able to determine how these activities begin. The team discovered that as two types of cancer cells reproduced and created more crowded conditions in the test site, these cells secreted certain proteins that encouraged migration. The researchers identified these proteins as IL-6 and IL-8.
“IL-6 and IL-8 seem to deliver a message to cancer cells, telling them to move away from the densely populated primary tumor,” said lead author Dr. Jayatilaka.
In the team's animal studies, the researchers found that applying two existing drugs—tocilizumab and reparixin—blocked the receptors that enable cancer cells to get their relocation orders. Tocilizumab is an approved medication for rheumatoid arthritis and is in trials for use in ovarian cancer cases. Reparixin is being evaluated as a possible treatment for breast cancer.
“In our 8-week experiment, when we used these two drugs together, the growth of the primary tumor itself was not stopped, but the spread of the cancer cells was significantly decreased,” Dr. Jayatilaka said. “We discovered a new signaling pathway that, when blocked, could potentially curb cancer's ability to metastasize.”
