Nobody likes to starve, and neither does cancer cells. A new study led by IDIBELL-ICO has discovered that, due to the lack of glucose, tumor cells respond by releasing a protein, called LIF, which increases aggressiveness and invasion capacity. The study, published today in Nature Metabolism, conducted in lung cancer models, suggests that LIF could be a good target against this type of cancer: if LIF is released in stressful situations as a survival mechanism, it is very likely that the tumor has less adaptability without it, making it more vulnerable to current treatments.
This discovery, led by the Preclinical and Experimental Research team of Thoracic Tumors (PRETT) of IDIBELL-ICO, in collaboration with researchers from the University of Barcelona (UB), goes one step further. Besides identifying LIF as responsible for the adaptability of the tumor to the lack of glucose, connecting the lack of nutrients with cancer aggressiveness, the study suggests a way to block its release. As far as the PRETT team has seen, supplementation with mannose, a type of sugar, could prevent LIF release by filling the lack of glucose, a thread from which they will continue to stretch in the future. It is an initial hypothesis that must be corroborated, and it joins other previous proposals to block LIF and its effects (such as direct inhibition of stress kinases).
Metabolic stress as the driving force of aggressiveness
The main fuel of cells is glucose. Our bodies are constantly working to ensure a regular supply of glucose to all cells in the organism, keeping levels within acceptable ranges so that everything works normally. When glucose is lacking, individual tissues and cells react and start various mechanisms to compensate for it (for example, they increase blood supply to have greater nutrient input).
Tumor cells work the exact same way. “When in metabolic stress (lack of glucose or oxygen), tumor cells defend themselves and the tissue changes to a more adaptable and aggressive state to survive. We have seen that its defense strategy is based on the release of a protein, LIF”, explains Dr. Cristina Muñoz, co-leader of the PRETT lab at IDIBELL-ICO.
Her team identified LIF as one of the most secreted proteins in lung cancer models that had undergone glucose deficiency. LIF is a protein that, in the healthy body, intervenes during embryonic development, generating an immunosuppressive environment and stimulating cell proliferation. “The tumor takes advantage of the physiological functions of this protein for its own benefit, using it to grow faster, colonize and dodge the immune system,” adds Dr. Muñoz.
But the most important thing is that “we have discovered that the stimulus to produce LIF, and all the adaptive response that follows it, is the lack of glucose and oxygen,” explains Joaquim Moreno, first author of the study and PRETT’s lab manager. “These are the critical stimuli for the secretion of this protein and, therefore, to overcome a risk situation for the tumor and promote cancerous progression”.
LIF, a good therapeutic target
To help the tumor survive, LIF stimulates the creation of new blood vessels to try to restore the arrival of blood and nutrients to tumor cells, while promoting the colonization of other tissues. In addition, it has some immunosuppressive effect, slowing the defense that the immune system could lift against cancer.
Having identified LIF as the director of the tumor response to the lack of glucose opens a hopeful door for the treatment of lung cancer. “Blocking LIF could be the key to blocking the adaptive response to cancer. Without this molecule, the tumor’s ability to adapt could be disarmed, making it more vulnerable to current treatments and the patient’s own immune response”, says Dr. Ernest Nadal, PRETT’s co-leader and ICO’s scientific director.
As the researchers have verified, without LIF, an anti-tumour environment is promoted in which tumor growth stops and the creation of new blood vessels to nourish cancer is prevented. All these data point to LIF as a potential target against lung cancer. It will be necessary to see, with more research, if this can be corroborated to have a new therapeutic strategy against this type of cancer.
About the Comprehensive Cancer Center (CCC)
This research is part of the Bellvitge Health Campus’s work as a Comprehensive Cancer Center (CCC), the highest European recognition in the field of oncology, awarded by the Organization of European Cancer Institutes (OECI). It is the only CCC in Spain and Catalonia, involving four independent public institutions (Bellvitge Hospital, IDIBELL, ICO, and UB) that take a coordinated, networked approach to cancer with a team of over 1,500 professionals who lead efforts from research and prevention to comprehensive care.
About IDIBELL
The Bellvitge Biomedical Research Institute (IDIBELL) is a research center established in 2004 specialized in cancer, neuroscience, translational medicine, and regenerative medicine. It counts on a team of more than 1.500 professionals who, from 73 research groups, publish more than 1.400 scientific articles per year. IDIBELL is participated by the Bellvitge University Hospital and the Viladecans Hospital of the Catalan Institute of Health, the Catalan Institute of Oncology, the University of Barcelona, and the City Council of L’Hospitalet de Llobregat.
IDIBELL is a member of the Campus of International Excellence of the University of Barcelona HUBc and is part of the CERCA institution of the Generalitat de Catalunya. In 2009 it became one of the first five Spanish research centers accredited as a health research institute by the Carlos III Health Institute. In addition, it is part of the “HR Excellence in Research” program of the European Union and is a member of EATRIS and REGIC. Since 2018, IDIBELL has been an Accredited Center of the AECC Scientific Foundation (FCAECC).