The tumor microenvironment offers new therapeutic targets
Cancer is more than just mutated cells that grow uncontrollably. Researchers like Florian Greten compare cancer to wounds that cannot heal. If, for example, you cut your finger and a scab has formed, the body’s repair program normally switches off again by itself. In cancer, however, the process continues and helps the tumor to grow.
A good 2,000 years ago, the Greek physician Galen suspected that cancer and inflammation were linked. In the 19th century, Rudolf Virchow, a German physician and pathologist, came to the same conclusion when he examined cross-sections of lung tumors under the microscope and saw the white blood cells typical of inflammation.
Around 100 years after Virchow, epidemiological data corroborated that people with chronic inflammatory diseases have a higher risk of cancer. Chronic gastritis induced by Helicobacter pylori, for example, can lead to stomach cancer or lymphoma. Chronic hepatitis B or C, which sometimes gives rise to liver cancer, is another example. In women, an infection with the human papillomavirus (HPV) entails the risk of developing cervical cancer, while in men it can trigger head and neck tumors. Today, antibiotic treatment for chronic gastritis or a preventive vaccination for HPV have proven to reduce the risk of cancer.
Cancer recruits scavenger receptors
It is only in the last 20 years or so that the causal links between cancer and inflammation have been examined in detail. At the turn of the millennium, the focus shifted to scavenger receptors (macrophages). These are found in the vanguard of the body’s immune defense. Initially, they circulate in the blood as monocytes. In the event of an infection or injury, they migrate into the tissue and differentiate into macrophages. In this form, they “eat” and degrade exogenous proteins (such as bacteria or viruses) and present them to the T cells of the immune system. To quickly neutralize the pathogens, the T cells produce customized antigens. At the same time, the scavenger receptors secrete chemoattractants (chemokines) to lure further macrophages into the tissue.
However, in the vicinity of cancer cells, i.e. in the tumor microenvironment, the macrophages “defect”. Their genetic program changes so that they do not fight the cancer cells but instead even promote their growth. Epidemiological data show that a patient’s chances of survival deteriorate if a particularly high number of these tumor-associated macrophages are detected near the cancer.
Blocking inflammatory pathways inhibits tumor growth
Florian Greten witnessed the early stages of this research during his time as a postdoctoral researcher at the University of California San Diego at the start of the 2000s. At that time, it was already known that people who regularly take aspirin have a lower risk of colorectal cancer. This was attributed to the drug’s anti-inflammatory effect, but why it worked was unknown. That was Greten’s motivation for investigating a signaling pathway that plays a central role in inflammation. This pathway works via a protein that controls the production of other proteins, the transcription factor NF-KB. This regulates the release of pro-inflammatory messenger substances (cytokines). Interrupting the signaling pathway prevents inflammation from developing. In 2004, Greten managed to show in mice with colorectal cancer that switching off NF-KB inhibits cancer growth – irrespective of whether the signaling pathway was interrupted in the tumor cells themselves or in the surrounding macrophages.
“It was the first time we were able to show that treating a cell type from a tumor’s microenvironment that is unmutated has an effect on its growth,” recalls Greten. “Research then practically exploded. Everyone started looking at more and more signaling pathways in macrophages. There was an increasing number of genetic models that examined what macrophages do when they are differentiated in one direction or the other.”
Meanwhile, researchers no longer examine just macrophages but the tumor’s whole microenvironment. This includes all inflammatory cells, blood vessels and connective tissue cells (fibroblasts), which are also activated when a wound heals. It is the cancer cells, however, that trigger radical changes in this microenvironment, which influence each other and in turn affect the tumor cell. The aim is to include this microenvironment in cancer treatment instead of just attacking the mutated cell. “To be honest,” says Greten, “the principle wasn’t all that new because scientists had already started back in the 1990s to target cells from the microenvironment by suppressing the formation of new blood vessels with drugs.”
Tumor microenvironment disrupts repair mechanisms
Greten and his group want to use their knowledge about the tumor microenvironment to improve patients’ response to chemotherapy on the one hand and develop more effective immunotherapies on the other. Why? Because in cancer, T cells, which are part of the body’s own repair mechanism, lose the ability to recognize and destroy mutated cells. Drugs known as checkpoint inhibitors, which prevent the cancer from turning T cells off, are already available. However, it is not known why they only work well with certain types of cancer such as malignant melanoma. Here, too, Greten assumes that the cause lies in the microenvironment, namely in the connective tissue, which suppresses the migration of T cells into the tumor. “If we can understand the process, we might be able to reverse it,” he hopes.
In the future, treatment will have to focus on several targets because tumor cells and their microenvironment constantly find ways to elude chemotherapy and the body’s own defenses. “We will probably need a different combination for each individual tumor,” Greten presumes. “This means, on the one hand, that we must eradicate cancer cells and, on the other hand, influence the microenvironment, in particular by activating and boosting the body’s own immune cells.”
Patient-oriented research
Under the umbrella of the Frankfurt Cancer Institute, a LOEWE Center funded by the State of Hesse [editor’s note: LOEWE stands for Landes-Offensive zur Entwicklung Wissenschaftlich-ökonomischer Exzellenz, Hesse’s State Offensive for the Development of Scientific and Economic Excellence, which funds research and development programs], researchers at Georg Speyer Haus and clinicians at University Hospital Frankfurt have joined forces in the search for better therapies. They are concentrating on tumors of the gastrointestinal tract, especially rectal cancer, on leukemia and brain tumors and, since recently, on metastasis. As an example of this successful cooperation, Greten mentions the collaboration with Claus Rödel and Emmanouil Fokas from the Radiotherapy Department.
Rödel, who heads the German Rectal Cancer Study Group, had noticed that certain patients responded particularly well to a combination of radiotherapy and chemotherapy prior to surgery, while others did not. By inducing a rectal carcinoma in mice and then irradiating it, Greten and his group were able to find a possible cause. It emerged that an inflammatory process in the connective tissue cells around the tumor caused the mice to respond less well to radiotherapy. “It transpired that the irradiation of the connective tissue cells was important and not that of the tumor cells,” says Greten, explaining the surprising result.
In retrospect, the clinicians would also have been able to demonstrate these differences in patients, too. Especially the messenger substance interleukin-1 was a contributing factor to the inflammation in the connective tissue. IL-1 is also upregulated in a number of chronic inflammatory diseases, such as rheumatoid arthritis. A drug against this has already been approved. “We were able to see that a mouse that previously failed to respond to radiotherapy becomes receptive to it when we block IL-1 with this drug,” says Greten. Thanks to the close collaboration with the hospital, it was possible to test the drug very quickly on patients with rectal cancer. Although this Phase 1 trial initially only tested whether it was safe to use the drug in combination with chemotherapy and radiotherapy, the patients were also seen to respond better to the latter. That is why the drug will now to be tested on cancer patients in a larger Phase 2 trial.
Neighborly help of the worst kind
Greten’s group recently made another surprising discovery: A mechanism between neighboring tumor cells that explains why chemotherapy cannot kill all cancer cells. Namely, the dying cells send their neighbors a “warning” and show them how to survive the cytotoxin. In organoids – tumor-like tissues cultivated in a petri dish – the surviving cancer cells had completely reprogrammed their signaling pathways within a few hours and were resistant to chemotherapy. If scientists could suppress this mechanism through medication, chemotherapy would be highly effective. Greten hopes to be able to test a promising active substance in a Phase 1 trial at the beginning of 2025.
The German Science and Humanities Council recently confirmed that research at Georg Speyer Haus is very good to outstanding. In 2023, Greten was listed as a “Highly Cited Researcher”. This shows that Georg Speyer Haus has established itself as an important hub for research into tumor microenvironments. And where would Greten like to be in ten years’ time? “Ideally, we will have developed therapies by then that have reached the patient. Because even if I no longer treat patients myself, I am nevertheless a doctor. That’s why I want to expand the translational concept of the Frankfurt Cancer Institute and quickly transfer our findings into clinical trials. And perhaps we will manage to make the checkpoint inhibitor work in colorectal cancer as well. So far, this has only been successful in 10 to 15 percent of cases, and we would like to know why,” he says.
About / Prof. Dr. Florian Greten After studying medicine in Hamburg and Vienna, Professor Florian Greten, born in 1972, spent four years as a researcher in the Department of Pharmacology at the University of California San Diego. Following his return to Germany, he completed his postdoctoral degree (Habilitation) in 2008 and was made professor at Medical Clinic II, TUM University Hospital, in 2010. In January 2011, he became a professor at the Institute of Molecular Immunology there. Since 2013, Florian Greten has headed the Georg Speyer Haus – Institute for Tumor Biology and Experimental Therapy and was at the same time appointed as Professor for Tumor Biology at the Faculty of Medicine, Goethe University Frankfurt. He is the spokesperson for the Frankfurt Cancer Institute.
greten@gsh.uni-frankfurt.de
The author / Anne Hardy, born in 1965, studied physics and earned her doctoral degree in the history of science. She is a freelance journalist specializing in science and medicine.
anne.hardy@t-online.de
