image: Participants at the congress CNIO-Caixa Research Frontiers Meeting ‘Metastasis’.
Credit: Laura M. Lombardía / CNIO.
Results presented by world leaders in metastasis research at CNIO change the very concept of this disease, and lead to new ways to fight it. Clinical trials based on these results are ongoing.
Metastasis is now considered a disease on its own, with a much earlier beginning than previously thought.
Solid evidence for a link between chronic stress and metastases is emerging. Key molecules for this interaction –a neurotransmitter in particular– have been identified.
Some bacteria proliferate in tumors. Specifically prepared for this purpose, bacteria could be used to activate the defensive response against cancer.
The main cause of death from cancer is metastasis, the process that spreads the tumor to other organs and which have still few treatment options. Research about it shows, however, major advances. Its results get to change our very concept of metastasis and lead to new ways of fighting it, some of them already in clinical trials. That is what world leaders in this area have presented at the CNIO-Caixa Research Frontiers Meeting 'Metastasis', held at the Spanish National Cancer Research Center (CNIO).
The first paradigm shift is that metastasis "is a distinct disease, with its own biological mechanisms," explains Eva González Suárez, head of the CNIO's Transformation and Metastasis Group and co-organizer of the congress.
Metastasis was considered until now the most advanced stage of an oncological process; but today it appears clearly as a phenomenon that evolves on its own and starts probably much earlier than previously thought, with a few very specific cells capable to colonize other organs, as Héctor Peinado, head of the CNIO's Microenvironment and Metastasis Group and also co-organizer of the congress, points out. Moreover, these metastatic cells might not come from the primary tumor, as assumed so far, but from other metastases.
Stress and changes in circadian rhythms influence metastasis
Increased knowledge of metastasis distinctive biology is opening up new fronts to combat it, some of them surprising. Various research projects presented at the CNIO explore the possibility of preventing or treating metastasis with strategies involving bacteria and drugs against hypertension; control of psychological stress; and blocking communication between cancer cells and neurons.
These projects belong to another conceptual shift in this area: metastasis is not just the product of a few genetic alterations but also the consequence of many other processes occurring simultaneously in the body. "We are seeing that metastasis, in addition to mutations and the microenvironment in contact with the metastatic cells, is also subject to the influence of stress and changes in circadian rhythms, for example," says Peinado.
"We knew the tumor disrupt appetite, sleep patterns... but we didn’t consider it relevant. Now we are beginning to understand why this happens," adds González Suárez.
The emerging field of cancer neuroscience
One of the key factors is being revealed by the young field of cancer neuroscience, which studies the recently discovered interaction between cancer and the nervous system, both central (the brain) and peripheral. It is such a novel area that Caroline Dive, from the Cancer Research UK Manchester Institute, admits she was unaware of it before co-organizing this congress.
"This greater understanding of the biology of metastasis is allowing us to think about new treatments to help patients," says Dive.
It has been observed that "tumor cells exchange signals using mechanisms similar to those used by neurons," says Manuel Valiente, head of the CNIO Brain Metastasis Group.
Frank Winkler, a pioneer in neuro-oncology, explained that "interactions between the nervous system and cancer can regulate oncogenesis, tumor growth, the spread of metastasis and resistance to treatment", in addition to stimulating inflammation and weakening the immune response against cancer.
Blocking neurotransmitters
Winkler, from the University of Heidelberg and the German Cancer Research Center, presented at the CNIO strategies to block communication between cancer cells and thus stop the advance of metastasis. As he explains in this review in Cell, there are already clinical trials in early stages that seek to disrupt and even destroy the signaling networks between tumor cells.
Erica Sloan, from Monash University in Australia, is also working on the relationship between cancer and the peripheral nervous system. Her research over the last decade provides solid evidence of the link between chronic stress and both the aggravation of cancer and the development of metastases. She also identifies key molecules in this link, particularly a neurotransmitter –one of the substances that mediate communication between neurons–.
Beta-blockers to prevent breast cancer metastasis
Sloan has shown that a type of drug already approved against hypertension, 'beta-blockers', intercept communication among the nervous system, the immune system and cancer. Her trials in breast cancer patients suggest that the use of beta-blockers significantly reduces the incidence of metastasis, and is therefore a therapeutic avenue to be explored. "The β-blockade reduces biomarkers associated with metastatic potential, and supports the need for larger phase III clinical trials," says Sloan.
Equally novel is the research carried out by Maria Rescigno at Humanitas University in Milan, Italy, on "the interrelation between human body and microbiota –the ecosystem of bacteria, viruses, and fungi that populate organs and tissues– in order to understand its role in disease."
"We are going to start treating cancer with bacteria"
Rescigno is the recent discoverer of the existence of an intestinal barrier that protects the organism from the entry of external agents and, at the same time, allows the absorption of nutrients. Her work is showing that there are bacteria which proliferate especially in the low-oxygen, dead-tissue environment found in tumors, which has suggested the possibility of using bacteria deliberately prepared to activate the defensive response against tumors.
Another line of research shows that microorganisms are involved in preparing tissues to host metastatic cells; preventing this nest preparation for metastasis using drugs would be another possible therapeutic avenue. González Suárez considers it relevant to highlight the trials Claudia Gravekamp, from Albert Einstein College of Medicine, is carrying out along this line. They involve treatments with bacteria against which we have been vaccinated in our childhood, as a trick to reactivate the immune response.
"We are going to start treating cancer with bacteria," says congress co-organizer Manuel Valiente.