To an unsuspecting observer, inflammation is simply the body’s protective response to infection or injury. But for many tumors, it is a partner in crime.
While epidemiological links between inflammation and cancer have long been established, the molecular dialogue between these two unlikely allies has been harder to listen in on. New studies by HMS researchers have managed to tap into the conversation, identifying novel and varied ways in which inflammatory signals conspire with processes of tumor initiation. These studies exemplify how diverse investigations are converging upon the inflammation–cancer theme.
A collaborative study from the laboratories of Laurence Rahme, HMS associate professor of surgery at Massachusetts General Hospital, and Norbert Perrimon, HMS professor of genetics and a Howard Hughes investigator, suggests that inflammatory signals induced by bacterial infection may interact with genetic predisposition to promote tumor growth. Specifically, the bacterium P. aeruginosa releases a molecule called pyocyanin that can mediate the tumorigenic effect of infection in fly intestines. These findings appear in the Dec. 8 issue of Proceedings of the National Academy of Sciences.
A separate study from the laboratory of Kevin Struhl, HMS professor of biological chemistry and molecular pharmacology, identifies an inflammatory signaling loop that mediates cellular transformation, the fundamental process by which a noncancer cell turns cancerous. Remarkably, this inflammatory loop induces and maintains the cancer state epigenetically—that is, without actually changing the genetic code. These findings appear in the Nov. 13 issue of Cell.
A complementary study appearing in the April 13 Cancer Cell, also from the Struhl laboratory, highlights the gene regulatory networks activated during transformation. Surprisingly, in addition to inflammatory genes, the transformation process turns on lipid metabolism genes. These findings connect cancer to metabolic diseases such as obesity, diabetes and atherosclerosis in addition to inflammation. Together the web of links suggests that a disruption of common molecular pathways may underlie diverse disease states.
Molecular ConnectionsLinks between inflammation and cancer crop up in different ways and at different places. The Rahme–Perrimon study makes the link through exploring the connection between bacterial infection and stem cell proliferation, said Chrysoula Pitsouli, a postdoctoral fellow in the Perrimon laboratory who conducted the work in collaboration with Yiorgos Apidianakis, an HMS instructor in surgery in the Rahme laboratory.
They were trying to connect the two processes because each one is thought to be important in human cancers. Infection with the bacterium Helicobacter pylori, for instance, increases the risk of gastric cancer, while hyperproliferation of stem cells is suspected in colorectal cancer.
Pitsouli and Apidianakis saw that infection of the fly gut with P. aeruginosa—or exposure to pyocyanin, a molecule secreted by this pathogen—increased proliferation of stem and progenitor cells. This rise followed the death of mature gut cells, in which the stress-signaling pathway JNK took center stage. Simply put, infection elicited inflammatory signaling, which then triggered overproliferation, a homeostatic response to replenish lost or damaged cells.
In flies genetically predisposed to cancer, this overproliferation led to changes in tissue architecture, called dysplasia, often an early indicator of cancer. In other words, when synergizing with other procancer forces, bacterially induced inflammatory signaling can promote initiating events in the process of tumor development.
In the Struhl Cell study, the inflammation–cancer link revealed itself more unexpectedly. Postdoctoral fellows Dimitrios Iliopoulos and Heather Hirsch had found a new way to transform noncancer cells into cancer cells. By simply turning on a procancer gene in an immortalized breast cell line—even for a period as short as five minutes—they were able to permanently alter the state of the cells without altering the genetic material. When the team set out to identify the gene activity patterns underlying this transformation process, they found that inflammatory molecules were at play.
“We saw a massive inflammatory signature,” said Struhl, “and that’s basically what started the paper.”
Iliopoulos and Hirsch identified a positive feedback mechanism by which inflammatory signals jumpstart and maintain the transformed state. The activation pattern of the inflammatory molecules in this loop was consistent in many different types of cancer cells. Though many of the individual inflammatory molecules had been linked to cancer, the pathway connecting them was previously unknown.
New Disease ModelsIn addition to uncovering cellular and molecular events that link inflammation to cancer in general, both groups address how inflammatory signals might promote the development of cancer stem cells in particular. Cancer stem cells are a breed of cancer cells that display unique properties. Though still controversial, they are of special interest because many researchers consider these cells to be tumor-initiating.
In the fly gut, inflammatory signaling prompted dysplasia by promoting the growth of stem and progenitor cells. In the transformation study, the small percentage of transformed cells acting as cancer stem cells are the ones Struhl describes as having “an extra souped-up inflammatory loop.” Consequently, understanding the molecular links between inflammation and cancer may help shed light on how cancer stem cells develop.
Both groups also set forth new models to exploit in future investigations of the crosstalk between inflammatory and tumorigenic processes. Pitsouli emphasizes that a major advance of the fly study is the ability to examine the inflammation–cancer link, and the contribution of specific bacterial factors to these processes, in a genetically tractable in vivo model. The Struhl studies provide a system for studying transformation in an isogenic manner (i.e., where the same cells serve as “before” and “after” models) so it is clear that any molecular changes observed are real consequences of the transformation process.
Such model systems are powerful not just because they offer a way to find new molecular mechanisms that tie inflammation to cancer, but also because they offer a way to design and test ways to sever this dangerous relationship.
Just where do we stand now in our understanding of inflammation’s effect on cancer?
“We’re getting a better understanding of the exact cell types and the signals that are involved in this link,” said Kornelia Polyak, HMS associate professor of medicine at Dana-Farber Cancer Institute. She added that researchers are also developing a better understanding of the bacteria living in our bodies and beginning to explore the influence of these bacteria on cancer risk. Combined, this knowledge could change approaches to cancer prevention and therapy.
While studying links between inflammatory signaling molecules and tumorigenic processes can provide valuable insights, Polyak cautions, it remains crucial to study the inflammation–cancer link in the context of actual tissue inflammation and of primary human tumors as well.
For more information, students may contact Laurence Rahme at rahme@molbio.mgh.harvard.edu, Norbert Perrimon at perrimon@genetics.med.harvard.edu or Kevin Struhl at kevin@hms.harvard.edu.
Conflict Disclosure: The authors of both studies declare no conflict of interest.
Funding Sources: Rahme–Perrimon study: National Institutes of Health, Howard Hughes Medical Institute, Shriners Burns Institute; Struhl study: National Institutes of Health, American Cancer Society
